CA2638773A1 - Vasopressin pathway polymorphisms as indicators of subject outcome in critically ill subjects - Google Patents

Abstract

The invention provides methods, nucleic acids, compositions and kits for predicting a subject's response to treatment with one or more vasopressin receptor agonists to identify subjects having a greater benefit from treatment with vasopressin receptor agonist(s). The method generally comprises determining a vasopressin pathway associated gene polymorphism genotype(s) of a subject for one or more polymorphisms in the these genes, comparing the determined genotype with known genotypes for the polymorphism that correspond with an improved response genotype to identify potential subjects having an inflammatory condition who are more likely to benefit from treatment with a vasopressin receptor agonist and subsequent to treatment recover from the inflammatory condition. The invention also provides for methods of treating such subjects with vasopressin receptor agonists based on the subject's genotype.

Description

Vasopressin Pathway Polymorphisms as Indicators of Subject Outcome in Critically Ill Subjects FIELD OF THE INVENTION
The field of the invention relates to the assessment and/or treatment of subjects with an inflammatory condition.

BACKGROUND OF THE INVENTION
Arginine vasopressin (AVP) has both vasoconstrictor and anti-diuretic properties. AVP is synthesized in the hypothalamus and secreted from posterior pituitary gland, secreted into the circulation and binds to several receptors. AVP binds to vasopressin-specific membrane bound receptor AVPRIA on vascular smooth muscle (MOUILLAC B. et al. J Biol Chem (1995) 270:
25771-25777), AVPR2 in the distal convoluted tubule and collecting ducts in the kidney and AVPRIB pituitary receptors that modify adrenocorticotropin hormone (ACTH) production (ORLOFF J. and HANDLER J. Am J Med (1967) 42: 757-768). Binding to AVPRIA
induces vasoconstriction. AVP has a very short half-life and is metabolized by leucyl/cystinyl aminopeptidase (LNPEP).

Under normal physiological conditions, AVP does not contribute much to the maintenance of blood pressure (GROLLMAN J Pharm Exper Therap (1932) 46:447-460; GRAYBIEL Am Heart J
(1941) 21:481-489; and WAGNER, J Clin Invest (1956) 35:1412-1418). However, when blood pressure falls, AVP is fundamental to the response to hypotension as AVP is released from the posterior pituitary and causes arterial smooth muscle to contract (vasoconstriction) (WAGNER, J
Clin Invest (1956) 35:1412-1418; AISENBREY J Clin Invest (1981) 67:961-968;
and SCHWARTZ Endocrinology (1981) 108:1778-1780). If AVP is not secreted by the posterior pituitary in response to hypotension, then blood pressure remains low or falls further as a result of inappropriate vasodilation.

Critically ill subjects with septic shock have been shown to have low serum AVP levels (LANDRY Circ. (1997) 95:1122-1125). Although AVP levels are initially high in septic shock, they fall within hours (GOETZ Proc. Exp. Biol. Med. (1974) 145(1):277-80;
WILSON Surg.
Gynecol. Obstet. (1981) 153(6):869-72; (MORALES D. et al. Circulation (1999) 100(3): 226-9);
and ERRINGTON J Physiol (1971) 217(1): 43P-45P). Indeed, septic shock develops in part because there is a defect in the baro-receptor-mediated increase in AVP
secretion (LANDRY Circ.

(1997) 95:1122-1125). AVP can be administered to subjects who have septic shock who are not responding adequately. It has been reported that AVP increases blood pressure, decreases need for vasopressors such as norepinephrine, and increases urine output (LANDRY DW et al. Circulation.
(1997) 95:1122-1125; HOLMES CL et al. Int. Care Med. (2001) 27:1416-1421). In a small, proof of concept randomized controlled trial of norepinephrine (NE) versus AVP in subjects with severe septic shock, it has been shown that AVP spared NE use, maintained mean arterial pressure and cardiac index, and improved measures of renal function including increased urine output and creatinine clearance ( PATEL BM et al. Anesthesiology (2002) 96:576-582).
Blood AVP levels were also found to be very low (1.3 +/- 0.9pg/ml) (HOLMES CL et al. Int. Care Med. (2001) 27:1416-1421; and PATEL BM et al Anesthesiology (2002) 96:576-582). Several other studies have also shown that AVP increases blood pressure in septic shock (LANDRY DW
et al.
Circulation (1997) 95:1122-5; MALAY MB et al. J Trauma (1999) 47(4): 699-703;
GOLD JA et al. Crit. Care Med. (2000) 28(1): 249-52; and MORALES DL. et al. Ann Thorac Surg. (2000) 69(1): 102-6).
Vasopressin is commonly used after cardiac surgery as studies have shown that AVP levels are lower after cardiac surgery compared to baseline. In addition, AVP infusion has been demonstrated to increase blood pressure after cardiac surgery (ARGENZIANO J
Circulation (1997) 96(9 Suppl):II-286-90; ARGENZIANO J Thorac. Cardiovasc Surg. (1998) 116(6):973-80;
CHEN Circulation (1999) 100(19 Suppl):I1244-6; and ROSENZWEIG Circulation (1999) 100(19 Suppl):II182-6).

Arginine vasopressin (also known as antidiuretic hormone or ADH) is encoded by the AVP -neurophysin II gene (AVP) which contains three exons and maps to chromosome 20p13. AVP is synthesized in the hypothalamus as a precursor polypeptide (prepro-AVP-NPII) and undergoes post-translational processing to yield three functional peptides: AVP, NPII, and copeptin (Entrez Gene; http://www.ncbi.nlm.nih.gov/entrez). The AVP-NP11 complex is transported along nerve axons to the posterior pituitary where it is secreted into the bloodstream or directly into the brain.
In addition to its vasoconstrictor properties,_AVP acts to maintain fluid homeostasis by signaling through AVPR2 receptors in the collecting ducts of the kidney (BIRNBAUMER M
Trends Endocrinol Metab (2000) 10:406-10) and plays a role in pH regulation (TASHIMA
Y et al Plufgers Arch (2001) 442(5):652-61. Furthermore, AVP is thought to be involved in cognition, tolerance, adaptation as well as complex sexual and maternal behavior (YOUNG
WS et al Neurosci (2006) 143(4):1031-9).

A representative human AVP mRNA sequence is listed in GenBank under accession numbers NM00490 (633 bp). NM 00490 contains AVP rs1410713 but not rs857242.

Human arginine vasopressin receptor lA (AVPRIA) is also known as the V la vasopressin receptor (V laR); SCCL vasopressin subtype 1 a receptor; V 1-vascular vasopressin receptor;
antidiuretic hormone receptor IA; and vascular/hepatic-type arginine vasopressin receptor.
AVPRIA maps to chromosomal region 12q14-q15. The protein encoded by this gene acts as receptor for arginine vasopressin (AVP). This receptor belongs to the subfamily of G-protein coupled receptors which also includes AVPRIB, AVPR2 and OXTR. AVPRIA agonist binding increases intracellular calcium concentrations by signaling through the phospholipase C cascade (OMIM: 600821). The downstream effects of this signaling cascade include cell contraction and proliferation, platelet aggregation, release of coagulation factors and glycogenolysis. AVPRIA
has been investigated for associations with social behaviors, including affiliation and attachment (YOUNG LJ et al Nature (1999) 400(6746):766-8) as well as essential hypertension (THIBONNIER M et al J Mol Cell Cardiol (2000) 32(4):557-564).

A representative human AVPRIA mRNA sequence is listed in GenBank under accession number NM_000706 (4154 bp). The NM_000706 sequence contains AVPRIA SNP rs3803107 (and rs 1042615), but not rs 1495027 or rs 10877970.

Homo sapiens leucyUcystinyl aminopeptidase (LNPEP) is also known as AT (4) receptor;
angiotensin IV receptor; insulin-regulated aminopeptidase; insulin-responsive aminopeptidase;
otase; oxytocinase; placental leucine aminopeptidase; and vasopressinase.
LNPEP maps to chromosomal region 5q15. The LNPEP gene encodes a metalloproteinase that cleaves polypeptides such as vasopressin, oxytocin, lys-bradykinin, met-enkephalin and dynorphin A
(Entrez Gene: www.ncbi.nlm.nih.gov/entrez). LNPEP also catalyzes the conversion of angiotensinogen to angiotensin IV (AT4) and is thought to play a role in memory processing by acting as a receptor for AT4 (LEW RA et al J Neurochem (2003) 86(2):344-50.
LNPEP also plays a role in the maintenance of pregnancy (NORMURA S et al Biochim Biophys Acta (2005) 1751(1):19-25).

A representative human LNPEP mRNA sequence is listed in GenBank under accession number NM_005575 (4470 bp). The NM_005575 sequence does not contain the LNPEP SNP rs 18059.

Homo sapiens leukocyte-derived arginine aminopeptidase (LRAP) is also known as endoplasmic reticulum aminopeptidase 2; (ERAP2). LRAP maps to chromosomal region 5q15, immediately upstream of LNPEP. The longest annotated transcript of LRAP (NM 022350) has 18 exons and is predicted to encode a protein of 915 amino acids (aa). LRAP is localized to the endoplasmic reticulum (ER) of the cell where it functions to cleave antigenic peptides greater than nine aa for presentation to major histocompatibility complex 1(MHC-1) molecules (TANIOKA T
et al J Biol Chem (2003) 278(34):32275-83).

A representative human LRAP mRNA sequence is listed in GenBank under accession number NM_022350 (3356 bp).

Genotype has been shown to play a role in the prediction of subject outcome in inflammatory and infectious diseases (MCGUIRE W. et al. Nature (1994) 371:508-10; NADEL S. et al. Journal of Infectious Diseases (1996) 174:878-80; MIRA JP. et al. JAMA (1999) 282:561-8;
MAJETSCHAK
M. et al. Ann Surg (1999) 230:207-14; STUBER F. et al. Crit Care Med (1996) 24:381-4;
STUBER F. et al. Journal of Inflammation (1996) 46:42-50; and WEITKAMP JH. et al. Infection (2000) 28:92-6). Furthermore, genotype can alter response to therapeutic interventions.
Genentech's HERCEPTIN was not effective in its overall Phase III trial but was shown to be effective in a genetic subset of subjects with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Similarly, Novartis' GLEEVEC is only indicated for the subset of chronic myeloid leukemia subjects who carry a reciprocal translocation between chromosomes 9 and 22.

SUMMARY OF THE INVENTION
This invention is based in part on the surprising discovery that vasopressin pathway SNPs from AVP, AVPRIA, LNPEP and LRAP are predictive or indicative of subject outcome, wherein subject outcome is the ability of the subject to recover from an inflammatory condition based on having a particular AVP, AVPRIA, LNPEP or LRAP genotype as compared to a subject not having that genotype.

This invention is also based in part on the surprising discovery of vasopressin pathway SNPs having an association with improved prognosis or subject outcome, in subjects with an inflammatory condition. Furthermore, various vasopressin pathway SNPs are provided which are useful for subject screening, as an indication of subject outcome, or for prognosis for recovery from an inflammatory condition.

This invention is also based in part on the identification that the particular nucleotide (allele) or genotype at the site of a given SNP may be associated with a decreased likelihood of recovery from an inflammatory condition ('risk genotype') or an increased likelihood of recovery from an inflammatory condition ('decreased risk genotype'). Furthermore, this invention is in part based on the discovery that the genotype or allele may be predictive of increased responsiveness to the treatment of the inflammatory condition with vasopressin receptor agonist (i.e. "adverse response genotype" (ARG) or "improved response genotype" (IRG)). The vasopressin receptor agonist may be vasopressin. The inflammatory condition may be SIRS, sepsis or septic shock.

This invention is also based in part on the surprising discovery that AVP, AVPRIA LNPEP and LRAP SNPs alone or in combination are useful in predicting the response a subject with an inflammatory condition will have to vasopressin receptor agonist treatment or vasopressin treatment. Whereby the subjects having an improved response genotype are more likely to benefit from and have an improved response to vasopressin receptor agonist treatment and subjects having a non-improved response genotype are less likely to benefit from the same treatment.
Furthermore, there are provided herein AVP, AVPRIA LNPEP and LRAP SNPs and SNPs in linkage disequilibrium (LD) thereto, which are also useful in predicting the response a subject with an inflammatory condition will have to vasopressin receptor agonist treatment or vasopressin treatment.
In accordance with one aspect of the invention, methods are provided for obtaining a prognosis for a subject having, or at risk of developing, an inflammatory condition, the method including determining a genotype of said subject which includes one or more polymorphic sites in the subject's vasopressin pathway gene sequences or a combination thereof, wherein said genotype is indicative of an ability of the subject to recover from the inflammatory condition.

In accordance with a further aspect of the invention, methods are provided for identifying a polymorphism in a vasopressin pathway gene sequence that correlates with prognosis of recovery from an inflammatory condition, the method including: obtaining vasopressin pathway gene sequence information from a group of subjects having an inflammatory condition; identifying at least one polymorphic nucleotide position in the vasopressin pathway gene sequence in the subjects; determining a genotypes at the polymorphic site for individual subjects in the group;

determining recovery capabilities of individual subjects in the group from the inflammatory condition; and correlating the genotypes determined in step (c) with the recovery capabilities determined in step (d) thereby identifying said vasopressin pathway gene sequence polymorphisms that correlate with recovery.

In accordance with a further aspect of the invention, a kit is provided for determining a genotype at a defined nucleotide position within a polymorphic site in vasopressin pathway gene sequence in a subject to provide a prognosis of the subject's ability to recover from an inflammatory condition, the kit including: a restriction enzyme capable of distinguishing alternate nucleotides at the polymorphic site; or a labeled oligonucleotide having sufficient complementary to the polymorphic site so as to be capable of hybridizing distinctively to said alternate. The kit may further include an oligonucleotide or a set of oligonucleotides operable to amplify a region including the polymorphic site. The kit may further include a polymerization agent. The kit may further include instructions for using the kit to determine genotype.

In accordance with a further aspect of the invention, methods are provided for treating an inflammatory condition in a subject in need thereof, the method including administering to the subject a vasopressin receptor agonist, wherein said subject has an improved response genotype in their vasopressin pathway associated gene sequence.

In accordance with a further aspect of the invention, methods are provided for treating an inflammatory condition in a subject in need thereof, the method including:
selecting a subject having an improved response genotype in their vasopressin pathway associated gene sequence; and administering to said subject one or more vasopressin receptor agonist(s).

In accordance with a further aspect of the invention, methods are provided for treating a subject with an inflammatory condition by administering a vasopressin receptor agonist, the method including administering the vasopressin receptor agonist to subjects that have an improved response genotype in their vasopressin pathway associated gene sequence, wherein the improved response genotype is predictive of increased responsiveness to the treatment of the inflammatory condition with a vasopressin receptor agonist. 6 In accordance with a further aspect of the invention, methods are provided for identifying a subject with increased responsiveness to treatment of an inflammatory condition with a vasopressin receptor agonist, including the step of screening a population of subjects to identify those subjects that have an improved response genotype in their vasopressin pathway associated gene sequence, wherein the identification of a subject with an improved response genotype in their vasopressin pathway associated gene sequence is predictive of increased responsiveness to the treatment of the inflammatory condition with the vasopressin receptor agonist.

In accordance with a further aspect of the invention, methods are provided for selecting a subject for the treatment of an inflammatory condition with a vasopressin receptor agonist, including the step of identifying a subject having an improved response genotype in their vasopressin pathway associated gene sequence, wherein the identification of a subject with the improved response genotype is predictive of increased responsiveness to the treatment of the inflammatory condition with the vasopressin receptor agonist.
In accordance with a further aspect of the invention, methods are provided for treating an inflammatory condition in a subject, the method including administering a vasopressin receptor agonist to the subject, wherein said subject has an improved response genotype in their vasopressin pathway associated gene sequence.
In accordance with a further aspect of the invention, methods are provided for treating an inflammatory condition in a subject, the method including: identifying a subject having an improved response genotype in their vasopressin pathway associated gene sequence; and administering a vasopressin receptor agonist to the subject.
In accordance with a further aspect of the invention, methods are provided for administering one or more vasopressin receptor agonist(s) to a subject in need thereof, said subject having an improved response genotype in their vasopressin pathway associated gene sequence.

In accordance with a further aspect of the invention, methods are provided for treating an inflammatory condition in a subject, the method including: identifying a subject having an adverse response genotype in their vasopressin pathway associated gene sequence; and selectively not administering a vasopressin receptor agonist to the subject.

In accordance with a further aspect of the invention, methods are provided for selectively not administering one or more vasopressin receptor agonist(s) to a subject, wherein said subject has an adverse response genotype in their vasopressin pathway associated gene sequence.

In accordance with another aspect of the invention, there is provided a use of a vasopressin receptor agonist in the manufacture of a medicament for the treatment of an inflammatory condition, wherein the subjects treated have an improved response polymorphism in their vasopressin pathway associated gene sequence.

In accordance with another aspect of the invention, there is provided a use of a vasopressin receptor agonist in the manufacture of a medicament for the treatment of an inflammatory condition, wherein the subjects treated do not have an adverse response polymorphism in their vasopressin pathway associated gene sequence.

In accordance with another aspect of the invention, there is provided a use of a vasopressin receptor agonist in the manufacture of a medicament for the treatment of an inflammatory condition in a subset of subjects, wherein the subset of subjects have an improved response polymorphism in their vasopressin pathway associated gene sequence.

In accordance with another aspect of the invention, there is provided a use of a vasopressin receptor agonist in the manufacture of a medicament for the treatment of an inflammatory condition in a subset of subjects, wherein the subset of subjects do not have an adverse response polymorphism in their vasopressin pathway associated gene sequence.

In accordance with another aspect of the invention, there is provided a commercial package containing, as active pharmaceutical ingredient, use of a vasopressin receptor agonist, or a pharmaceutically acceptable salt thereof, together with instructions for its use for the curative or prophylactic treatment of an inflammatory condition in a subject, wherein the subject treated has an improved response polymorphism in their vasopressin pathway associated gene sequence.
In accordance with another aspect of the invention, there is provided a commercial package containing, as active pharmaceutical ingredient, use of a vasopressin receptor agonist, or a pharmaceutically acceptable salt thereof, together with instructions for its use for the curative or prophylactic treatment of an inflammatory condition in a subject, wherein the subject treated does not have an adverse response polymorphism in their vasopressin pathway associated gene sequence.

The method or use may further include determining the subject's APACHE II
score as an assessment of subject risk. The method or use may further include determining the number of organ system failures for the subject as an assessment of subject risk. The subject's APACHE II
score may be indicative of an increased risk when > 25. 2 or more organ system failures may be indicative of increased subject risk.

The improved response genotype may be found at one or more of the following polymorphic sites:
rs 18059; rs27711; rs 10051637; rs 1410713; rs857240; rs857242; and rs 1495027; or a polymorphic site in linkage disequilibrium thereto. The polymorphic site in linkage disequilibrium is selected from one or more of the following: rs2762; rs10051637; rs1477364; rs7731592;
rs7736466;
rs1363974; rs2351010; rs1423357; rs1544777; rs2161548; rs38032; rs38034;
rs38041; rs27436;
rs27306; rs27307; rs27397; rs27659; rs2771 1; rs27290; rs38030; rs27294;
rs27747; rs39602;
rs248215; rs27302; rs2278018; rs1559355; rs3734015; rs4869315; rs2247650;
rs2549781;
rs2549782; rs2161657; rs251339; rs187265; rs2548527; rs1056893; rs2548523;
rs2255546;
rs2255637; rs1019503; rs251344; rs1981846; rs10071975; rs7700332; rs38042;
rs18059; rs9127;
rs7972829; rs10784339; rs3803107; rs11836346; rs7308008; rs11835545;
rs7959001;
rs11832877; rs10877977; rs2201895; rs7302323; rs10877986; rs2030106 and rs18059; rs27296;
rs27300; rs27613; rs2771 1; rs38033; rs38035; rs38036; rs38041; rs38043;
rs716848; rs1216565;
rs1230358; rs1363907; rs1974871; rs2042385; rs2113050; rs2113189; rs2161658;
rs2255633;
rs2255634; rs2287988; rs2548524; rs2548529; rs2548530; rs2548532; rs2548533;
rs2548536;
rs2548538; rs2548539; rs2548540; rs2549783; rs2549784; rs2549790; rs2549791;
rs2549794;
rs2549795; rs2549796; rs2549797; rs2617447; rs2910686; rs2927609 rs3797796;
rs3849749;
rs3849750; rs4360063; rs4869314; rs4869316; rs6556942; rs7713127; rs7716222;
rs7719705;
rs 10044354; rs 10051637; rs 10058476; rs 12516666; and rs 12716486.

The improved response genotype may be selected from one or more of the following: rs 18059CT;
rs 18059TT; rs27711 GG; rs 10051637GA; rs 10051637AA; rs 1410713AC; rs 1410713AA;
rs857240CC; rs857242CC; rs 1495027CC; and rs 1495027CT; or a polymorphic site in linkage disequilibrium thereto. The adverse response genotype which may be selected from one or more of the following: rs 18059CC; rs27711 AA; rs 10051637GG; rs 1410713CC;
rs857240CT;
rs857242AC; and rs 1495027TT; or a polymorphic site in linkage disequilibrium thereto. The genotype of the polymorphic site in linkage disequilibrium may be selected from one or more of the polymorphic sites and corresponding genotypes set out in TABLES 1B and 1D.

The subject having one or more improved response genotypes may be selectively administered the vasopressin receptor agonist. The subject having one or more adverse response genotypes may be selectively not administered the vasopressin receptor agonist.

In accordance with a further aspect of the invention, methods are provided for selecting a group of subjects for determining the efficacy of a candidate drug known or suspected of being useful for the treatment of an inflammatory condition, the method including determining a genotype at one or more polymorphic sites in a vasopressin pathway gene sequence for each subject, wherein said genotype is indicative of the subject's ability to recover from the inflammatory condition and sorting subjects based on their genotype. The method may further include, administering the candidate drug to the subjects or a subset of subjects and determining each subject's ability to recover from the inflammatory condition. The method may further include comparing subject response to the candidate drug based on genotype of the subject.

The polymorphic site may be selected from one or more of the following: rs 18059; rs27711;
rs38041; rs 10051637; rs 1410713; rs857240; rs857242; rs 10877970; rs3803107;
and rs 1495027; or a polymorphic site in linkage disequilibrium thereto. The method of claim 2, wherein the polymorphic site in linkage disequilibrium may be selected from one or more of the following:
rs2762; rs10051637; rs1477364; rs7731592; rs7736466; rs1363974; rs2351010;
rs1423357;
rs1544777; rs2161548; rs38032; rs38034; rs38041; rs27436; rs27306; rs27307;
rs27397; rs27659;
rs27711; rs27290; rs38030; rs27294; rs27747; rs39602; rs248215; rs27302;
rs2278018;
rs 1559355; rs3734015; rs4869315; rs2247650; rs2549781; rs2549782; rs2161657;
rs251339;
rs187265; rs2548527; rs1056893; rs2548523; rs2255546; rs2255637; rs1019503;
rs251344;
rs1981846; rs10071975; rs7700332; rs38042; rs18059; rs9127; rs7972829;
rs10784339;
rs3803107; rs11836346; rs7308008; rs11835545; rs7959001; rs11832877;
rs10877977;
rs2201895; rs7302323; rs10877986; rs2030106; rs 1495027; rs10877962;
rs1042615; rs 16856;
rs18059; rs27296; rs27300; rs27613; rs27711; rs38033; rs38035; rs38036;
rs38041; rs38043;
rs716848; rs 1216565; rs 1230358; rs 1363907; rs 1974871; rs2042385;
rs2113050; rs2113189;
rs2161658; rs2255633; rs2255634; rs2287988; rs2548524; rs2548529; rs2548530;
rs2548532;
rs2548533; rs2548536; rs2548538; rs2548539; rs2548540; rs2549783; rs2549784;
rs2549790;
rs2549791; rs2549794; rs2549795; rs2549796; rs2549797; rs2617447; rs2910686;
rs2927609 rs3797796; rs3849749; rs3849750; rs4360063; rs4869314; rs4869316; rs6556942;
rs7713127;
rs7716222; rs7719705; rs 10044354; rs 10051637; rs 10058476; rs 12516666; and rs 12716486.

The method may further include comparing the genotype determined with known genotypes, which are known to be indicative of a prognosis for recovery from the subject's type of inflammatory condition, or another inflammatory condition.
The method may further include obtaining vasopressin pathway gene sequence information for the subject. The genotype may be determined using a nucleic acid sample from the subject. The method may further include obtaining the nucleic acid sample from the subject.
The genotype may be determined using one or more of the following techniques: restriction fragment length analysis;
sequencing; micro-sequencing assay; hybridization; invader assay; gene chip hybridization assays;
oligonucleotide ligation assay; ligation rolling circle amplification; 5' nuclease assay; polymerase proofreading methods; allele specific PCR; matrix assisted laser desorption ionization time of flight (MALDI-TOF) mass spectroscopy; ligase chain reaction assay; enzyme-amplified electronic transduction; single base pair extension assay; and reading sequence data. The genotype of the subject may be indicative of increased risk of death or organ dysfunction from the inflammatory condition. The subject may be critically ill and the genotype is indicative of a prognosis of severe cardiovascular or respiratory dysfunction.

The genotype may include at least one of the following risk genotypes:
rs18059CT; rs18059TT;
rs27711 GA; rs27711 GG; rs38041 GA; rs38041 GG; rs 10051637GA; rs 10051637GG;
rs 1410713AA; rs857240CC; rs857242CC; rs 10877970CC; rs3803107TT; and rs 1495027TT; or a polymorphic site in linkage disequilibrium thereto. The genotype may include at least one of the following risk alleles: rs3803107T; and rs 10877970C; or a polymorphic site in linkage disequilibrium thereto.

The genotype of the subject may be indicative of decreased risk of death or organ dysfunction from the inflammatory condition. The subject may be critically ill and the genotype is indicative of a prognosis of mild cardiovascular or respiratory dysfunction. The genotype may include at least one of the following reduced risk genotypes: rs18059CC; rs27711AA;
rs38041AA;
rs 10051637AA; rs 1410713CC; rs 1410713AC; rs857240TT; rs857240CT; rs857242AA;
rs857242AC; rs10877970TT; rs10877970CT; rs3803107CC; rs3803107CT; rs1495027CC
and rs1495027CT; or a polymorphic site in linkage disequilibrium thereto. The genotype may include at least one of the following reduced risk alleles: rs3803107C; and rs 10877970T; or a polymorphic site in linkage disequilibrium thereto.

Alternatively, the genotype of the polymorphic site in linkage disequilibrium may be selected from one or more of the polymorphic sites and corresponding genotypes set out in TABLES 1B and 1D.
The inflammatory condition may be selected from the group consisting of:
sepsis, septicemia, pneumonia, septic shock, systemic inflammatory response syndrome (SIRS), Acute Respiratory Distress Syndrome (ARDS), acute lung injury, aspiration pneumonitis, infection, pancreatitis, bacteremia, peritonitis, abdominal abscess, inflammation due to trauma, inflammation due to surgery, chronic inflammatory disease, ischemia, ischemia-reperfusion injury of an organ or tissue, tissue damage due to disease, tissue damage due to chemotherapy or radiotherapy, and reactions to ingested, inhaled, infused, injected, or delivered substances, glomerulonephritis, bowel infection, opportunistic infections, and for subjects undergoing major surgery or dialysis, subjects who are immunocompromised, subjects on immunosuppressive agents, subjects with HIViAIDS, subjects with suspected endocarditis, subjects with fever, subjects with fever of unknown origin, subjects with cystic fibrosis, subjects with diabetes mellitus, subjects with chronic renal failure, subjects with acute renal failure, oliguria, subjects with acute renal dysfunction, glomerulo-nephritis, interstitial-nephritis, acute tubular necrosis (ATN), subjects , subjects with bronchiectasis, subjects with chronic obstructive lung disease, chronic bronchitis, emphysema, or asthma, subjects with febrile neutropenia, subjects with meningitis, subjects with septic arthritis, subjects with urinary tract infection, subjects with necrotizing fasciitis, subjects with other suspected Group A
streptococcus infection, subjects who have had a splenectomy, subjects with recurrent or suspected enterococcus infection, other medical and surgical conditions associated with increased risk of infection, Gram positive sepsis, Gram negative sepsis, culture negative sepsis, fungal sepsis, meningococcemia, post-pump syndrome, cardiac stun syndrome, myocardial infarction, stroke, congestive heart failure, hepatitis, epiglottitis, E. coli 0157:H7, malaria, gas gangrene, toxic shock syndrome, pre-eclampsia, eclampsia, HELLP syndrome, mycobacterial tuberculosis, Pneumocystic carinii, pneumonia, Leishmaniasis, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura, Dengue hemorrhagic fever, pelvic inflammatory disease, Legionella, Lyme disease, Influenza A, Epstein-Barr virus, encephalitis, inflammatory diseases and autoimmunity including Rheumatoid arthritis, osteoarthritis, progressive systemic sclerosis, systemic lupus erythematosus, inflammatory bowel disease, idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, systemic vasculitis, Wegener's granulomatosis, transplants including heart, liver, lung kidney bone marrow, graft-versus-host disease, transplant rejection, sickle cell anemia, nephrotic syndrome, toxicity of agents such as OKT3, cytokine therapy, and cirrhosis. The inflammatory condition may be SIRS. The inflammatory condition may be sepsis.
The inflammatory condition may be septic shock.

The vasopressin receptor agonist may be vasopressin.

In accordance with another aspect of the invention, there are provided two or more oligonucleotides or peptide nucleic acids of about 10 to about 400 nucleotides that hybridize specifically to a sequence contained in a human target sequence consisting of a subject's vasopressin pathway associated gene sequence, a complementary sequence of the target sequence or RNA equivalent of the target sequence and wherein the oligonucleotides or peptide nucleic acids are operable in determining the presence or absence of two or more polymorphism(s) or in their vasopressin pathway associated gene sequence selected from of the following polymorphic sites: rs 18059; rs27711; rs38041; rs 10051637; rs 1410713; rs857240;
rs857242; rs 10877970;
rs3803107; and rs1495027; or one or more polymorphic sites in linkage disequilibrium thereto.
In accordance with another aspect of the invention, there are provided two or more oligonucleotides or peptide nucleic acids selected from the group including of: (a) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:1 having a T at position 201 but not to a nucleic acid molecule including SEQ ID NO:1 having a C at position 201; (b) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:1 having a C at position 201 but not to a nucleic acid molecule including SEQ ID
NO:1 having a T at position 201; (c) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID
NO:2 having a G at position 201 but not to a nucleic acid molecule including SEQ ID NO:2 having a A at position 201; (d) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:2 having an A at position 201 but not to a nucleic acid molecule including SEQ ID NO:2 having a G at position 201;
(e) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:3 having an A at position 201 but not to a nucleic acid molecule including SEQ ID NO:3 having a G at position 201; (f) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:3 having a G at position 201 but not to a nucleic acid molecule including SEQ ID NO:3 having an A at position 201; (g) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:4 having a G at position 201 but not to a nucleic acid molecule including SEQ ID
NO:4 having an A
at position 201; (h) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:4 having an A at position 201 but not to a nucleic acid molecule including SEQ ID NO:4 having a G at position 201; (i) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:5 having an A at position 201 but not to a nucleic acid molecule including SEQ ID NO:5 having a C at position 201; (j) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:5 having a C at position 201 but not to a nucleic acid molecule including SEQ ID
NO:5 having an A at position 201; (k) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID
NO:6 having an T
at position 201 but not to a nucleic acid molecule including SEQ ID NO:6 having a C at position 201; (1) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:6 having a C at position 201 but not to a nucleic acid molecule including SEQ ID NO:6 having an T at position 201; (m) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:7 having an A at position 201 but not to a nucleic acid molecule including SEQ ID NO:7 having a C at position 201; (n) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:7 having a C at position 201 but not to a nucleic acid molecule including SEQ ID
NO:7 having an A
at position 201; (o) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:8 having a T at position 201 but not to a nucleic acid molecule including SEQ ID NO:8 having a C at position 201; (p) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:8 having a C at position 201 but not to a nucleic acid molecule including SEQ ID NO:8 having a T at position 201; (q) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:9 having a C at position 201 but not to a nucleic acid molecule including SEQ ID
NO:9 having a T at position 201; (r) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID
NO:9 having a T at position 201 but not to a nucleic acid molecule including SEQ ID NO:9 having a C at position 201;

(s) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO: 10 having a T at position 201 but not to a nucleic acid molecule including SEQ ID NO:10 having a C at position 201; (t) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule including SEQ ID NO:10 having a C at position 201 but not to a nucleic acid molecule including SEQ ID
NO: 10 having a T at position 201; (u) an oligonucleotide or peptide nucleic acid capable of hybridizing under high stringency conditions to a nucleic acid molecule including a first allele for a given polymorphism selected from the polymorphisms listed in TABLE 1D but not capable of hybridizing under high stringency conditions to a nucleic acid molecule including a second allele for the given polymorphism selected from the polymorphisms listed in TABLE 1D;
and (v) an oligonucleotide or peptide nucleic acid capable of hybridizing under high stringency conditions to a nucleic acid molecule including the second allele for a given polymorphism selected from the polymorphisms listed in TABLE 1 D but not capable of hybridizing under high stringency conditions to a nucleic acid molecule including the first allele for the given polymorphism selected from the polymorphisms listed in TABLE 1D.

In accordance with another aspect of the invention, there is provided an array of oligonucleotides or peptide nucleic acids attached to a solid support, the array including two or more of the oligonucleotides or peptide nucleic acids as set out herein.
In accordance with another aspect of the invention, there is provided a composition including an addressable collection of two or more oligonucleotides or peptide nucleic acids, the two or more oligonucleotides or peptide nucleic acids selected from the oligonucleotides or peptide nucleic acids as set out herein.
In accordance with another aspect of the invention, there is provided a composition including an addressable collection of two or more oligonucleotides or peptide nucleic acids, the two or more oligonucleotides or peptide nucleic acids consisting essentially of two or more nucleic acid molecules set out in SEQ ID NO: 1-264 or compliments, fragments, variants, or analogs thereof.
In accordance with another aspect of the invention, there is provided ancomposition including an addressable collection of two or more oligonucleotides or peptide nucleic acids, the two or more oligonucleotides or peptide nucleic acids consisting essentially of two or more nucleic acid molecules set out in TABLES 1C and 1D or compliments, fragments, variants, or analogs thereof.

The oligonucleotides or peptide nucleic acids described herein may further include one or more of the following: a detectable label; a quencher; a mobility modifier; a contiguous non-target sequence situated 5' or 3' to the target sequence or 5' and 3' to the target sequence.
In accordance with another aspect of the invention, there is provided a computer readable medium including a plurality of digitally encoded genotype correlations selected from the vasopressin pathway associated gene SNP correlations in TABLE 1E, wherein each correlation of the plurality has a value representing an ability to recover from an inflammatory condition and a value representing an indication of responsiveness to treatment with a vasopressin receptor agonist.
The oligonucleotides or peptide nucleic acids may further include one or more of the following: a detectable label; a quencher; a mobility modifier; a contiguous non-target sequence situated 5' or 3' to the target sequence or 5' and 3' to the target sequence. The oligonucleotides or peptide nucleic acids may alternatively be of about 10 to about 400 nucleotides, about 15 to about 300 nucleotides.
The oligonucleotides or peptide nucleic acids may alternatively be of about 20 to about 200 nucleotides, about 25 to about 100 nucleotides. The oligonucleotides or peptide nucleic acids may alternatively be of about 20 to about 80 nucleotides, about 25 to about 50 nucleotides. The genotype may be determined using a nucleic acid sample from the subject.
Genotype may be determined using one or more of the following techniques: restriction fragment length analysis;
sequencing; micro-sequencing assay; hybridization; invader assay; gene chip hybridization assays;
oligonucleotide ligation assay; ligation rolling circle amplification; 5' nuclease assay; polymerase proofreading methods; allele specific PCR; matrix assisted laser desorption ionization time of flight (MALDI-TOF) mass spectroscopy; ligase chain reaction assay; enzyme-amplified electronic transduction; single base pair extension assay; and reading sequence data. A
determination of whether a site is in linkage disequilibrium (LD) with another site may be determined based on an absolute r2 value or D' value. When evaluating loci for LD those sites within a given population having a high degree of linkage disequilibrium (for example an absolute value for D' of > 0.5 or r 2 > 0.5) are potentially useful in predicting the identity of an allele of interest (for example associated with the condition of interest). A high degree of linkage disequilibrium may be represented by an absolute value for D' of > 0.6 or r2 > 0.6. Alternatively, a higher degree of linkage disequilibrium may be represented by an absolute value for D' of > 0.7 or r2 > 0.7 or by an absolute value for D' of > 0.8 or r2 > 0.8. Additionally, a high degree of linkage disequilibrium may be represented by an absolute value for D' of > 0.85 or r2 > 0.85 or by an absolute value for D' of > 0.9 or rz > 0.9. Two or more oligonucleotides or peptide nucleic acids may include 3 or more;
4 or more; 5 or more; 6 or more; 7 or more; 8 or more; 9 or more; 10 or more;
I 1 or more; 12 or more; 13 or more; 14 or more; 15 or more; 16 or more; 17 or more; 18 or more;
19 or more; or 20 or more.

Sequence variations may be assigned to a gene if mapped within 2 kb or more of an mRNA
sequence feature. In particular, such a sequence may extend many kilobases (kb) from a vasopressin pathway gene and into neighbouring genes, where the LD within a region is strong.

BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE 1 shows a Kaplan-Meier curve for a cohort of Caucasian Subjects with systematic inflammatory response syndrome by genotype of Leucyl aminopeptidase (LNPEP) rs18059 (CC = dashed CT/TT = solid).
FIGURE 2 shows Kaplan-Meier survival curves for a cohort of Caucasian Subjects with systematic inflammatory response syndrome by genotype of Arginine Vasopressin (AVP) rs 1410713 (AA = dashed CC/AC = solid).
FIGURE 3 shows Kaplan-Meier survival curves for a cohort of Caucasian Subjects with sepsis by genotype of Arginine Vasopressin (AVP) rs1410713 (AA = dashed CC/AC
= solid).
FIGURE 4 shows Kaplan-Meier survival curves for a cohort of Caucasian Subjects with septic shock by genotype of Arginine Vasopressin (AVP) rs1410713 (AA = dashed CC/AC =
solid).
FIGURE 5 shows Kaplan-Meier survival curves for a cohort of Caucasian Subjects with systematic inflammatory response syndrome by genotype of Arginine Vasopressin (AVP) rs857242 (AC/AA = solid vs. CC = dashed).
FIGURE 6 shows Kaplan-Meier survival curves for a cohort of Caucasian Subjects with sepsis by genotype of Arginine Vasopressin (AVP) rs857242 (AC/AA = solid vs.
CC = dashed).
FIGURE 7 shows Kaplan-Meier survival curves for a cohort of Caucasian Subjects with septic shock by genotype of Arginine Vasopressin (AVP) rs857242 (AC/AA = solid vs. CC =
dashed).
FIGURE 8 shows Kaplan-Meier survival curves for a cohort of Caucasian Subjects with systematic inflammatory response syndrome by genotype of arginine vasopressin receptor (AVPRIA) rs3803107 (CC/CT = solid vs. TT = dashed).

FIGURE 9 shows a Kaplan Meier survival curve over 28 days for a cohort of Asian Subjects with systematic inflammatory response syndrome by allele of arginine vasopressin receptor (AVPRIA) rs3803107 (C = solid vs. T = dashed).
FIGURE 10 shows a Kaplan Meier survival curve over 28 days for a cohort of Asian Subjects with systematic inflammatory response syndrome by allele of arginine vasopressin receptor (AVPRIA) rs10877970 (T = dashed vs. C = solid).

DETAILED DESCRIPTION OF THE INVENTION
1. DefiniNons In the description that follows, a number of terms are used extensively, the following definitions are provided to facilitate understanding of the invention.

"Vasopressin Receptor Agonist" as used herein includes any vasopressin molecule, vasopressin derivative, vasopressin variant, vasopressin analogue, non-peptidyl analogues and any prodrug thereof, metabolite thereof, isomer thereof, combination of isomers thereof, or pharmaceutical composition of any of the preceding. Such agonists may be capable of binding to or interacting with a vasopressin receptor and initiating one or more of the types of responses typically produced by the binding of an endogenous vasopressin molecule to a vasopressin receptor (for example, AVPRIA, AVPRIB, AVPR2 and OXTR). Such activity may be present at the time of or following, administration to a subject. Vasopressin receptor agonists may be used alone or in combination with other vasopressin receptor agonists or other medications.
Vasopressin receptor agonists may be synthesized or purified. Examples of vasopressin receptor agonists capable of increasing blood pressure, include, but are not limited to, arginine vasopressin (AVP), lysine vasopressin (LVP), triglycil-lysine vasopressin (also known as Terlipressin or Glycopressin), Octapressin, Ornipressin, Desmopressin, Desmopressin acetate, Lypressin, Felypressin, and Argipressin. Vasopressin analogues may be 1- 3 amino acids such as AIa-AVP, Ser-Ala-AVP, Thr-Ser-Ala-AVP(KALISZAN R. et al. Pharmacol Res Commun (1988) 20(5):377-381) or 3-beta- (2-thienyl)-L-alanine)-8-lysine-vasopressin and other similar analogues (Smith CW. Acta Pharmacol Toxicol (Copenhag) (1978) 43(3):190-195). Examples of derivatives, variants, analogues or compositions etc. may found in US patent applications:
20050075328; 20040229798;
20030134845;20030021792;20030018024;20030008863;20030004159;20020198196;
20020198191; 20020049194; 20050075328; 20040229798; 20030018024; and 20020198191 and issued US patents: 6,903,091; 6,831,079; 6,642,223; 6,620,807; 6,511,974;

6,344,451; 6,335,327;
6,297,234; 6,268,360; 6,235,900; 6,204,260; 6,194,407; 6,096,736; 6,096,735;
6,090,803;

4,908,475; 4,810,778; 4,760,052; 4,711,877;6,903,091; 6,620,807; 6,344,451;
6,297,234; and 6,268,360.

"Vasopressin" as used herein includes: Antidiuretic hormone; Argiprestocin;
Arginine Vasopressin; Arginine oxytocin; Pitressin tannate; Arginine vasotocin;
Vasotocin; Vasopressin, isoleucyl; 3-Isoleucyl vasopressin; 1-[[19-amino-l3-butan-2-yl-10-(2-carbamoylethyl)-7-(carbamoylmethyl)-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-l,2-dithia-5,8,11,14,17-pentazacycloicos-4-yl]carbonyl]-N-[ 1-(carbamoylmethylcarbamoyl)-4-guanidino-butyl]-pyrrolidine-2-carboxamide (IUPAC name). Vasopressin is a nine amino acid peptide (Cys-Tyr-t0 Ile-Gln-Asn-Cys-Pro-Arg-Gly, cyclic 1-6 disulfide) secreted from the posterior pituitary and binds to receptors in blood vessels, the brain and distal or collecting tubules of the kidney to promote vasoconstriction or reabsorption of water back into the circulation.
Vasopressin receptor targets, include AVPRIA, AVPRIB, AVPR2 and OXTR. Vasopressin, for example, is sold as PRESSYN
ARTM by Ferring Inc., and also sold in various formulations as VASOPRESSIN by Ferring Inc., Sandoz Canada Inc. and Pharmaceutical Partners of Canada Inc. Similarly, PITRESSINTM is sold by Warner-Lambert Company, Parke-Davis Division, as a synthetic injectable vasopressin (8-Arginine vasopressin). It is substantially free from the oxytocic principle and is standardized to contain 20 pressor units/mL. The solution contains 0.5% Chlorobutanol (chloroform derivative) as a preservative. Also, DIAPIDTM is sold as a nasal spray by Sandoz Inc. The current published indications for vasopressin (from the label of Ferring's PRESSYN ARTM) are "Vasopressin is intended for use in the prevention of treatment of post-operative abdominal distension, dispelling of gas shadows in abdominal roentgenography and symptomatic control of diabetes insipidus."
"Genetic material" includes any nucleic acid and can be a deoxyribonucleotide or ribonucleotide polymer in either single or double-stranded form.

A "purine" is a heterocyclic organic compound containing fused pyrimidine and imidazole rings, and acts as the parent compound for purine bases, adenine (A) and guanine (G).
A "Nucleotide" is generally a purine (R) or pyrimidine (Y) base covalently linked to a pentose, usually ribose or deoxyribose, where the sugar carries one or more phosphate groups. Nucleic acids are generally a polymer of nucleotides joined by 3'-5' phosphodiester linkages. As used herein "purine" is used to refer to the purine bases, A and G, and more broadly to include the nucleotide monomers, deoxyadenosine-5' -phosphate and deoxyguanosine-5' -phosphate, as components of a polynucleotide chain.

A "pyrimidine" is a single-ringed, organic base that forms nucleotide bases, cytosine (C), thymine (T) and uracil (U). As used herein "pyrimidine" is used to refer to the pyrimidine bases, C, T and U, and more broadly to include the pyrimidine nucleotide monomers that along with purine nucleotides are the components of a polynucleotide chain.

A nucleotide represented by the symbol M may be either an A or C, a nucleotide represented by the symbol W may be either an T/U or A, a nucleotide represented by the symbol Y may be either an C or TIU, a nucleotide represented by the symbol S may be either an G or C, while a nucleotide represented by the symbol R may be either an G or A, and a nucleotide represented by the symbol K may be either an G or T/U. Similarly, a nucleotide represented by the symbol V may be either A or G or C, while a nucleotide represented by the symbol D may be either A or G or T, while a nucleotide represented by the symbol B may be either G or C or T, and a nucleotide represented by the symbol H may be either A or C or T.
A "polymorphic site" or "polymorphism site" or "polymorphism" or "single nucleotide polymorphism site" (SNP site) or single nucleotide polymorphism" (SNP) as used herein is the locus or position with in a given sequence at which divergence occurs. A
"polymorphism" is the occurrence of two or more forms of a gene or position within a gene (allele), in a population, in such frequencies that the presence of the rarest of the forms cannot be explained by mutation alone. The implication is that polymorphic alleles confer some selective advantage on the host.
Preferred polymorphic sites have at least two alleles, each occurring at frequency of greater than 1%, and more preferably greater than 10% or 20% of a selected population.
Polymorphic sites may be at known positions within a nucleic acid sequence or may be determined to exist using the methods described herein. Polymorphisms may occur in both the coding regions and the noncoding regions (for example, promoters, introns or untranslated regions) of genes.
Polymorphisms may occur at a single nucleotide site (SNPs) or may involve an insertion or deletion as described herein.

A "risk genotype" as used herein refers to an allelic variant (genotype) at one or more polymorphic sites within the vasopressin pathway gene (i.e. AVP, AVPRIA and LNPEP) sequences described herein as being indicative of a decreased likelihood of recovery from an inflammatory condition or an increased risk of having a poor outcome. The risk genotype may be determined for either the haploid genotype or diploid genotype, provided that at least one copy of a risk allele is present.

Risk genotype may be an indication of an increased risk of not recovering from an inflammatory condition. Subjects having one copy (heterozygotes) or two copies (homozygotes) of the risk al lele (for example rs 18059 CT, rs 18059 TT) are considered to have the "risk genotype" even though the degree to which the subjects risk of not recovering from an inflammatory condition may increase, depending on whether the subject is a homozygote rather than a heterozygote. Such "risk alleles" or "risk genotypes" may be selected from the following:
rs18059CT; rs18059TT;
rs27711 GA; rs27711 GG; rs38041 GA; rs38041 GG; rs 10051637GA; rs 10051637GG;
rs1410713AA; rs857240CC; rs857242CC; rs10877970TT; rs3803107TT; and rs1495027CC; or a polymorphic site in linkage disequilibrium thereto.

A "decreased risk genotype" as used herein refers to an allelic variant (genotype) at one or more polymorphic sites within the vasopressin pathway gene (i.e. AVP, AVPRIA and LNPEP) sequences described herein as being indicative of an increased likelihood of recovery from an inflammatory condition or a decreased risk of having a poor outcome. The decreased risk genotype may be determined for either the haploid genotype or diploid genotype, provided that at least one copy of a risk allele is present. Decreased risk genotype may be an indication of an increased likelihood of recovering from an inflammatory condition. Subjects having one copy (heterozygotes) or two copies (homozygotes) of the decreased risk allele (for example rs 1410713 CC rs 1410713 AC) are considered to have the "decreased risk genotype" even though the degree to which the subjects risk of not recovering from an inflammatory condition may increase, depending on whether the subject is a homozygote rather than a heterozygote.
Such "decreased risk alleles" or "decreased risk genotypes" or "reduced risk genotypes" may be selected from the following: rs 18059CC; rs27711 AA; rs38041 AA; rs 10051637AA; rs 1410713CC; rs 1410713AC;
rs857240TT; rs857240CT; rs857242AA; rs857242AC; rs 10877970TT; rs 10877970CT;
rs3803107CC; rs3803107CT; rs1495027CC and rs 1495027CT; or a polymorphic site in linkage disequilibrium thereto.

An "improved response genotype" (IRG) or improved response polymorphic variant (IRP) as used herein refers to an allelic variant or genotype at one or more polymorphic sites within the vasopressin pathway associated polymorphisms selected from arginine vasopressin (AVP), arginine vasopressin receptor IA (AVPRIA) leucyl/cystinyl aminopeptidase (LNPEP) or leukocyte-derived aminopeptidase (LRAP) as described herein as being predictive of a subject's improved survival in response to vasopressin receptor agonist treatment (for example rs 18059TT, rs27711 GG, rs 10051637AA, rs 1410713AA, rs857240CC, rs857242CC or rsl495027CC), or a polymorphic site in linkage disequilibrium thereto.

An "adverse response genotype" (ARG) or adverse response polymorphic variant as used herein refers to an allelic variant or genotype at one or more polymorphic sites within the vasopressin pathway associated polymorphisms selected from arginine vasopressin (AVP), arginine vasopressin receptor lA (AVPRIA), leucyl/cystinyl aminopeptidase (LNPEP) or leukocyte-derived aminopeptidase (LRAP) as described herein as being predictive of a subject's decreased survival in response to vasopressin receptor agonist treatment (for example rs18059CC, rs27711 AA, rs 10051637GG, rs 1410713CC, rs857240CT, rs857242AC or rs 1495027TT), or a polymorphic site in linkage disequilibrium thereto. Subjects having a ARG are preferably selected for treatments not involving vasopressin receptor agonist administration.

A"clade" is a group of haplotypes that are closely related phylogenetically.
For example, if haplotypes are displayed on a phylogenetic (evolutionary) tree a clade includes all haplotypes contained within the same branch.

The pattern of a set of markers along a chromosome is referred to as a "Haplotype". Accordingly, groups of alleles on the same small chromosomal segment tend to be transmitted together.
Haplotypes along a given segment of a chromosome are generally transmitted to progeny together unless there has been a recombination event. Absence of a recombination event, haplotypes can be treated as alleles at a single highly polymorphic locus for mapping.

As used herein "haplotype" is a set of alleles of closely linked loci on a chromosome that tend to be inherited together. Such allele sets occur in patterns, which are called haplotypes.
Accordingly, a specific SNP or other polymorphism allele at one SNP site is often associated with a specific SNP or other polymorphism allele at a nearby second SNP site or other polymorphism site. When this occurs, the two SNPs or other polymorphisms are said to be in LD because the two SNPs or other polymorphisms are not just randomly associated (i.e. in linkage equilibrium).

In general, the detection of nucleic acids in a sample depends on the technique of specific nucleic acid hybridization in which the oligonucleotide is annealed under conditions of "high stringency"
to nucleic acids in the sample, and the successfully annealed oligonucleotides are subsequently detected (see for example Spiegelman, S., Scientific American, Vol. 210, p. 48 (1964)).
Hybridization under high stringency conditions primarily depends on the method used for hybridization, the oligonucleotide length, base composition and position of mismatches (if any).
High-stringency hybridization is relied upon for the success of numerous techniques routinely performed by molecular biologists, such as high-stringency PCR, DNA
sequencing, single strand conformational polymorphism analysis, and in situ hybridization. In contrast to Northern and Southern hybridizations, these aforementioned techniques are usually performed with relatively short probes (e.g., usually about 16 nucleotides or longer for PCR or sequencing and about 40 nucleotides or longer for in situ hybridization). The high stringency conditions used in these techniques are well known to those skilled in the art of molecular biology, and examples of them can be found, for example, in Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, New York, N.Y., 1998.

"Oligonucleotides" as used herein are variable length nucleic acids, which may be useful as probes, primers and in the manufacture of microarrays (arrays) for the detection and/or amplification of specific nucleic acids. Such DNA or RNA strands may be synthesized by the sequential addition (5'-3' or 3'-5') of activated monomers to a growing chain, which may be linked to an insoluble support. Numerous methods are known in the art for synthesizing oligonucleotides for subsequent individual use or as a part of the insoluble support, for example in arrays (BERNFIELD MR. and ROTTMAN FM. J. Biol. Chem. (1967) 242(18):4134-43;
SULSTON J. et al. PNAS (1968) 60(2):409-415; GILLAM S. et al. Nucleic Acid Res.(1975) 2(5):613-624; BONORA GM. et al. Nucleic Acid Res.(1990) 18(11):3155-9;
LASHKARI DA. et al. Proc Nat Acad Sci (1995) 92(17):7912-5; MCGALL G. et al. PNAS (1996) 93(24):13555-60;
ALBERT TJ. et al. Nucleic Acid Res.(2003) 31(7):e35; GAO X. et al. Biopolymers (2004) 73(5):579-96; and MOORCROFT MJ. et al. Nucleic Acid Res.(2005) 33(8):e75). In general, oligonucleotides are synthesized through the stepwise addition of activated and protected monomers under a variety of conditions depending on the method being used.
Subsequently, specific protecting groups may be removed to allow for further elongation and subsequently and once synthesis is complete all the protecting groups may be removed and the oligonucleotides removed from their solid supports for purification of the complete chains if so desired.

"Peptide nucleic acids" (PNA) as used herein refer to modified nucleic acids in which the sugar phosphate skeleton of a nucleic acid has been converted to an N-(2-aminoethyl)-glycine skeleton.
Although the sugar-phosphate skeletons of DNA/RNA are subjected to a negative charge under neutral conditions resulting in electrostatic repulsion between complementary chains, the backbone structure of PNA does not inherently have a charge. Therefore, there is no electrostatic repulsion.

Consequently, PNA has a higher ability to form double strands as compared with conventional nucleic acids, and has a high ability to recognize base sequences.
Furthermore, PNAs are generally more robust than nucleic acids. PNAs may also be used in arrays and in other hybridization or other reactions as described above and herein for oligonucleotides.

An "addressable collection" as used herein is a combination of nucleic acid molecules or peptide nucleic acids capable of being detected by, for example, the use of hybridization techniques or by any other means of detection known to those of ordinary skill in the art. A
DNA microarray would be considered an example of an "addressable collection".

In general the term "linkage", as used in population genetics, refers to the co-inheritance of two or more nonallelic genes or sequences due to the close proximity of the loci on the same chromosome, whereby after meiosis they remain associated more often than the 50% expected for unlinked genes. However, during meiosis, a physical crossing between individual chromatids may result in recombination. "Recombination" generally occurs between large segments of DNA, whereby contiguous stretches of DNA and genes are likely to be moved together in the recombination event (crossover). Conversely, regions of the DNA that are far apart on a given chromosome are more likely to become separated during the process of crossing-over than regions of the DNA that are close together. Polymorphic molecular markers, like SNPs, are often useful in tracking meiotic recombination events as positional markers on chromosomes.

Furthermore, the preferential occurrence of a disease gene in association with specific alleles of linked markers, such as SNPs or other polymorphisms, is called "Linkage Disequilibrium" (LD).
This sort of disequilibrium generally implies that most of the disease chromosomes carry the same mutation and the markers being tested are relatively close to the disease gene(s).

For example, in SNP-based association analysis and LD mapping, SNPs can be useful in association studies for identifying polymorphisms, associated with a pathological condition, such as sepsis. Unlike linkage studies, association studies may be conducted within the general population and are not limited to studies performed on related individuals in affected families. In a SNP association study the frequency of a given allele (i.e. SNP allele) is determined in numerous subjects having the condition of interest and in an appropriate control group.
Significant associations between particular SNPs or SNP haplotypes and phenotypic characteristics may then be determined by numerous statistical methods known in the art.

Association analysis can either be direct or LD based. In direct association analysis, potentially causative SNPs may be tested as candidates for the pathogenic sequence. In LD
based SNP
association analysis, SNPs may be chosen at random over a large genomic region or even genome wide, to be tested for SNPs in LD with a pathogenic sequence or pathogenic SNP. Alternatively, candidate sequences associated with a condition of interest may be targeted for SNP identification and association analysis. Such candidate sequences usually are implicated in the pathogenesis of the condition of interest. In identifying SNPs associated with inflammatory conditions, candidate sequences may be selected from those already implicated in the pathway of the condition or disease of interest. Once identified, SNPs found in or associated with such sequences, may then be tested for statistical association with an individual's prognosis or susceptibility to the condition.
For an LD based association analysis, high density SNP maps are useful in positioning random SNPs relative to an unknown pathogenic locus. Furthermore, SNPs tend to occur with great frequency and are often spaced uniformly throughout the genome. Accordingly, SNPs as compared with other types of polymorphisms are more likely to be found in close proximity to a genetic locus of interest. SNPs are also mutationally more stable than variable number tandem repeats (VNTRs) and short tandem repeats (STRs).

In population genetics linkage disequilibrium refers to the "preferential association of a particular allele, for example, a mutant allele for a disease with a specific allele at a nearby locus more frequently than expected by chance" and implies that alleles at separate loci are inherited as a single unit (Gelehrter, T.D., Collins, F.S. (1990). Principles of Medical Genetics. Baltimore:
Williams & Wilkens). Accordingly, the alleles at these loci and the haplotypes constructed from their various combinations serve as useful markers of phenotypic variation due to their ability to mark clinically relevant variability at a particular position, such as position 201 of SEQ ID NO:1 (see Akey, J. et al. Eur J Hum Genet (2001) 9:291-300; and Zhang, K. et al.
(2002). Am J Hum Genet. 71:1386-1394). This viewpoint is further substantiated by Khoury et al.
((1993).
Fundamentals of Genetic Epidemiology. New York: Oxford University Press at p.
160) who state, "[w]henever the marker allele is closely linked to the true susceptibility allele and is in [linkage]
disequilibrium with it, one can consider that the marker allele can serve as a proxy for the underlying susceptibility allele."

As used herein "linkage disequilibrium" (LD) is the occurrence in a population of certain combinations of linked alleles in greater proportion than expected from the allele frequencies at the loci. For example, the preferential occurrence of a disease gene in association with specific alleles of linked markers, such as SNPs, or between specific alleles of linked markers, are considered to be in LD. This sort of disequilibrium generally implies that most of the disease chromosomes carry the same mutation and that the markers being tested are relatively close to the disease gene(s). Accordingly, if the genotype of a first locus is in LD with a second locus (or third locus etc.), the determination of the allele at only one locus would necessarily provide the identity of the allele at the other locus. When evaluating loci for LD those sites within a given population having a high degree of linkage disequilibrium (i.e. an absolute value for r2> 0.5) are potentially useful in predicting the identity of an allele of interest (i.e. associated with the condition of interest). A high degree of linkage disequilibrium may be represented by an absolute value for r2 > 0.6.
Alternatively, a high degree of linkage disequilibrium may be represented by an absolute value for r2 > 0.7 or by an absolute value for r2> 0.8. Additionally, a high degree of linkage disequilibrium may be represented by an absolute value for r2 > 0.85 or by an absolute value for r2 > 0.9.
Accordingly, two SNPs that have a high degree of LD may be equally useful in determining the identity of the allele of interest or disease allele. Therefore, we may assume that knowing the identity of the allele at one SNP may be representative of the allele identity at another SNP in LD.
Accordingly, the determination of the genotype of a single locus can provide the identity of the genotype of any locus in LD therewith and the higher the degree of linkage disequilibrium the more likely that two SNPs may be used interchangeably. For example, in the population from which the tagged SNPs were identified from the SNP identified by rs18059 is in "linkage disequilibrium" with the SNP identified by rs2762, whereby when the genotype of rs 18059 is T the genotype of rs2762 is G. Similarly, when the genotype of rs 18059 is C the genotype of rs2762 is A. Accordingly, the determination of the genotype at rs18059 will provide the identity of the genotype at rs2762 or any other locus in "linkage disequilibrium" therewith.
Particularly, where such a locus is has a high degree of linkage disequilibrium thereto.

LD is useful for genotype-phenotype association studies. For example, if a specific allele at one SNP site (e.g. "A") is the cause of a specific clinical outcome (e.g. call this clinical outcome "B") in a genetic association study then, by mathematical inference, any SNP (e.g.
"C") which is in significant LD with the first SNP, will show some degree of association with the clinical outcome.
That is, if A is associated (-) with B, i.e. A-B and C-A then it follows that C-B. Of course, the SNP that will be most closely associated with the specific clinical outcome, B, is the causal SNP -the genetic variation that is mechanistically responsible for the clinical outcome. Thus, the degree of association between any SNP, C, and clinical outcome will depend on LD
between A and C.

Until the mechanism underlying the genetic contribution to a specific clinical outcome is fully understood, LD helps identify potential candidate causal SNPs and also helps identify a range of SNPs that may be clinically useful for prognosis of clinical outcome or of treatment effect. If one SNP within a gene is found to be associated with a specific clinical outcome, then other SNPs in LD will also have some degree of association and therefore some degree of prognostic usefulness.

By way of prophetic example, if multiple polymorphisms were tested for individual association with an improved response to vasopressin receptor agonist administration in our SIRS/sepsis/septic shock cohort of ICU subjects, wherein the multiple polymorphisms had a range of LD with LNPEP rs 18059 and it was assumed that rs 18059 was the causal polymorphism, and we were to order the polymorphisms by the degree of LD with rs 18059, we would expect to find that polymorphisms with high degrees of LD with rs18059 would also have a high degree of association with this specific clinical outcome. As LD decreased, we would expect the degree of association of the polymorphism with an improved response vasopressin receptor agonist administration to also decrease. It follows that any polymorphism, whether already discovered or as yet undiscovered, that is in LD with one of the improved response genotypes described herein will likely be a predictor of the same clinical outcomes that rs 18059 is a predictor of. The similarity in prediction between this known or unknown polymorphism and rs 18059 would depend on the degree of LD between such a polymorphism and rs 18059.

Numerous sites have been identified as polymorphic sites in the vasopressin pathway associated genes (see TABLE IA). Furthermore, the polymorphisms in TABLE 1A are linked to (in LD
with) numerous polymorphism as set out in TABLE 1B below and may also therefore be indicative of subject prognosis.

TABLE 1A. Polymorphisms in the vasopressin pathway associated genes genotyped in a cohort of critically ill Subjects with severe sepsis. Minor Allele Frequencies (MAFs) for Caucasians were taken from Hapmap.org (Thorisson GA. et al. The International HapMap Project Website.
Genome Research (2005)15:1591-1593).
Mar 2006 Chromo-Polymorphism Name somal Minor (Alleles) Official Gene position Minor Allele Name rs# (Build 36) allele Fre uenc Mar 2006 Chromo-Polymorphism Name somal Minor (Alleles) Official Gene position Minor Allele Name rs# (Build 36) allele Fre uenc leucyUcystinyl aminopeptidase LNPEP rs 18059 (C/T) (LNPEP) rs 18059 96377824 T 0.39 leucyl/cystinyl aminopeptidase LNPEP rs27711 (G/A) (LNPEP) rs27711 96371495 A 0.49 leucyl/cystinyl aminopeptidase LNPEP rs38041 (A/G) (LNPEP) rs38041 96356058 G 0.48 leucyUcystinyl aminopeptidase LNPEP rs 10051637 (A/G) (LNPEP) rs 10051637 96305246 G 0.49 arginine vasopressin AVP rs1410713 (A/C) (AVP) rs1410713 3008350 C 0.44 arginine vasopressin AVP rs857240 (C/T) (AVP) rs857240 3023629 T 0.09 arginine vasopressin AVP rs857242 (C/A) (AVP) rs857242 3029101 A 0.1 arginine vasopressin receptor AVPR 1 A rs 10877970 (T/C) 1 A(AVPR 1 A) rs 10877970 61837421 C 0.09 arginine vasopressin receptor AVPRIA rs3803107 (C/T) lA(AVPRIA) rs3803107 61827101 T 0.13 arginine vasopressin receptor AVPRIA rs1495027 (C/T) 1A(AVPRIA) rs1495027 61890334 T 0.42 TABLE 1B. Polymorphisms in linkage disequilibrium with those listed in TABLE
lA above, as identified using the Haploview program (BARRETT JC. et aZ. Bioinformatics (2005) 21(2):263-5 (http://www.broad.mit.edu/mpg/haploview/)) and the LD function in the Genetics Package in R (R
Core Development Group, 2005 - R Development Core Team (www.R-project.org).
Linkage Disequilibrium between markers was defined using r2 whereby all SNPs available on Hapmap.org (phase II) (cohort H), all SNPs genotyped internally using the Illumina Goldengate assay (cohort I) and all SNPs sequenced using the Sequenom Iplex Platform (cohort S) in our genes of interest were included. A minimum r2 of 0.5 was used as the cutoff to identify LD SNPs.
The genes are identified, along with the alleles, rs designation and the chromosomal position (March 2006 Build 36). An LD allele was only predicted for those cohorts that had sufficient power and NA
designations indicate that the sample sizes were insufficient to make an allele designation with confidence at the time of filing. However, the assignment of allele designations for NA designated LD alleles is a routine procedure. A`*' indicates that there is more than one RSID assigned to a single SNP.

Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
TC
LNPEP (T) 96377824 rs18059 H/I C 96346251 rs10044354 H/I A 96305246 rs10051637 H T 96323283 rs10058476 I T 96345363 rs10476696 S NA 96238651 rs1230360 S NA 96240263 rs1230363 S NA 96240337 rs1230364 S NA 96240415 rs1230365 H G 96278559 rs1363907 H/I A 96319572 rs1363974 H/I T 96324514 rs1423357 H G 96310648 rs1477364 H A 96339986 rs1544777 H A 96259206 rs2113189 H/I G 96343901 rs2161548 H/I C 96319685 rs2351010 H A 96396635 rs248215 I A 96298789 rs2548225 H G 96265683 rs2548530 H A 96264334 rs2548532 H C 96257128 rs2549783 H A 96268198 rs2549791 H T 96270305 rs2549794 S NA 96239682 rs2617436 H T 96293411 rs2617447 I T 96372034 rs27289 H/I A 96375844 rs27290 H G 96383016 rs27294 H T 96387382 rs27296 H T 96389163 rs27300 H T 96360314 rs27306 H G 96364261 rs27307 H G 96366372 rs27397 H/I C 96356722 rs27436 H G 96365029 rs27613 H/I G 96299054 rs2762 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
H/I G 96369308 rs27659 H G 96371495 rs27711 H G 96385668 rs27747 H T 96278345 rs2910686 I T 96302142 rs2910792 H C 96277835 rs2927609 S NA 96239688 rs35199417 H/I G 96342514 rs3797796 H T 96379440 rs38030 H T 96347643 rs38032 H/I A 96347892 rs38033 H/I C 96348175 rs38034 H C 96349036 rs38035 H A 96349259 rs38036 H G 96356058 rs38041 H/I G 96362547 rs38043 H T 96260289 rs3849749 H G 96390210 rs39602 H A 96318909 rs4360063 H G 96251952 rs6556942 I C 96307418 rs6871162 H G 96290756 rs716848 I G 96315986 rs7703341 H A 96313894 rs7713127 H C 96318762 rs7716222 H G 96312042 rs7719705 H/I G 96314716 rs7731592 H G 96315467 rs7736466 I T 96346342 rs9314181 GA
LNEP (G) 96371495 rs27711 S NA 96346167 rs10038651 H/I C 96346251 rs10044354 H/I A 96305246 rs10051637 H T 96323283 rs10058476 S NA 96309577 rs10061936 H/I G 96326898 rs10071975 H/I G 96280573 rs1019503 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
S NA 96251278 rs10434708 I G 96298936 rs1046395 I T 96345363 rs10476696 S NA 96276415 rs10537702 S NA 96276948 rs10546363 H/I T 96271195 rs1056893 S NA 96284454 rs10592692 S NA 96255974 rs10707238 I G 96247321 rs11135483 1 G 96247645 rs11135484 S NA 96312725 rs11135485 S NA 96357847 rs11311774 S NA 96370825 rs11414909 1 A 96247097 rs11750025 H C 96291635 rs1216565 S NA 96289812 rs1216566 S NA 96289595 rs1216567 NA 96289402 rs1216568 S NA 96288290 rs1216569 S NA 96287473 rs1216570 1 T 96246767 rs12189125 H G 96237497 rs1230358 I A 96279965 rs1230381 H T 96254538 rs12516666 H A 96333392 rs12716486 1 C 96247776 rs13167902 S NA 96304809 rs13170029 I A 96248383 rs13189819 S NA 96321566 rs13358339 H/I G 96278559 rs1363907 S NA 96278860 rs1363908 H/I A 96319572 rs1363974 S NA 96274642 rs1363975 S NA 96274551 rs1363976 I A 96274463 rs1363977 H /I T 96324514 rs1423357 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
I A 96299523 rs1423566 H G 96310648 rs1477364 H A 96339986 rs1544777 I T 96329454 rs1559267 I G 96249877 rs1559354 H/I T 96252451 rs1559355 S NA 96252485 rs1559356 S NA 96252486 rs1559357 S NA 96268737 rs17087165 H T 96377824 rs18059 S NA 96278754 rs 1820148 S NA 96332914 rs1820149 H/I G 96262870 rs187265 H C 96252291 rs1974871 H/I G 96294618 rs1981846 S NA 96260377 rs2042383 H G 96273749 rs2042385 S NA 40328876 rs210687 H/I A 96340258 rs2113050 H A 96259206 rs2113189 I A 96262074 rs2113190 H/I G 96343901 rs2161548 H/I T 96258562 rs2161657 H/I C 96265401 rs2161658 H/I A 96255506 rs2247650 H A 96274871 rs2255546 H T 96275079 rs2255633 H T 96275107 rs2255634 H G 96275134 rs2255637 H/I T 96250335 rs2278018 I A 96251008 rs2278019 H /I A 96263082 rs2287988 S NA 96247939 rs2303208 I T 96247941 rs2303209 H/I C 96319685 rs2351010 S NA 96277431 rs2351011 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
H A 96396635 rs248215 H/I C 96260794 rs251339 S NA 96262168 rs251340 S NA 96283585 rs251343 H G 96284683 rs251344 I A 96298789 rs2548225 I G 96301169 rs2548516 S NA 96276759 rs2548520 S NA 96276684 rs2548521 I T 96276213 rs2548522 H A 96272696 rs2548523 H/I A 96272357 rs2548524 H G 96270341 rs2548527 H/I G 96265976 rs2548529 H/I G 96265683 rs2548530 H A 96264334 rs2548532 H C 96264157 rs2548533 H T 96258158 rs2548536 H/I T 96257898 rs2548538 H A 96257260 rs2548539 H T 96255934 rs2548540 H T 96255878 rs2549781 H T 96256756 rs2549782 H/I C 96257128 rs2549783 H T 96257276 rs2549784 S NA 96265593 rs2549787 S NA 96268026 rs2549789 H C 96268168 rs2549790 H/I A 96268198 rs2549791 H/I T 96270305 rs2549794 H G 96270394 rs2549795 H/I T 96271099 rs2549796 H/I G 96271274 rs2549797 S NA 96271659 rs2549798 S NA 96271666 rs2549799 S NA 96275390 rs2549800 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
I A 96276020 rs2549801 S NA 96297394 rs2617434 H/I T 96293411 rs2617447 I T 96372034 rs27289 H/I A 96375844 rs27290 S NA 96376026 rs27291 S NA 96382934 rs27293 H G 96383016 rs27294 H/I T 96387382 rs27296 S NA 96388556 rs27298 S NA 96388807 rs27299 H T 96389163 rs27300 I A 96399506 rs27302 S NA 96359090 rs27305 H/I T 96360314 rs27306 H/I G 96364261 rs27307 H G 96366372 rs27397 H/I C 96356722 rs27436 H G 96365029 rs27613 H/I G 96299054 rs2762 I C 96387089 rs27621 H/I G 96369308 rs27659 I T 96389819 rs27712 H G 96385668 rs27747 I G 96381359 rs27993 I T 96365244 rs27997 H/I T 96278345 rs2910686 S NA 96277457 rs2910688 I C 96299979 rs2910787 S NA 96302151 rs2910789 I T 96302142 rs2910792 H C 96277835 rs2927609 S NA 96259970 rs3096167 S NA 96259968 rs3096168 I A 96382420 rs31398 S NA 96364859 rs3214461 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
S NA 96322341 rs33918743 S NA 96268622 rs33934033 S NA 96243448 rs34037881 S NA 96353305 rs34323164 S NA 96354765 rs34340727 S NA 96258006 rs34701361 S NA 96306710 rs34815125 S NA 96314264 rs34962665 S NA 96344773 rs35304156 S NA 96357125 rs35475916 S NA 96371146 rs35562078 S NA 96301058 rs35929998 S NA 96314613 rs36019589 H/I T 96254184 rs3734015 H/I G 96342514 rs3797796 I G 96378979 rs38029 H/I T 96379440 rs38030 S NA 96381204 rs38031 H/I T 96347643 rs38032 H/I A 96347892 rs38033 H/I C 96348175 rs38034 H/I C 96349036 rs38035 H A 96349259 rs38036 I G 96353419 rs38040 H G 96356058 rs38041 H/I A 96361106 rs38042 H/I G 96362547 rs38043 S NA 96363546 rs38044 H T 96260289 rs3849749 H/I A 96260334 rs3849750 S NA 96320877 rs3909451 H/I G 96390210 rs39602 rs3985004/rs3 S NA 96260693 3912722*
96260692 or rs3985004 or S NA 96260693 rs33912722*
S NA 96363405 rs42983 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
S NA 96357127 rs430827 H A 96318909 rs4360063 H/I T 96254981 rs4869314 H A 96255028 rs4869315 S NA 96259011 rs5869737 S NA 96278700 rs5869740 H/I G 96251952 rs6556942 S NA 96260062 rs6859160 S NA 96260071 rs6859168 S NA 96249932 rs6868302 I C 96307418 rs6871162 S NA 96260108 rs6873441 S NA 96260131 rs6874656 S NA 96345686 rs6879678 I G 96303477 rs6887500 H G 96290756 rs716848 H G 96333368 rs7700332 I G 96315986 rs7703341 H/I A 96313894 rs7713127 H C 96318762 rs7716222 H G 96312042 rs7719705 I T 96345247 rs7722694 S NA 96306799 rs7726445 H/I G 96314716 rs7731592 I C 96311577 rs7733312 H G 96315467 rs7736466 I A 96397921 rs9127 I T 96346342 rs9314181 AG
LNPEP (G) 96356058 rs38041 S NA 96346167 rs 10038651 H/I C 96346251 rs10044354 H/I A 96305246 rs10051637 H T 96323283 rs10058476 S NA 96309577 rs10061936 I G 96310559 rs10069361 H/I G 96326898 rs10071975 H/I G 96280573 rs1019503 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
S NA 96251278 rs10434708 I C 96251530 rs10434709 I T 96345363 rs10476696 S NA 96276415 rs10537702 S NA 96276948 rs10546363 H/I T 96271195 rs1056893 S NA 96284454 rs10592692 S NA 96255974 rs10707238 I A 96247182 rs11135482 I G 96247321 rs11135483 I G 96247645 rs11135484 S NA 96312725 rs11135485 S NA 96357847 rs11311774 S NA 96370825 rs11414909 I A 96247097 rs11750025 H C 96291635 rs1216565 S NA 96289812 rs1216566 S NA 96289595 rs1216567 S NA 96289402 rs1216568 S NA 96288290 rs1216569 S NA 96287473 rs 1216570 I T 96246767 rs12189125 I A 96279965 rs1230381 I T 96280110 rs1230382 H T 96254538 rs12516666 H A 96333392 rs12716486 I C 96247776 rs13167902 S NA 96304809 rs13170029 I A 96248383 rs13189819 S NA 96321566 rs13358339 H G 96278559 rs1363907 S NA 96278860 rs1363908 H/I A 96319572 rs1363974 S NA 96274642 rs1363975 S NA 96274551 rs1363976 I A 96274463 rs1363977 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
H/I T 96324514 rs1423357 I A 96299523 rs1423566 H G 96310648 rs1477364 H A 96339986 rs1544777 I T 96329454 rs1559267 I G 96249877 rs1559354 H/I T 96252451 rs1559355 S NA 96252485 rs1559356 S NA 96252486 rs1559357 S NA 96268737 rs17087165 I T 96263169 rs171647 H T 96377824 rs18059 S NA 96278754 rs1820148 S NA 96332914 rs1820149 H/I G 96262870 rs187265 I C 96260628 rs193993 H C 96252291 rs1974871 H/I G 96294618 rs l 981846 S NA 96260377 rs2042383 H G 96273749 rs2042385 S NA 40328876 rs210687 H/I A 96340258 rs2113050 H A 96259206 rs2113189 I A 96262074 rs2113190 I C 96272094 rs2113191 H/I G 96343901 rs2161548 H/I T 96258562 rs2161657 H/I C 96265401 rs2161658 H/I A 96255506 rs2247650 I G 96261652 rs2248374 H/I A 96274871 rs2255546 H/I T 96275079 rs2255633 H T 96275107 rs2255634 H G 96275134 rs2255637 H/I T 96250335 rs2278018 I A 96251008 rs2278019 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
H/I A 96263082 rs2287988 S NA 96247939 rs2303208 I T 96247941 rs2303209 H/I C 96319685 rs2351010 S NA 96277431 rs2351011 H/I A 96396635 rs248215 H/I C 96260794 rs251339 S NA 96262168 rs251340 I T 96262599 rs251342 S NA 96283585 rs251343 H G 96284683 rs251344 I A 96298789 rs2548225 I G 96301169 rs2548516 S NA 96276759 rs2548520 S NA 96276684 rs2548521 I T 96276213 rs2548522 H/I A 96272696 rs2548523 H/I A 96272357 rs2548524 I G 96271373 rs2548526 H G 96270341 rs2548527 H/I G 96265976 rs2548529 H G 96265683 rs2548530 H A 96264334 rs2548532 H/I C 96264157 rs2548533 I T 96259364 rs2548534 I C 96258455 rs2548535 H T 96258158 rs2548536 I G 96257978 rs2548537 H/I T 96257898 rs2548538 H A 96257260 rs2548539 H T 96255934 rs2548540 H T 96255878 rs2549781 H/I T 96256756 rs2549782 H C 96257128 rs2549783 H T 96257276 rs2549784 I T 96258042 rs2549785 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
S NA 96265593 rs2549787 I G 96266142 rs2549788 S NA 96268026 rs2549789 H C 96268168 rs2549790 H/I A 96268198 rs2549791 H T 96270305 rs2549794 H/I G 96270394 rs2549795 H/I T 96271099 rs2549796 H/I G 96271274 rs2549797 S NA 96271659 rs2549798 S NA 96271666 rs2549799 S NA 96275390 rs2549800 I A 96276020 rs2549801 S NA 96297394 rs2617434 H T 96293411 rs2617447 I T 96372034 rs27289 H/I A 96375844 rs27290 S NA 96376026 rs27291 I G 96382736 rs27292 S NA 96382934 rs27293 H G 96383016 rs27294 H/I T 96387382 rs27296 S NA 96388556 rs27298 S NA 96388807 rs27299 H T 96389163 rs27300 I A 96399506 rs27302 S NA 96359090 rs27305 H T 96360314 rs27306 H G 96364261 rs27307 H/I G 96366372 rs27397 H/I C 96356722 rs27436 H G 96365029 rs27613 H/I G 96299054 rs2762 I C 96387089 rs27621 H/ I G 96369308 rs27659 H G 96371495 rs27711 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
H G 96385668 rs27747 I G 96381359 rs27993 H/I T 96278345 rs2910686 S NA 96277457 rs2910688 I C 96299979 rs2910787 S NA 96302151 rs2910789 I T 96302142 rs2910792 H C 96277835 rs2927609 S NA 96259970 rs3096167 S NA 96259968 rs3096168 I A 96382420 rs31398 S NA 96364859 rs3214461 S NA 96322341 rs33918743 S NA 96268622 rs33934033 S NA 96243448 rs34037881 S NA 96353305 rs34323164 S NA 96354765 rs34340727 S NA 96258006 rs34701361 S NA 96306710 rs34815125 S NA 96314264 rs34962665 S NA 96344773 rs35304156 S NA 96357125 rs35475916 S NA 96371146 rs35562078 S NA 96301058 rs35929998 S NA 96314613 rs36019589 H/I T 96254184 rs3734015 H/I G 96342514 rs3797796 I G 96378979 rs38029 H/I T 96379440 rs38030 S NA 96381204 rs38031 H T 96347643 rs38032 H/I A 96347892 rs38033 H/I C 96348175 rs38034 H/I C 96349036 rs38035 H A 96349259 rs38036 I G 96353419 rs38040 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
H/I A 96361106 rs38042 H/I G 96362547 rs38043 S NA 96363546 rs38044 H T 96260289 rs3849749 H/I A 96260334 rs3849750 S NA 96320877 rs3909451 H/I G 96390210 rs39602 96260692 or rs3985004 or S NA 96260693 rs33912722*
S NA 96363405 rs42983 S NA 96357127 rs430827 H A 96318909 rs4360063 H/I T 96254981 rs4869314 H A 96255028 rs4869315 H G 96259219 rs4869316 S NA 96259011 rs5869737 S NA 96278700 rs5869740 H G 96251952 rs6556942 S NA 96260062 rs6859160 S NA 96260071 rs6859168 S NA 96249932 rs6868302 I C 96307418 rs6871162 S NA 96260108 rs6873441 S NA 96260131 rs6874656 S NA 96345686 rs6879678 I G 96303477 rs6887500 H G 96290756 rs716848 H G 96333368 rs7700332 I G 96315986 rs7703341 H/I A 96313894 rs7713127 H C 96318762 rs7716222 H G 96312042 rs7719705 I T 96345247 rs7722694 S NA 96306799 rs7726445 H/I G 96314716 rs7731592 H G 96315467 rs7736466 I A 96397921 rs9127 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
I T 96346342 rs9314181 GA
LNPEP (A) 96305246 rs 10051637 S NA 96346167 rs 10038651 H/I C 96346251 rs10044354 H T 96323283 rs10058476 S NA 96309577 rs10061936 I G 96310559 rs10069361 H/I G 96326898 rs10071975 H/I G 96280573 rs 1019503 S NA 96251278 rs 10434708 1 C 96251530 rs10434709 I G 96298936 rs1046395 I T 96345363 rs10476696 S NA 96276415 rs10537702 S NA 96276948 rs10546363 H/I T 96271195 rs1056893 S NA 96284454 rs10592692 S NA 96255974 rs10707238 I G 96247321 rs11135483 I G 96247645 rs11135484 S NA 96312725 rs11135485 S NA 96357847 rs11311774 S NA 96370825 rs11414909 I A 96247097 rs11750025 H C 96291635 rs1216565 S NA 96289812 rs1216566 S NA 96289595 rs1216567 S NA 96289402 rs1216568 S NA 96288290 rs1216569 S NA 96287473 rs1216570 I T 96246767 rs12189125 H G 96237497 rs1230358 I A 96279965 rs1230381 I T 96280110 rs1230382 H T 96254538 rs12516666 H A 96333392 rs12716486 I C 96247776 rs13167902 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
S NA 96304809 rs13170029 I A 96248383 rs13189819 S NA 96321566 rs13358339 H/I G 96278559 rs 1363907 S NA 96278860 rs1363908 H/I A 96319572 rs 1363974 S NA 96274642 rs1363975 S NA 96274551 rs 1363976 I A 96274463 rs1363977 H/I T 96324514 rs 1423357 I A 96299523 rs1423566 H G 96310648 rs1477364 H A 96339986 rs1544777 I T 96329454 rs1559267 I G 96249877 rs1559354 H/I T 96252451 rs 1559355 S NA 96252485 rs1559356 S NA 96252486 rs1559357 S NA 96268737 rs17087165 I T 96263169 rs171647 H/I T 96377824 rs 18059 S NA 96278754 rs1820148 S NA 96332914 rs1820149 H/I G 96262870 rs187265 I C 96260628 rs193993 H C 96252291 rs1974871 H/I G 96294618 rs1981846 S NA 96260377 rs2042383 H G 96273749 rs2042385 S NA 40328876 rs210687 H/I A 96340258 rs2113050 H A 96259206 rs2113189 I A 96262074 rs2113190 I C 96272094 rs2113191 H/I G 96343901 rs2161548 H/I T 96258562 rs2161657 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
H/I C 96265401 rs2161658 H/I A 96255506 rs2247650 I G 96261652 rs2248374 H A 96274871 rs2255546 H/I T 96275079 rs2255633 H T 96275107 rs2255634 H G 96275134 rs2255637 H/I T 96250335 rs2278018 I A 96251008 rs2278019 H/I A 96263082 rs2287988 S NA 96247939 rs2303208 I T 96247941 rs2303209 H/I C 96319685 rs2351010 S NA 96277431 rs2351011 H/I A 96396635 rs248215 H/ I C 96260794 rs251339 S NA 96262168 rs251340 I T 96262599 rs251342 S NA 96283585 rs251343 H G 96284683 rs251344 I A 96298789 rs2548225 I G 96301169 rs2548516 I G rs2548517 S NA 96276759 rs2548520 S NA 96276684 rs2548521 I T 96276213 rs2548522 H/I A 96272696 rs2548523 H/I A 96272357 rs2548524 I G 96271373 rs2548526 H G 96270341 rs2548527 H/I G 96265976 rs2548529 H/I G 96265683 rs2548530 H A 96264334 rs2548532 H/I C 96264157 rs2548533 I T 96259364 rs2548534 I C 96258455 rs2548535 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
H T 96258158 rs2548536 I G 96257978 rs2548537 H/I T 96257898 rs2548538 H A 96257260 rs2548539 H T 96255934 rs2548540 H T 96255878 rs2549781 H/I T 96256756 rs2549782 H/I C 96257128 rs2549783 H T 96257276 rs2549784 I T 96258042 rs2549785 S NA 96265593 rs2549787 I G 96266142 rs2549788 S NA 96268026 rs2549789 H C 96268168 rs2549790 H/I A 96268198 rs2549791 H/I T 96270305 rs2549794 H/I G 96270394 rs2549795 H/I T 96271099 rs2549796 H/I G 96271274 rs2549797 S NA 96271659 rs2549798 S NA 96271666 rs2549799 S NA 96275390 rs2549800 I A 96276020 rs2549801 S NA 96297394 rs2617434 H/I T 96293411 rs2617447 I T 96372034 rs27289 H/I A 96375844 rs27290 S NA 96376026 rs27291 I G 96382736 rs27292 S NA 96382934 rs27293 H G 96383016 rs27294 H/I T 96387382 rs27296 S NA 96388556 rs27298 S NA 96388807 rs27299 H T 96389163 rs27300 I A 96399506 rs27302 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
S NA 96359090 rs27305 H/I T 96360314 rs27306 H/I G 96364261 rs27307 H/I G 96366372 rs27397 H/I C 96356722 rs27436 H G 96365029 rs27613 H/I G 96299054 rs2762 I C 96387089 rs27621 H/I G 96369308 rs27659 H/I G 96371495 rs27711 I T 96389819 rs27712 H G 96385668 rs27747 I G 96381359 rs27993 I T 96365244 rs27997 H/I T 96278345 rs2910686 S NA 96277457 rs2910688 I C 96299979 rs2910787 S NA 96302151 rs2910789 I T 96302142 rs2910792 H C 96277835 rs2927609 S NA 96259970 rs3096167 S NA 96259968 rs3096168 I A 96382420 rs31398 S NA 96364859 rs3214461 S NA 96322341 rs33918743 S NA 96268622 rs33934033 S NA 96243448 rs34037881 S NA 96353305 rs34323164 S NA 96354765 rs34340727 S NA 96258006 rs34701361 S NA 96306710 rs34815125 S NA 96314264 rs34962665 S NA 96344773 rs35304156 S NA 96357125 rs35475916 S NA 96371146 rs35562078 S NA 96301058 rs35929998 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
S NA 96314613 rs36019589 H/I T 96254184 rs3734015 H/ I G 96342514 rs3797796 I G 96378979 rs38029 H/I T 96379440 rs38030 S NA 96381204 rs38031 H/I T 96347643 rs38032 H/I A 96347892 rs38033 H/I C 96348175 rs38034 H/I C 96349036 rs38035 H A 96349259 rs38036 I G 96353419 rs38040 H/I G 96356058 rs38041 H/I A 96361106 rs38042 H/I G 96362547 rs38043 NA 96363546 rs38044 H T 96260289 rs3849749 H/I A 96260334 rs3849750 S NA 96320877 rs3909451 H/I G 96390210 rs39602 96260692 or rs3985004 or S NA 96260693 rs33912722*

S NA 96363405 rs42983 S NA 96357127 rs430827 H A 96318909 rs4360063 H/I T 96254981 rs4869314 H A 96255028 rs4869315 S NA 96259011 rs5869737 S NA 96278700 rs5869740 H/I G 96251952 rs6556942 S NA 96260062 rs6859160 S NA 96260071 rs6859168 S NA 96249932 rs6868302 I C 96307418 rs6871162 S NA 96260108 rs6873441 S NA 96260131 rs6874656 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
S NA 96345686 rs6879678 I G 96303477 rs6887500 H G 96290756 rs716848 H G 96333368 rs7700332 I G 96315986 rs7703341 H/I A 96313894 rs7713127 H C 96318762 rs7716222 H G 96312042 rs7719705 I T 96345247 rs7722694 S NA 96306799 rs7726445 H/I G 96314716 rs7731592 I C 96311577 rs7733312 H G 96315467 rs7736466 I A 96397921 rs9127 I T 96346342 rs9314181 AVPR CT
IA (C) 61837421 rs10877970 H G 61816874 rs7972829 H C 61824913 rs10784339 H T 61827101 rs3803107 H G 61840232 rs11836346 H A 61844229 rs7308008 H G 61849214 rs11835545 H A 61851233 rs7959001 H T 61852342 rs11832877 H C 61853617 rs10877977 H G 61860197 rs2201895 H T 61862861 rs7302323 H T 61868529 rs10877986 H A 61884651 rs2030106 S NA 61824725 rs10747983 S NA 61833506 rs10877969 S NA 61834359 rs7294536 AVPR AT
IA (T) 61827101 rs3803107 H G 61816874 rs7972829 H C 61824913 rs10784339 H C 61837421 rs10877970 H G 61840232 rs11836346 Tag Tag RSIDs of SNP Polymorp Polymorph- Polymorph- Polymorph-Gene (IRP) h-isms ism RSID Cohort LD Allele ism in LD ism in LD
H A 61844229 rs7308008 H G 61849214 rs11835545 H A 61851233 rs7959001 H T 61852342 rs11832877 H C 61853617 rs10877977 H T 61862861 rs7302323 H T 61868529 rs10877986 H A 61884651 rs2030106 AVPR CT
IA (T) 61890334 rs1495027 H T 61807179 rs10877962 H T 61830476 rs1042615 H G 61900977 rs16856 S NA 61825030 rs36014760 S NA 61826743 rs11174811 S NA 61828619 rs34462214 S NA 61831947 rs3021529 S NA 61833506 rs10877969 S NA 61834359 rs7294536 S NA 61824725 rs10747983 NA as used above indicates that the LD allele with the information currently available to the inventors could not with any confidence be assigned without further routine analysis, due to the lack of suitable information currently available regarding the corresponding allele designations. However, it would be well within the abilities of a person of skill in the art to make LD allele designations for the NA polymorphisms using routine analysis.

It will be appreciated by a person of skill in the art that further linked polymorphic sites and combined polymorphic sites may be determined. A haplotype of vasopressin pathway associated genes can be created by assessing polymorphisms in vasopressin pathway-associated genes in normal subjects using a program that has an expectation maximization algorithm (i.e. PHASE). A
constructed haplotype of vasopressin pathway associated genes may be used to find combinations of SNPs that are in LD with the tag SNPs (tSNPs) identified herein.
Accordingly, the haplotype of an individual could be determined by genotyping other SNPs or other polymorphisms that are in LD with the tSNPs identified herein. Single polymorphic sites or combined polymorphic sites in LD may also be genotyped for assessing subject response to vasopressin receptor agonist treatment.

It will be appreciated by a person of skill in the art that the numerical designations of the positions of polymorphisms within a sequence are relative to the specific sequence. Also the same positions may be assigned different numerical designations depending on the way in which the sequence is numbered and the sequence chosen, as illustrated by the alternative numbering of the equivalent polymorphism (rs3803107), whereby the same polymorphism identified C/T at position 3536 of the NM_000706.3 (GI:33149325), which corresponds to position 201 of SEQ ID
NO:9.
Furthermore, sequence variations within the population, such as insertions or deletions, may change the relative position and subsequently the numerical designations of particular nucleotides at and around a polymorphic site.

Polymorphic sites in SEQ ID NO:1-10 are identified by their variant designation (i.e. M, W, Y, S, R, K, V, B, D, H or by "-" for a deletion, a "+"or for example "G" etc. for an insertion).
Polymorphic sites in SEQ ID NO: 11-264 are identified by their allelic change (i.e. A, C, G, T or by "-" for a deletion, a "+"or for an insertion).

An "rs" prefix designates a SNP in the database is found at the NCBI SNP
database (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Snp). The "rs" numbers are the NCBI
rsSNP ID form.
TABLE 1C below shows the flanking sequences for a selection of vasopressin pathway associated gene SNPs providing their rs designations and corresponding SEQ ID NO
designations. Each polymorphism is at position 201 within the flanking sequence, and identified in bold and underlined.
GENE SNP SEQ FLANKING SEQUENCE
ID
NO:
LNPEP rs 18059 1 TTAAGTTAGATGATTTTCTGAGGTCTCTTCTAATGGTTAAGATTTTTATC
ATTTTCTATTTCATAAGGCTTTCAGCTAGCAGCCTTAATAAAAACCAGTG
CCTGGAACATGACCTGGCCTGTAGTGACACTCAGTAAACGTTGAGTGAAT
AAATGATTGAAACACACCAGAAACAAGTGCATTTGAGTGCTTTTACACAC
YGTGCTTAGTGCTTAATGTAGATTACCTCATTTAATTATCACACAGTGCC
AAGGTAGATATTTCTACCCCCATTAAATAAACGAGGAGACGGAATAGCTT
CTTTAAAGTCACTTACCTAGTAAGTGATAAAGCTGAAATTCAAACCCAGA
TAAATTTCACTCCAAAGACTTCTGTTTCTGTTATATTGCTATTTGTAAAA
TCAATTTGTGTCCTAGCAACGTCGTCTTTCCAGGATACCTTTAGAAAAAT
TAAAGCTTTCTTCTTGTCATATTCTTTTGAAAAGCTTGCAGACCATATAT
TTAAGGTTTCAAGTGACTGGCCCACATCTAGTTGTTCTCCTAAAAATGAA
ATTGTCAACTTAAGAGA
LNPEP rs2771 1 2 TTTTTTCTATTCTCAAAAGAAAGGTAGCAGAGAGGGTGACTTCAGGCTTC
TTTTATGCTGTAATACTTTAGTATAGTGTATTATTTTGATGCTTGATGGT
TGGTTAAATCTTTAATATATTTTCTTTCTTTTTTTAAATATATTTTCATG
TGTTCTAATTCAAGGGTTGTTGGGTTAGTTCATTAGTTCAGTTGTATATA
RGAGTTATGTTTGGTCAATGTATTTGTCTCCTTTTCTCACATACATGAGT

TTTGAACAATTAGTATTTATTGTGCACAAGAAATGCTGATGGGGCCATTT
TTCCAGTTTACATATTGAGGAATTATATTTTTTAAAGTTTCCCTCTTCCC
TTTCTTCCTCCCTCTCTCTCTCTCTTTCTTATCCACATTTTACTCAGACC
TAAGATCTTTAACTATAGGAGATTTTCGTATTAAATCTAATGCAAAACAT
TCATGTTT
LNPEP rs38041 3 TGTGGGGAAGAATCTCTTTCCCTAAGTTGCACCCTTCTGACAACTCAAAC
TGTAGCTGTCAGGGCTGGATTTTTTTTTTTTTTCATCTCCTGCCGGAATG
GGGTTCTCTGTTAATTTTGGAGAGGGGGTTTCTGAGAAAATGGCAAAGGG
TACTGTTTGTATGACATGGAGAGAAAGAAAGAAAATTATATGGGTACATA
RCACCCCCATTCTTCCCTAACACCTTGTCTCTATTTTGCCCTAGATGAGG
TGCTTAACTAGCATTGGGTATGGTTTGGGTGATGTCATGACAGTGGCAGG
ATATGAATAGGATGTATTCTGGTCAGTTTATTTTCTACATCAAACACCTT
ATATGAATCTAGCCTTTGTGAAGACTTCATGACAAGCTGGCATATGAGCA
LNPEP rs10051637 4 TGGCCAGCCTACTATTCTTTATAGCCTGGCTTTGCTTCACTTTTCTACTG
GTGCTTGTGATAGAACAATGAACCAATTAATTTTTTTAAAATTCCATCCT
TAACATGTA.AATGAGGAGGAAACCAGGTCATTTGCCAAATAAGGAAAATT
CA.AGCTTCCAAGGGAGTTTCAAAAAACAATGGAGGATCAAGTTCAATTGT
RGGAGACTTTTTGAAATTCTTTTTCTTCTAATACATATTGCTTAATGAAG
GTACTCCTGGGCATTCCACATATTTCAAAAATGTAGTCACTGAACCAGAA
CTTGAATCAGTTGTCTGAATTTCTCTGGATTGTGGGGCTCAGAGTCTTCT
CCAGCCAATGATCTGGGGTGAAGGAAGTTAAAGAAGGCTTCTTCAACTGA
AVP rs1410713 5 GCTATTAGATCTAATAAGTACATTTAGCAAGATCACAGGGTACAAAGTCA
ACAATAATTCATAATTCTATATACTAACAATAACTACTTGGAAATTAAAT
TTTAAAACACAGTACTATTTAAAATAGTGTGAAAAATATGAAATCTTTTG
GGTAGAAATCTTACATAATATATACAAATTCTATATGCTGAACTAATAAA
MTGCTGATGGAAGAA.ATAGAAGACCTGAATAACTGGAGAGATATATTTGT
TTATTGATTTGGAAGACTCATCAGAGTAAAGATGTCAGTTCTCCCCAAAT
TGATTGAAAGATCCAACACAATTCTAATTAAACTCCCAATAGGATTTTTT
TGTAGAAATCATTAAGTTGATTCTAAAATTTATACAGAATGACAAAGGAA
CTAGAATAGCCAAAACAATTTTGAAAAAGAACAAAGTTGGAAAAGCCACA
CAACCTGATAAAGTTATCATATTCAAAATAGTATAATATTATAGAAAGGA
TAGATCTAGGCCAGGTGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGG
AVP rs857240 6 CAGGCCTGGCTGAAATTCAGGGATGGCATCTAGGGCTTCCCCACTCCTGT
CTGGTACCCTCCACATGTCTGAGTGTCCCTCCTTGTGGCAAGGGGACAGC
CACAAAATGGGTTCCCTCTTCTGAGCCTCTCCGCTCTCAGGGAGGAGAAA
CCTGCCCAGAGTCCCCACCCCTAAATCCCTCCAGACTGGACAAGCACCAC
YAGCCGGCTGCCTTCTTTGGGTTAGGCCAGCCAAAGCTCACCCCTAAGAT
TAGGTGTGCTCACAGGCCCCTGACAAAATGGGGTCCTGTTGGTGAGGAAG
AGGAGGGACGGGACTGGCTGCTGGGTCAGTAACTGGGGTATTTGTCCCCG
GCCCCAGGCTGGAAGGCATTGGTAGACTTGTACAGATCACTTCACTTGTG
GGGACCCTGTGGCACAGAGAGACCCCGTGGCTTGTCCGGGACCACACAGC
TAAGCCGGGCAGAACTACTGAGCGAGGAGCCTATCAGTCCTGGTTCCCAA
AVP rs857242 7 CCAGAGGAAGGCCAGCTGCAAACCACTGACCCCAATGTGCGGCATCTGAG
GGACGGACACGCCCAGGGGTCAAGAGAACGGAGCCTGGGAGTGGCATCCA
CAGGGTCTGCTGTAGGCGACTCCAGTGCCTTCCTCTTGATCCCTCTGCTC
AGGTGCCTACTCCAGGGAGGGGCTGGCTTTTTGGATTAGGTTGGATGATG
MCCATCCTCAAGTGTCTGAATAAAGCTCCTTCAGAGTGAATGCAATGGAG
AA.AGGGTAGTGCCTTGAGAGGATCTCAGGATGATAGTAGGAAGGGAAATA
AATGCTGTAAAGCTAAGCAGCCCTCACCCCCACAAATCCACTGAGATCTT
TTCTTTTCTTTTAGAGAGGGTCTCACTCTATTGCCCAGGCTGGGGGGCAG
TGGCACAAACACAGCTCGCTGCAGCCTTCACCTCCTGGGCTCAAGCGATC
CTCCCATCTCAGCCTCCTGAGTAGCTGGGACTACAGACGTGTGCCACCAT
GCCCAGCTAATTACGTTACCCAGGCTGGTCTTGAACTCCTGGGCTCGAAC
AVPR1 rs 10877970 8 ATGGCTTTTTAAAATTTAAAATCATTTAAATGGTTGAGTTTAAGACTTTT
GCTCCTAATGAATTCATATTCATTTGGGTGTTCTGCATCTTCATGGTCAG
A CAGTTTTGCTATCCTGTCTAAATTTGATCATCAAGACTCATTCTTCCAGC
ATGCTGGCAACATTGAGACTACCTCTGTGTATTCATTAATTTGTTTTTCA
YGAGTGAAAAGGTTTGCATTGTTTGAAGGGTGCTGAACAAAGTTGTGATA
CTATAATTTTTTGTTTATCTGCTGTGA.ATACTATTTATTAGAATTTTTAA
ATACTTATTTGCCTCTATTTTTCTTTAGGTTTGACAGGGGTTAGTTTTTA
AAAAATATATTCTTTTTTAGGCATATTTAATTTAATTTCAGTAATCAATT
AVPR1 rs3803107 9 AATCAATTCATTGTGTATGAGACTGTGTTTCTAGTTGCATTTTCATATTG
CTACCAAAAACTAGACATTATTTTGTATGGAATATTAATGGAAACATGCT
GTACTAAAATATGCAGGTCTGATTCCCAGAAATACAACAGAAGTTATATT

A TTTAAAGGAAAAATCATAACCACCCTAGCTTTATATTTTGTTGTTAGTTT
YTTTTATTTTCATTTCTAACATAAGTAAGACTTGATTGGTTTAAAAGTCA
CATAAAATGCGGCACTATTTCTGAACAAAGAGAGCTCATCATCAGTCTTA
ATATTCAGAGAAAACTTCAGAGAAATTATGTTTTCATCCATTAAAATTAA
TTTGTGCATCAGAAAATGCAGCCTTAAACAGTGTCCAGGAGATGGGATGG
AVPR1 rs1495027 10 CATATCAAGAAGAATGTGAGTATTTTGGAGGTCCATCCTAGTTATAAGGA
AACTTCAAACCGTATCATGAGAGAAATGTTGAAAATAACTGTTTCTACTG
A AAGAAACAGTAAAGGCTCTAGATTTCAAATATTTTGAGAGTCATTATGTG
TAACAGGAATTAGACTTGTTCTGAATGTTCCTAAAGAATGGAATGAGTGT
YAAAGTTTGTAAATTTACATTTATTTGCACGATTACTTGTTTTATATGTT
TCCCCTCCGCTGGTGTCTAAGCTTCCTGATGGCAAAAGTTAGATTTGGTC
ACCAATTTATCCCCAGTGCCTAACATGCATAAGAGCCACTTATATAATGG
TTAACAGACTGAGAGAAATTTTTTTTATTCTCTAGTGTAGGAGTTAGGGT
ACAAAATAAGTTGTTATAACAAA

The Sequences given in TABLE 1C (SEQ ID NO:1-10) above and in TABLE 1D (SEQ ID
NO:11-264) would be useful to a person of skill in the art in the design of primers and probes or other oligonucleotides for the identification of vasopressin pathway associated gene SNP alleles and or genotypes as described herein.

TABLE 1D below shows the flanking sequences for a selection of vasopressin pathway associated gene SNPs in LD with the tagged SNPs in TABLE 1 C, providing their rs designations and corresponding SEQ ID NO designations. However, where a SNP in LD is also an htSNP it only occurs in TABLE 1 C above. Each SNP is at position 200 of the flanking sequence (unless otherwise indicated) and is underlined.
GENE SNP SEQ FLANKING SEQUENCE
ID
NO:
TCTTCAGACCCTCCAATAAAACTTATTTAATCCTAAATGGGTCCTGT
TAAAAATTCCTTCATTATTTTGTCATGCTTTAAGACCCAGGCAAAAC
TCTTGGTGGGCTTTTGTTAAATTCCAGCCTTTGTATAAGGGCACTGG
CTTTTAATATTTAACTTAACCACTCAGCCAGTACTGAAACAGTTGTT
ATGGAGGCCTGCRTTAGTGAGATCTGGCTTGCCACACTTGTGTTACC
CACTCTTTCCAGAGTATACTTTCTTCCCTTCTTCACCTTTTCAAATA
LNPEP CTCATCTTTTTAGGCCCTCTTCAGGTTTTCTGCATGTTTCCTTATAA
Region TATCTTCAACCTCTAGTCAGAATTTGTTTCCTTCCCTTTGTTCCCAT
rs10038651 11 TGCTTTATTTTCATTGTTAGGACAT
CAGGCAAAACTCTTGGTGGGCTTTTGTTAAATTCCAGCCTTTGTATA
AGGGCACTGGCTTTTAATATTTAACTTAACCACTCAGCCAGTACTGA
AACAGTTGTTATGGAGGCCTGCGTTAGTGAGATCTGGCTTGCCACAC
TTGTGTTACCCACTCTTTCCAGAGTATACTTTCTTCCCTTCTTCACC
TTTTCAAATACTYATCTTTTTAGGCCCTCTTCAGGTTTTCTGCATGT
TTCCTTATAATATCTTCAACCTCTAGTCAGAATTTGTTTCCTTCCCT
LNPEP TTGTTCCCATTGCTTTATTTTCATTGTTAGGACATGACTTACAGCCT
Region GATGTAAGTTTCTGTTCATTGTATAAACCTCTGCCTTTCCCAGTTTA
rs10044354 12 TTGCAGATCCTTTAGTAACTAGGAT
TGAGGATTGGTTCCAGGATCCCCTCCCCCCTACCAAAATCCACCAAT
ATTCAATCCCTGTATATTTGCATATAACCAGTTTACACGAATCATCC
CATTTACTTTAAATTATCTTTAGATTACTTACAAAACATAATACAAT
GTAAATACTATGTAAATTATACTGTATTATATTATTATTTTTGATTT
TTTCAATTTTTTWAAATCTGCCATTCAGTCTATAGATCTGGAACCTG
TAGATACAGACTAACTGTATTTGGATAATTTCATAATTTTAATGAGA
LNPEP GAAAGGGGAGAGGGGAAAGCCTGGTTTACTGCCCATGATGAAGTAGT
Region AATACAGTAAATTTAGTTGAGACATCAGCCAACCTTTTTTGAATACC
rs10058476 13 TACTAAGTACCTGGCTGAGAGAGTT

TCCATTTTTCTCTTTTTGAATTTTTTCCTTTTCACATTACTTTAGTA
ATTTGTTCTTCATCTCTTATTTTTATCACCTAGACAGAAAATATAGC
AAAGCATAAATCATTTTTCAGGTCACCATGCTTCATTCTTCTTTTAT
TGGGGAAGGGGCAGTGGTGATCCGGGAAGAAGCATAGTGTAAACATT
TTAATACAAATTYCTCTTTTTTTTTTTTTTTGAGATGGAGTCTTGCT
CTGTCTCCCAGGCTGGAGTGCAGTGGCACGATCTCGGCTCACTGCAA
LNPEP CCTCTACCTCCCGGGTTCCAGTGATTCTCCTGCCTCAGCCTCCCGAG
Region TAGCTGGGATTACAGGCATGCACCACCATGCCCGGCTAATTTTTATA
rs10061936 14 TTTTTAGTGGAGACAGGGTTACACC
ATATTCAAATCCTGGCTCTTTATTCACTAGCTCTCTGATTCTTAAGG
ATATTACCAGAATATCTTAATATCTTTAGTTAAAAACCTAAAATGTA
CATTCAAAACTTAAAACTTTTTTGAAATTAGCAGTGGTCTAAGATAA
GTGGTGGTTTGAGCATATTCCAGCCTTAGTGAGGTTTTGAAAAGCTG
GGAACTAATGGTRTTTCTTGGATCCTAATTCTTTACTAAGGGCTTGA
GGCCATTATAGGAGGATTCTTTCCATTTCATATTTATTAACAATTTT
LNPEP GAATTTGCAACACTTTCATGGAAGTGTTGCCTAAAGCATGGGTCCCC
Region AATTTGCATGTCAAGGACCATGCTAGGAACTGGGCTTCACAGCAGGA
rs10069361 15 GGTGAGCAGTGGGCAAGTGAGCGTT
ATTTGGGTCCACTAATTAGAGTTCTTCATCTTTCTTTTTACATGTGG
ATATGTGTTGCCTTTCATTCATCTGTAATTTCCAGGTCCTTAAAAAA
AAAAAGTAGATTGAGAATGCAGGCATTTTGAAGACTGGGTGCAAAAA
TCCTAGAATTCTGCCTCCCAACCCCAACCCCCAACCCCAAGGTATTA
GGTTTTTCTTGCSCATACCTAATTTGGCAGCAGTGTTATTTTGAGGA
CTCATTTTTGTAGGATCTTTCTGATACATAACTCAGTTTTCATAAAA
LNPEP ACAATTTTTATATTTTTCATTTAATGACACAATATTTAATTATTATA
Region AAACCATAATTACAAGTTTAACTAACATAAATCAGCTTGAGAACAAA
rs10071975 16 CAACTAATTCTTAGAGTAGAGTGCC
TGCTCTCTGAAATGCCCTGCTAAATGCTTCTCTTAATTATTTGAATA
AGGTAGTTTGGAATAAAGAAAGAAAAGATCACTCTACATACAGATAG
TAAACTTAATTTGTGATCCTATATATGAGACAGTATAAAAATACAGA
TAAGTTTTAGAAAGACTCAAAACAATATGTAAATGACTGATGTTTGC
ATTATTAAGGAARACTTGGGATGTTGGGTCAAGAGGGGAAAGTGTTA
GTCAATCCACTTTGGAGCAATATCATGAAGGTCAATTATAATTCCAT
LNPEP ATACCTTTCTTTGATGCCACAGTCAGAGATAGAATACAGTTTGGGTG
Region GCCATGGATGTGCCCCAATACAGTACACATTTTTTGGTTAAATTTGT
rs1019503 17 TTTCAGATCATTTCATGGAATCTTT
GGAAAGAGATGGGGAGAAAAAGAAGGAACACAGTGACTGCTCTGTTC
AAAATAGGGGTCCACATGTCCAAGATGCTGTGGCTCCCTGTGGCGGA
CATCAACGCTCTCATCCATTATGCTCCTCTTCTGTGGGAGGGAAACA
CACCTCCCATCGTGCTGCTCTTCTATGCCCAGCAGCATTGATTAGAG
AATGGATTTTCCWTTAAAAAATACATACACACACACACACACACACA
CACACACACACGCATTGCATATTAGAATTAGAGGGATTTCTGGAGGA
LNPEP ATCACCATACCTTATTTGTACAAGGTCAGCAATCTTTTATAAAAGTT
Region GTCAAAAGTTTATGTAGAGAGAGAACTGAAAACTATGCTTCCATCCG
rs10434708 18 TTATCTGTGTTGGGCACTGAGGTTG
CATATTAGAATTAGAGGGATTTCTGGAGGAATCACCATACCTTATTT
GTACAAGGTCAGCAATCTTTTATAAAAGTTGTCAAAAGTTTATGTAG
AGAGAGAACTGAAAACTATGCTTCCATCCGTTATCTGTGTTGGGCAC
TGAGGTTGGATGGTAAGACTGTGGAACAGATTTTTAAAAAATTGCAG
GAAACAGATCATYTGGTTGTGGTAGTAGGTCTTTACATGAGATGATA
CTCATAGTCTATCTTGCTTTTAATTTTCTATCTTAAAAAATAAAAAA
LNPEP CGTTATTTTTAGAAGGTTGTAGAGAAGCGATCCCCAACCTTTTTGAC
Region ACTAGGGACCAGATTTGTGGAAACAATTTTTCCACGAAGATTGGGTG
rs10434709 19 GATGGTTTTTGGATGAAACTGTTCC

TTGTATGCTGTGCTTCATTCATGGGGCTGTGAACTACTGATTATATT
CTCCCTATTCCTAATGTAGAATGCTTTATTCTACTGCCATCTTTCTG
TCTGCACTGTTTAATTAGGCTTACTGATAACAACTTTAATTCTGAAT
TTTCTTTCTCATTCAGGTTCTATTTGTAATTACTAAGACTTAAAGAA
TAGTCTGGTGAARTTACTCGAAGAATTAAGGAAGGTTTGAGCTAAAA
TGAACTAGAGACCATCTAGTACTTTAGTGTAAAATATGTTTAATACA
LNPEP AGTCGTTAAGTCCTTGTAAGTGACTATTCCAATGTTCATTCTTTGTT
Region TTTGGAAGAATGCTTGGAGTTACCATGTTTTTAAATGTGAAATTTCA
rs1046395 20 TCTAAATTAAAAAAAAAATCTCTGT
TCCCAAAGTGCTGGGATTTCAGGCGTGAGCCACCTGGCCTGGACTGT
AATTGAGGATTTTTCTGTGTCATATTCTCAACTGTTGTTGGTGTGCT
ACAGAAAGAGGAGGAAATTTTTTTTAATCTCTGAGGCGAGTAAAGGA
AACCAGAATACTACAGGACACCTAATTTTTTCAATCTTCATGAAAAT
GCAAGCTGTGAAKTTGAGGTTTGGTATCGTGAAGCCAGAGTCTGTAC
AGATAATTCGCAGCAATTAATGACCACCCTTCTTAATAATCTTCCAT
LNPEP CAGAAACCTTTTTAAGACCTCAGTGGCCAGTTGCAGCCTACCTTTGT
Region GGCTTCATCTCCAGCCACACTGGACAGCCACCCCCAGTTTCTGCACA
rs 10476696 21 TGCACTGCTCTCTTGTGTTCCCGGA

TGAGAGTTCAACCAAGTAACATTGCCCCACTAAACACAATGTTTAAA
CACAGTGGTATCCAAAATGGGATGAGGAAGTGTGCAAGAAGTGCAAT
ACATTAGAGTGTCTATTATTTCTTATCTAATTTTAAATTTTATATTG
TTATAAATTTATAAACATAAATGATATATAGTATAAAAAGTTAAATA
AATACATTATTTATTT -TTTCATGCTTTTAATTTTTTTACCATACCTTAACATATGCATATAAT
TTTTTTTAATTAATTTATTTTTTTTGAGACGGAGTTTCATTCTCGTT
LNPEP GCCCAGGCTGGAGTGCAATGGCGCCATGTTGGCTCACTGCAACCTCC
Region ACCTCCCGGGTTCAAGTGACTCTCCTGCCTCAGCCTCCTGAGTAGCT
rs10537702 22 GGGATTACAGGC

GTGTGAGCCACCGCGCCCAGCCCATATAATTTATAAATAAAAATATG
TATATTGGGAAGTTCTTGCTCAAAAAATCTTTACTGACTGGAGTATG
TAGTAACAAAAAAAGTAGGGAACACTGCTTTAAACAGAAACATAAAA
TTAAACATAAACATTGCTGAATAACTAACCATATTTCCCAAAGAAGC
TGTATCTACATTTT/-TCATTTTATAGTAAAATTTGATAAGTTTCACAGCTTTAGAATTGTAC
TGGATGAATGTTATTATGGTAATTCACCGTATCTATTGTAATACACA
LNPEP AGCTTATCACATAGTTATTAATATACATTAAAAATATAATACATGAT
Region ATAATAAACATAAGGTCAGTATTTCTATGACTTTCTATGGTGTTTCT
rs10546363 23 TTTTATTTTCAG
GGACTAAATTTAGCCTCTCTGTTAACCATCTCATATTTTCTGCAGCG
TTACCTTCTTCAGTATTTTAAGCCAGTGATTGACAGGCAAAGCTGGA
GTGACAAGGGCTCAGTCTGGGACAGGATGCTCCGCTCGGCTCTCTTG
AAGCTGGCCTGTGACCTGAACCATGCTCCTTGCATCCAGAAAGCTGC
TGAACTCTTCTCYCAGTGGATGGAATCCAGTGGAAAATTAAAGTAGA
TGTAGACTTCTGTCCTACCCTTTGTTCTTTTCTCTTTGATGTAAAAG
LNPEP TCTTTGATCAAGCAAGACATTAGGTCTAAAACCTTTTAGTGAGGATA
Region GAAAAAAAAACATGCTGGGCATTACAAACCCTGTTTCATGCTCTCAC
rs1056893 24 ATTGTAAGTGCTATGTATGGAGACT
CTTCAGAAGATTGCTGCCCACTTGTAAAGTAATCTGAAGACTGTCAG
AAAAGGAATAGTGCTTAAACTGTTTCTAGAAGCTACAGACTTATAAT
TTTCTGTTCTGTAACTATAACCAGGCTCTTCTGAATCTTAGAATCTT
ATTGTTGAAGCTTTGGTCCGTCTAGAGATTTTAATCTTAGAGACATA
CACTAGATGTGCA/-GTATTAGGCATATAGACTAAATAAATAAAACATAAAAGCACATAAAA
GAATAGTAATATTTAAAATGCATAATACAGATCAAATATAGGTAAAG
LNPEP GGTAAATATGTCAATTATATTTATGCATCCTTTTTATTTGATTTATA
Region TATTTTTTAAATCTTAGACCTTTATTGTTTCTAGTGGCCCACTGAAG
rs10707238 25 TAAGTCAGGGGC

TGTAGAATTTAGTAGCAAAAACATTTGCCATCAAAGTAGACTAGATA
ATTTATGGTAATGCTTCAAGCTATTTTCTCTTGCCAAAGCAAATCGT
AATCTTATCCAACATGTCAAACATGCTTAATAAGCTGCAGTCAGCAT
CATCACAAGCCTGACTCCCAGAAAGGGCTCAGGGATAGAGGTGGGGA
AGAGCCTGTCTARGAGTTGTGACTAGCTTGAAGAAAATGTTTTCAGA
TTATTGGATCTGTATCCATTCAGTATTTGGGGGCATTGTACCATGGT
LNPEP GAAGACCATCTCTGAGACAAGCTGCCCAGACCAAATGAAGATAGAAT
Region TCAGTCATTACCCAGTGATCTTGATAGATGCAGCTGACGAGACTGCA
rs11135482 26 GGCTGAAAAGTTTCTGCTTCCTCAG
ATCATCACAAGCCTGACTCCCAGAAAGGGCTCAGGGATAGAGGTGGG
GAAGAGCCTGTCTAGGAGTTGTGACTAGCTTGAAGAAAATGTTTTCA
GATTATTGGATCTGTATCCATTCAGTATTTGGGGGCATTGTACCATG
GTGAAGACCATCTCTGAGACAAGCTGCCCAGACCAAATGAAGATAGA
ATTCAGTCATTASCCAGTGATCTTGATAGATGCAGCTGACGAGACTG
CAGGCTGAAAAGTTTCTGCTTCCTCAGGAGATGGACAGAAGCTTAAA
LNPEP TTACTAATGACCTCCTTGGCCTGACTGCTTTCATTGCTGAATCAATG
Region AAGCAAAGATAAAATAAGACCATGACTCAAGCTGTCACGCAGCAAGT
rs11135483 27 GAGAGAATGAGCATCATCTTTGGAG
CAATGAAGCAAAGATAAAATAAGACCATGACTCAAGCTGTCACGCAG
CAAGTGAGAGAATGAGCATCATCTTTGGAGTCACACGGTCACATCCA
CATCTTGGTCCTACCGTGGAACTAGCCATGTGATCTCCAACAATTCT
GTGAACATTTCAGAGTCTCTGTTTCCTCACCTGAGAAACAACACCAA
CCTCACACCCACRTAACAGGATTAAAAGATAATGTGCAGCCTCTAGT
TCAGTTTCACTTCCTGTTTTCTTTTTCCACAGGGGTGTACTTCTTGT
LNPEP ACAACAAATAAAGGGAAAGGGGCCATTATCTGGTATTTTACTTAAAA
Region GCACAGAAGTTGAATTGATGCCAGTGTTGGAAATTATTGCATTTTAA
rs11135484 28 GAAAATAGAAATATGTAATATTTTT
TTCTTGCTGTGTCCTCACATGGTCTTTGTTCTGTGCATATGTGGAGA
GAGCGAGCTTTGCTGTTTCTTTCTATCAAGGACACCAATCCTATTGG
ATTAGGGCTCTACCCTTATGACCGAATTTAACCTTAATTACCATCTT
AAAAGCCCTGTCTCCAAATGCAATCACAATGGGGGTTAGTGCTTTTT
TTCTTTTTTTGGSGGGGGGCGCGGGGGACAGAGTCTTGCTCTGCCAC
CCAGGCTGGAGTGCAGTGGCGCGATCTCAGCTCACTGCAAGCTCCGC
LNPEP CTCCCGGGTTCACGCCATTCTCCTGCCTCAGCCTCCCAAGTAGCTGG
Region GACCACAGGCGCCCACACCACGCCTGGCTAATTTTTTGTATTTTTTA
rs11135485 29 GTAGAGACGGGGTTTCACTGTGTTA

ATATTTTATTTTTAAAGTAAATTTATACAACTTTTGTAAGTTCTAAA
TTAATTTGAATATAGTTTGTTTTAACTATAGTATCAGTATATCTTTA
AGATATTGTAATCAGGTTATAGATAATTAATATGACACTTCAGCCAA
TTATTTAAAAAATTCCTGAGGCTGTAAATATCCTGTGGGTTAATTGT
TTTCTCTCCCCCC/-AGTGGTTTGGCAATCTGGTAACAATGAAGTGGTGGAATGACCTATGG
CTAAATGAAGGTTTTGCCACTTTCATGGAGTATTTCTCTTTGGAAAA
LNPEP AATATTCAAAGAGCTTTCTAGTGTAAGTACAGGGTTTCTTTGGCCTA
Region CTATGAATGCTAGGAGGAAAAATAGTCAAATCACATTTTCATGTATT
rs11311774 30 TTCTGTGCATCT

CCCTTGCCTCCTCACTCCCTCGGCCTACTCCTGTTTATTCTTCAGAT
CTTAGCTCAGCCATTGCTTGCTCCAGGAAACCTTTCCTTCCCTGAAG
ACAGTTTAGATGCCCTACTTAGGTTTTTTAATAACATTCTCTACTTC
TCCACTCATAATATACTGTAAGTACTGTTCACTCATATCTATCCTCA
TATTAGGTATTT C/_ CCCCATTGACGGTAGTGATCATGGCTATATGAATCACTGTAAATCAC
TTTTAGCACTTAGTAGGCACACAAAAACTTAATGAATTAGTAAATTT
LNPEP TAGTCCATAATGAAGTGACTCCAGTCTCACTATAAAAATTTCTAGGA
Region AAAGAACATGCAAAGCCTGATAAAATGATGTTTTCTTTTTCTCTTCC
rs11414909 31 TCTTCTTAGTAA

CTTTTCTTACAGTATTTTATCAGTACCTTCCTCTTTATTGGAGCTTA
GAAATAGATTTCAAATAGAATTCAGCAAAATTAAATTCTGTAGAATT
TAGTAGCAAAAACATTTGCCATCAAAGTAGACTAGATAATTTATGGT
AATGCTTCAAGCTATTTTCTCTTGCCAAAGCAAATCGTAATCTTATC
CAACATGTCAAAMATGCTTAATAAGCTGCAGTCAGCATCATCACAAG
CCTGACTCCCAGAAAGGGCTCAGGGATAGAGGTGGGGAAGAGCCTGT
LNPEP CTAGGAGTTGTGACTAGCTTGAAGAAAATGTTTTCAGATTATTGGAT
Region CTGTATCCATTCAGTATTTGGGGGCATTGTACCATGGTGAAGACCAT
rs11750025 32 CTCTGAGACAAGCTGCCCAGACCAA
TAAAATTCTAAGCCTCCCAAGTGACTGAACAGACCATGTCTTGGCCA
AGGGGACCCCAGGGTAACCTTGAAAACTAAATTCTCATTCATGACAG
GATGCCAGGGTCAAACAAGCCTTATTATACCCCTTCCTCAATATTCA
GGATTAGCCTTTCTTCCCTAAGGGCTAAACGGAAACCAGCCCTTTTG
AAAGATTCCACCMCTAATATCAACCAACCACCTGATATTGCCTCTAG
TTTTTTGCCTGATAAGAGATCACCACATGGAGTGGTTCTGGCCCATC
LNPEP TCCAGAGAATGCACAGTAAGAGTTTTCATGTCCTCTGCTTCACCTTT
Region TGATGTCAGAGGACTGAAAACTCCACCCTCGGATCATGTTAACACTG
rs1216565 33 CCATTTTTTGTATATGGGACCCATG
GTGCTGGGATTATAGACATGAACCACCACGCCTGGCTATCTTTTCAT
TTCTTGATACTATCCTTTGAAGCATACTTTGTTGATACTTATCTTCA
ACCTTATTTCCATTACAATGAAGTTGTTATGAGTTGAATAGTGTCCT
CCAAAATTTATCTGTTAAATTTATAATCCCCCATATTTCAGAATGTG
ACCTTATTTGAARTAGGGTTGTTGCAGATGTATTAGTTAAGATAAGG
TCATACTGGAGTAGGGTGGGCTTCCAATTCAATATGACTAGTGTCCT
LNPEP TATTAAAAGAGGAAGTTTGGACACAGGTATGCACACAGGAAGAATGT
Region CATGTGAACACTGGAGTTACTTGCCACAAGCCTAGGGACTATTAGAA
rs1216566 34 CCTAGGAGATAGGCCTAGAACAGAT
TTGCTCTTTTGCCCAGGCTGGAGTGCAGTGGCATGATCTCTGCTCAC
TGCAAACTCTGCTTCCCAGGTTCAAGTGATTCTCATGCCTCAGCCTA
TTGAGTAGCTGGGATTACAGACACAGACCACCATACACAGCTAATTT
CTTGTATTTTGTATTTTTAGCTAAGCTGGTCTCAAACTTCTGGCCTC
AAGTGATCCGCCYACCTCAGCCTCTCAAAGTGCTGGGATTATAGACA
TGAACCACCACGCCTGGCTATCTTTTCATTTCTTGATACTATCCTTT
LNPEP GAAGCATACTTTGTTGATACTTATCTTCAACCTTATTTCCATTACAA
Region TGAAGTTGTTATGAGTTGAATAGTGTCCTCCAAAATTTATCTGTTAA
rs1216567 35 ATTTATAATCCCCCATATTTCAGAA
TCCCAAAGTGCTGGAATTACAGTCCTTTGCCTACTTTTAATTGGATT
ATTTATCTTTTATCATTAAATTTAAAAATTCTTTATATATGCTAGAT
ACAAGTCCCTTGTGAAGTCCCTTGGTTTGTAAGTATTTTCTCCTATT
CTGTGAACTGTCTTTTCATTTCTTTCTTTCTTTCTTTCTTTGAGACA
GAGTCTTGCTCTKTTGCCCAGGCTGGAGTGCAGTGGCATGATCTCTG
CTCACTGCAAACTCTGCTTCCCAGGTTCAAGTGATTCTCATGCCTCA
LNPEP GCCTATTGAGTAGCTGGGATTACAGACACAGACCACCATACACAGCT
Region AATTTCTTGTATTTTGTATTTTTAGCTAAGCTGGTCTCAAACTTCTG
rs1216568 36 GCCTCAAGTGATCCGCCCACCTCAG
AGCCTGGGCAACCTGGTGAAACCCCGTCTCTATGAAAAATAAAAAAA
TTAGCCAGGCATGGTGATGCATGTCTGTAGTCCCAGCTACTTGTGGG
GCTGAGGCGGGAGGTTCGCTTGAGCCTGGGAGATCGAGGCTGCAGCG
AGCTGAGACTGCACCAGTGCACTCCAGCCTGAGCAACAGAGTAAGAC
CCTGTCTTGAA.AMAAACAAACAAACAAACAAAAATGGTAGATGAATG
TTCATAGCTGCATTATTCACAATAGCCAA.AAAGTATAAACAACACAA
LNPEP ACGTCCATCAACTGATGAATGGATAAATAGAATGTGAAACATTTATA
Region TGTATAATAGAATATTATTCAACAATAAAAAGAAAGTACTGACATGT
rs1216569 37 TAAAACATAGATGAACCTTTTAAAA

TTGAATGAAATCTGTACCTTTTTAAATAGTAGCAACCAGATGGGGGA
AAACAAACTTGCTTGAGCAATGGTGAATGGAGATACTCACAGTATAA
TTTGCTTTTTTTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTC
GCCCAGGGCTGCAGTGGCGTGATCTCGGCTCACTGCAACCTCTGCCT
CCCAGGTTCAAGYGATTCTCCTGCCTCAGCCTCCCAAGTAGCTGGGA
CTACAGGCGCGTGCCACCACGCCCGACTAATTTTTTGTATTTTTAGT
LNPEP AGAGATGGGGTTTCACCGTGTTAGCCAAAATGGTCTCAACCTCCTGA
Region CCTCATGATCTGTCCACCTGGGCCTCCCAAAGTGCTGGGATTACAGG
rs1216570 38 CTTGAGCCACCATGCCCAGCCATTA
AACCATAGCAAACGCCCATTTGCCTCCGAACCATCTCTGCCACCAGC
CTTCTAGTAGCCCAGACGTATTTCCCCATAGTCTCACAGCCTCACGC
CTCTGCCAGTAACCCCTCCACACACTTGACTAAATGGTTTTGCTGCT
GAGTTTGGTCAGAAGACCACAATAATACCCCAGCTCTCAGCCCCTAC
CATAAGACAGCAYCTCCTCTGCTGGGAGTGGATATCCAGAGAACACT
GGTTGAATCAGCTTCCTAAAAATGGAGACGGTTGTTGGGGAAAATTA
LNPEP ATTTGCTGGATAGAGTTCTTAAAAATTACAGCCCTGTATATACTTTG
Region ACTTTTCTTACAGTATTTTATCAGTACCTTCCTCTTTATTGGAGCTT
rs12189125 39 AGAAATAGATTTCAAATAGAATTCA
TGCTAAATCTGGGTACTGGAAAGGATAAAGAGAGGGCAGAGCAAAGG
CCAGAGGTTTCATCTTTGTGGAAGGTCTGTATTCAGAGCAGAGAGGA
AGTTGAAGCCCAACTCAAACAGGCAGATAAAGAGAGATCAAAGAGAT
GAGCATGAGATACAGTCCCCTCGTGCCCAAGGAGACAGGGTGGTTAC
AGACATGGAAAAKCTGAGAATAATCACCTCTGATAAAGATCACAGAA
GCTGCCCGGGAGGTGTTTGGTAAGCTTGGAGTTACGTTTGTGGGGTG
LNPEP GATGGGCAGAAGTCAGATTTCATAGCACTGAGGATGCAGCACAAGGA
Region GAAGTTCAAGATCAATTCCTAAGACAACAACTTGGCACTAAAAAACA
rs1230358 40 TAAACTATGTTCTGAAGGCTTTACC
TTGAGAGAGAGCCTCGCTCTGTCGCCCAGGCTGGAGTGCAGCAGCAC
GATCTCGGCTCACTGCAACTTCCACCTCCCTGGTTCAAGCGATTCTC
GTGCCTCAGCCTCCCGAGTAGCTAGGACTACGGGCATGTGCCACCAT
GCCCGGCTAATTTTTGTATTTTTAGTAGAGGTAGGGTTTCACCATGT
TGGTGAGGCTGGYCTCGAATTCCTGACCTCAGGTGATCTGCCCACCT
TGGCCTCCCAAAATGCTGGCATTACAGACCTGAGTCACTGTGCCCGG
LNPEP TCCTGTTTCTTTATCTGAACACTAAGGACTTGTACTAGCTGGCCTTT
Region ACAACCCTTACTAGTTCTAAAGTTAAAGACTGTGTGAGTAAAGCTTT
rs1230360 41 TCTCTCTACTCTTATCAATCAAGTA
GGGCAACATGGTGACACATTGTCTTTCAAAAAAAATAAAATATGGCC
AGGCGCAGTGACCCACGCCTGTGATCTCAGCACTTTGGGAGGCTGAG
GCAAGTGGATCACCTGAGGTCAGGAGTTCGAGACTAGCCAGGCCAAC
ATGGTGAAACCCCGTCTCTACTAAAAATACAAAAATTAGCTGGGTGT
GGTGGCACATACYTGTAATCCCAGCTACTCGGGAGGCTGAGGGAGAA
GAATCACTTGAACCCCAGAGGCAGAGGTTGCAGTGAGCCAAGATAGT
LNPEP GCCACTGCATTCCAACCTGGACAACAGCGAGATTCCGTCTCAAAAAC
Region ATAAATAAATGAATAAAAATAAAGTAGGCTGGTCACAGTGGCTCACG
rs 1230363 42 CTTGTAATCCCAACAGTTTGGGAGG
CAGCACTTTGGGAGGCTGAGGCAAGTGGATCACCTGAGGTCAGGAGT
TCGAGACTAGCCAGGCCAACATGGTGAAACCCCGTCTCTACTAAA.AA
TACAAAAATTAGCTGGGTGTGGTGGCACATACCTGTAATCCCAGCTA
CTCGGGAGGCTGAGGGAGAAGAATCACTTGAACCCCAGAGGCAGAGG
TTGCAGTGAGCCRAGATAGTGCCACTGCATTCCAACCTGGACAACAG
CGAGATTCCGTCTCAAAAACATAAATAAATGAATAAAAATAAAGTAG
LNPEP GCTGGTCACAGTGGCTCACGCTTGTAATCCCAACAGTTTGGGAGGAT
Region TGCTTGAGTTTAGGAGTTTGAGACCAGCCTGGGTAACAGGGAGACCC
rs1230364 43 CCATCTCTACAAAAAAGGTAGCCGA

CCGTCTCTACTAAAAATACAAAAATTAGCTGGGTGTGGTGGCACATA
CCTGTAATCCCAGCTACTCGGGAGGCTGAGGGAGAAGAATCACTTGA
ACCCCAGAGGCAGAGGTTGCAGTGAGCCAAGATAGTGCCACTGCATT
CCAACCTGGACAACAGCGAGATTCCGTCTCAAAAACATAAATAAATG
AATAAAAATAAARTAGGCTGGTCACAGTGGCTCACGCTTGTAATCCC
AACAGTTTGGGAGGATTGCTTGAGTTTAGGAGTTTGAGACCAGCCTG
LNPEP GGTAACAGGGAGACCCCCATCTCTACAAAAAAGGTAGCCGAGTGTGG
Region CGGTGTGTGTCTGTAGTCCCAGCTACTCTGGAGGCTGAGGTGGGAGG
rs1230365 44 ATCACTTGAGCCCAGGAAGTTGAGG
AGTATTCTATAGTTTGCCCAACCAGTTTTACGTCCAAGGAAAATTAG
CCAATGCATAAAATATACAAACTATGAAAGGCAAGGATCAGGAAACC
AGAGACTTTGCCACCAAATCTCAGATTATTAGAAACTAGGTGTCAGG
GTTTATCAAGAAGGCCAGGAAGGCCTTTTGGGTTAAGCCTTACATTC
ATGAAGAACCTCRAGGGTAGATTTTTGAGAGCATTCCAAATGAATGG
TCTCTGGTCAAATGAATGAATGGTCAAATGAATAAATCTGCCCTCAC
LNPEP AGAGATACAAAAGGAAAAGGAATATAATTCATACCATTTGGTTTAAG
Region CCTTACATTCATGAAGTACCTCAAGGGTAGATTTTTGAGATCATTCC
rs1230381 45 AAATGAAGTCGAATCTGCCCTCACA
ATCAAGAAGGCCAGGAAGGCCTTTTGGGTTAAGCCTTACATTCATGA
AGAACCTCAAGGGTAGATTTTTGAGAGCATTCCAAATGAATGGTCTC
TGGTCAAATGAATGAATGGTCAAATGAATAAATCTGCCCTCACAGAG
ATACAAAAGGAAAAGGAATATAATTCATACCATTTGGTTTAAGCCTT
ACATTCATGAAGWACCTCAAGGGTAGATTTTTGAGATCATTCCAAAT
GAAGTCGAATCTGCCCTCACAGAGACACAAGAAAGGAATATAATTCA
LNPEP TACACTATTGCATTTTTAATAAATCTTTTGAAATTTGCAGAATTAGA
Region TTGTATTGTGTATTTTCGGTTAAATGATAATTGAATGTAAATATTTA
rs1230382 46 GATGCAGCACCATATTTTATAACCC
CATAATGAAATACTTCAAGTGAAATTTGATGGGTTGATGATCCTGGG
CACATACCTAACTCTCTGAAGTTCAGTGTCCCCATCTATAAAATTAA
GTTAATAATAGTTCTGTTTCATAAAGCTGTTCTGAGGATTATGGATA
GGGAAAGTGTGCGGATCACATAGTAAGCACTCAATAAGTATTAGTTA
TTAATGATGATGWCAACGGCCACTACAACTACAAGAAATACTACTAT
TTCTTGCAAAATAACTTATCTAAGGGCCATCTATCAACACTGTATTA
LNPEP CATACAAATGTGGAATTGTAAAACTAGGTCTATAGATATTGGAGACT
Region ATTCCCTCTATTTCATTTCTGAAAACTCTCAGTAATGCAGTAAATTA
rs12516666 47 TTAAAGTCACCAAAATTGTCTTTCA
TTCTTTTTTCCCTCTCATTTAGTTCTTTTTTAGTCTTGATTTCCCCA
CGGAGAGTCTCATCTATTCACATATTCTCATTTTTTCCTTTTTAAAA
TACATCTTCCTGCTTAATGATGGGGATACAATTGAAAAATAATAAAA
CACGTCTTCTTCAGGGATTCTTTTTTATTTATAATGGCTACTCTAAA
GACTCACTAAATRCAATGCAATATCTGGACCACCTTAAGATTGCTTT
CTAATGATTTTGTTTACTTAGGGTTCACATTTTCTTGTTTCATTAAA
LNPEP TGTCTAGTAATTTTTTATTACATATTGAATAGTGTCAATGGCACATG
Region GTAGAGATGCTGAATTP.AAAAAAACTCTGTAAAATGTTGATTTTTCT
rs12716486 48 CTCTCTGTCTCTGTAGACAGCTTAG
CAACAATTCTGTGAACATTTCAGAGTCTCTGTTTCCTCACCTGAGAA
ACAACACCAACCTCACACCCACATAACAGGATTAAAAGATAATGTGC
AGCCTCTAGTTCAGTTTCACTTCCTGTTTTCTTTTTCCACAGGGGTG
TACTTCTTGTACAACAAATAAAGGGAAAGGGGCCATTATCTGGTATT
TTACTTAAAAGCMCAGAAGTTGAATTGATGCCAGTGTTGGAAATTAT
TGCATTTTAAGAAAATAGAAATATGTAATATTTTTATGCTTTCAATC
LNPEP AACAAAATGAGATTTGGCATTTTTGTGCTTTGGGGATCTCAAAAGCA
Region GGGCTTTTTGTTTTCAACAGAGTGTTGGGGTAAAAGCAATGGAGGTA
rs13167902 49 AGAGAGGCTACAGAATACTAGGAGA

AGCCAGGAGTTGAGGTTGAAGTCACCATTGCAGATGCTTAAGTCAAC
TATTTTAATAAATGATTACCAGTTGTTTAAAAAAAAAAAAAAGAAAA
CTATAGAGAGCTATCTACCTTTTGGGACTACCATGGTAGCAGTCATT
TGCTGTTCCTTTTTTTGGGAGGGACGGGAACAGGGTCTTGCTTGGCT
GGAGTGCAGTGGYACGGCCACAGCACTGCAGCCTTGACTTCTCAGGC
TCAAGCGATTCTCCTGCCTCAGCCTCCCGAGTAACTGGGACCACAGG
LNPEP TGCACACCACCATGCCTGGCTAATTTTTGTATTTTTTGTAGAGATGG
Region AGTTTTGCCATGTTGGCCAGGCTGGTCTCGAACTCCTGGGCTCCAAT
rs13170029 50 GTTCTGCCTGTCTTGACCTCCCCAA
ATACCTTGTAGCCTACATAGTTTGTGATTTCCACTCTCTGAGTGGCT
TCACTTCATCAGGGGTCAAGGTGAGACTGAGTTCTAACGTTCTACGC
AGTGCAGAAAAGTGTCCTGAGAGCAATGAACTTTTGTTTTCTCATGT
TTTTCATTGTTATCAAAGTATTATGTTTATATTACAAGAAGAGATAG
ATAAAAAACTAARTTAAAAATTATCCATAGTCCTGTCACCAAGATAC
AACTACTGATAATATTAATGTAAGCCTTCCAAATATTTTCTATATGT
LNPEP ATGTCAGCATATATGGGTGTACATAGTAACAGTATTTACTTACTATA
Region TATGTAAAGGTAATTTTCAAAGTATATATATATATATATATATATAT
rs13189819 51 ATACACACACACACACACACACACA
ATTCAGCCAACTACTTTTAAAATTTATCTTTTTTTTTTTTTTTTTTT
TTTTGAGACCAAGTCTCACTCTTTTGCCCAGGCTGGAGTGCAATGGT
GTGATCTTGGCTCACCACAACCTCTGCCTCCTGGGTTCAAGTGATTC
TCTTGCCTCAGCCTCCCGAGTAGCTGGGATTACAGGCATGTACCACC
ACACCTGGCTAAYTTTTGTTTTTTAGTAGAGATGGGGTTTCACCATG
TTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGTGATCCACCTGCC
LNPEP TTGGCCTCCCAAAGTGCTGAGATTACAGGCGTGAGCCACCGTGCCTG
Region GCCAAAATTTATCTTAATTCAGACTTTACAATTGACTTTATTAAATA
rs13358339 52 AATATTTTTAAGTAGAAGAAATGTT
AAATCATTTAACTTCTTTAGCCACATTGTGGTCACTTGTAAGATGAG
GATTTATAATTTTTGTCTTACTTTACCTATTGTTTGAAAATAAAGTG
AACAATTATGCAGAAAAGTAGAAAATAACCTTTTAGAGGTTGGCAGA
GAAATGCCTATACCTGTGTGTATGTAATTTGCAAGCTCTTTTGAAAA
TTTTTGGAAGACRAAGTGGTTTTATTGTTTCTTTATTTTTGAAACTG
CCTCGCTCTGTCAGCCAGGCTGGAGTGCAGTGGCACCATCTTGGCTC
LNPEP ATTGTAACCTCCACCTGCTGGGTTCAAGCAATCCTCCCGCCTCAGCC
Region TTCCAAGTAGCTGGGACTACAGGCATGCACCATCATGTCCGACTAAT
rs1363907 53 TTTTGTTGTTGTTGTTGTTATTTTT
GGGTTCAAGCAATCCTCCCGCCTCAGCCTTCCAAGTAGCTGGGACTA
CAGGCATGCACCATCATGTCCGACTAATTTTTGTTGTTGTTGTTGTT
ATTTTTTGTAGAGTCAGGGGTTCTGGCATGTTGCCTAGGCTCGTATT
GAACTCCTGAGCTCAATTGATCTGCCCACCTTGGCCTCCCGAAGTGC
TGGGATTACAGGYGTGAACCACCACACTCGGCCAAGACAAAGTGTTA
GTAATTTTTTTCTTCAATATTTTACAGGTGAAACTATTTTTTGAATC
LNPEP TCTTGAGGCTCAAGGATCACATCTGGATATTTTTCAAACTGTTCTGG
Region AAACGATAACCAAAAATATAAAATGGCTGGAGAAGAATCTTCCGACT
rs1363908 54 CTGAGGACTTGGCTAATGGTTAATA
AACTTTTGCAGGTTCATGCACAGATTTAAGGGATCCTCTTTTCTGAT
TCTCTCCCCTCTGGGATTTCCCCCATGCTGTATAGCCTACAGGGTCT
ACTTCTGGTTTCTCTGGATAGAAATATGGGACTCATTGGAATTTTAC
CTGTTGGCATTTCCACACCACTCTGTGACCAAAGCCTGCCTTCAGGG
CAAAGTAGAGAARGGAAATGGAACAATATTAAAACAGAAACTCACCC
CTGTGTGTTTTGCTTCAGCAAGTTTTTGACCCTATAACCTATTATAA
LNPEP AGTGAAATGAAAATGTGGACACCTGTGAAGCGGTCCGAGTGCAAAAT
Region TTGTCTAGACTTTCAATTTTTTTCCCCAGTCTTTTAGAGTTGTCTCC
rs1363974 55 TACCTAATTCAACAACAATTTTAGT

GCATGAAGGAGAGCTGCCAAGTTCTGTGTCTTGATAACCTTTCCTTC
CATTCCTAGTTCAATTAACCTGAAGAAAGAAAAATAATTTGTTTCTA
AATAGTAGGTATTATGTACATGGACATTAACTCAAGCCACCAATATA
TTAAAAGAATAGAACAGAAAGAGGCATGATAAAAGTATAATTACCAA
TTTTTTAATGTTYCAATTAAACTTTTACTTTTTTAGAAATAATTTTT
ATTTTGTTCCTATCAAAAACATTTACTTATTATTTCAAATAAGTTTG
LNPEP ATTAGCATCATTTACACATCTTATATGCAAGAATGTATTTTTACAAC
Region AATAATTTTTCTTCAAGTTTCTGAAGATAAAACATAACCGCTTGTCT
rs1363975 56 AGTCTCAATCATATGATTAATAACT
CTAAATAGTAGGTATTATGTACATGGACATTAACTCAAGCCACCAAT
ATATTAAAAGAATAGAACAGAAAGAGGCATGATAAAAGTATAATTAC
CAATTTTTTAATGTTTCAATTAAACTTTTACTTTTTTAGAAATAATT
TTTATTTTGTTCCTATCAAAAACATTTACTTATTATTTCAAATAAGT
TTGATTAGCATCRTTTACACATCTTATATGCAAGAATGTATTTTTAC
AACAATAATTTTTCTTCAAGTTTCTGAAGATAAAACATAACCGCTTG
LNPEP TCTAGTCTCAATCATATGATTAATAACTAGGGAATACCTGTTTTCAC
Region TATTTGCATTTTGTCAATATATTCTTTTCTGAAAGTAAAGTTAAAGC
rs1363976 57 CATACACATTCTGATTCAATTATCT
AATTACCAATTTTTTAATGTTTCAATTAAACTTTTACTTTTTTAGAA
ATAATTTTTATTTTGTTCCTATCAAAAACATTTACTTATTATTTCAA
ATAAGTTTGATTAGCATCATTTACACATCTTATATGCAAGAATGTAT
TTTTACAACAATAATTTTTCTTCAAGTTTCTGAAGATAAAACATAAC
CGCTTGTCTAGTMTCAATCATATGATTAATAACTAGGGAATACCTGT
TTTCACTATTTGCATTTTGTCAATATATTCTTTTCTGAAAGTAAAGT
LNPEP TAAAGCCATACACATTCTGATTCAATTATCTTATGCCTTTAAAACTG
Region GTGGCTGAAGTTTTAGTGACTTCACTGAATTTGTGTCAGTTTACTTA
rs1363977 58 TAACAATTTAGTTAAATTATTGAAC
AACATTGTCAGTGGTGGTAGTGACGATGATGAACTTGGTTTTACTTT
TTCAGTGTCTAACCTGGTCCCGTGCTAGGACCCCAGGCAGAGCTTCC
TATGAAGTCACGTACAACAAGGCCTTTGGGCTTAAGAGAAAAAGCTC
ACAGCTGCACAGAGGGAGGAGTTTTTATATAAAGAATACAAAATGTT
CTGAATACCAAGWGTTTCATTCTCTCCTTATGTTTCTGAGTTGAAAT
TTGAAGTAATCATGAGACACTGCATGTGTTCCCATTTCAAAGATGCC
LNPEP ACAGAATCATAAAACTAGTATGTAGCATATAATTTCAATTTTGTCTT
Region AGGGGATAAATTAGTCTAAGAATAGTATACCAAAACATTAATTGTGA
rs1423357 59 TAATAGTGTAGTGATCAATTTATGA
ATCATCACACCCAGACCAATGGGAGCATTATACATGCATTATTTTTT
GTACTCAAAAGGATGAAGTATATAACTGTCTACTGTACCATGTCATT
TGAAAACACTAGAAAATTCTACAGCAATCCTTCAAAAGTTTTCAAAT
AAATACCCTGTCCATCTTAAACCTGAAAAGCACTTCAAATTGCTAAC
ATTTAATTTCTTRTTGACTGTAGATATTGTCGTTTCTGTTTTCCTTG
TAAAAGGATGCTAAATAAGGCTCCAAGGAGTGATTGCTACATTAACC
LNPEP AAAATTATGCACTGCCAAGCTGTCTCCAGCATCAACTCTGAAAGATA
Region GGAAAGAATCAGAAATCCAATTTCCTACATGAAAGTTGAAGCATTGC
rs1423566 60 TTCTTTTTTTGTTCTCTTCTGTGGG
ATCCCTCCCCAGTGCAGTTCACAATAGGGTTCATGCTCCTATGGGAC
TCTAATACCACCCTGATCTGACAGGAGAGGCGCCCAGGCGGTAACGC
TCACTTGCCCACTGCTCACCTCCTGCTGTGAAGCCCAGTTCCTAGCA
TGGTCCTTGACATGCAAATTGGGGACCCATGCTTTAGGCAACACTTC
CATGAAAGTGTTRCAAATTCAAAATTGTTAATAAATATGAAATGGAA
AGAATCCTCCTATAATGGCCTCAAGCCCTTAGTAAAGAATTAGGATC
LNPEP CAAGAAACACCATTAGTTCCCAGCTTTTCAAAACCTCACTAAGGCTG
Region GAATATGCTCAAACCACCACTTATCTTAGACCACTGCTAATTTCAAA
rs1477364 61 AAAGTTTTAAGTTTTGAATGTACAT

CATGGTGTGCAGTATGGTTGTTTCCCATGGAAATATGTTGTACTTCT
GAAAGCCATGGAAGCATGAAAAACAGATTGAATTATAATTTTATCTG
ACTTTTATTGTCTTTTGATCTTTTTAAAAATCATTTCTTGCTTATGG
AAATTTCCCATATAATTTGCTGCTTCCCATTTGCTGTGGGACAGAAA
CATTCCTCTTTCRGGGGAAAACAATAACCCATCCTGTTGCTTAGCCA
TACTCAATCTTAGAAATGGGCATACCAGCTTGTGGTGCTCCCTAGAG
LNPEP AGAATGAGACTCAGGGATGAGACCCACAAATACCTTGGAAGCAGATT
Region TGAGGCCTGTTGGACAGAAATTCTGGGATTGCAGTGCCCAAACCCTA
rs 1544777 62 GAAGGGGAACCGTGGACTGTAGGTG
TCACTCTCTCCCCACTACACACCACTGGCAGCCCCTCAACCCTGGAA
AAAGGAAATTATGCACACTATTTGCCTATACAGTCTTTCACATTTAG
GATGAAATATTGAGTTCCAAAACCTGCTCTACATTTACTTTTCTAGA
ATAACGGATACATTTCAATCCTGGTAACTTTTTGCTGTTCAAGAATT
AGAAGTTGAGGAWAGAAGGTTTAGGAAACTCTCAAGGCCCGGTTTAT
GCTGTAGAAAAAAAGAATTTCTGCATAAGTAAACTGCAATTATAAAT
LNPEP TTTGCTCCAAATATGAATAATTCCTCCAAGGAGAGGTTCATAACCTC
Region ATTCATCTTTGTATTCCTGGTGCCTAGCAGGGAAGAAACCTGCCATA
rs 1559267 63 AATGTTGAAATGAAAGTAGCAATAA
ATGAATATGTAGATATATGAGTTGTGTAGCACACATACACATCATGG
CACCTCTGCACTTAGACATGGATGTCTATGCATAGACATGGATGTGC
AGGAGGTGAATGGCACTTCAGAGGACAGGTTCCTGTCAGCCTCTTTG
GATTCACGTCCCAGCTCTACAACTTTCAGCCTGGGTGATCTGGAGCA
AGTTACTAAATCRTTATGTGTTTTTATTGCTTCACCTATAAAATGGC
ACCTGCTTCATAGAGTGGGCACAAGTATTAAATTAGATTTTATACGT
LNPEP AAGCATTCAGCACAGTGCCTGGTAAACTGTCAAAAAATGGTGGCCGT
Region TTACATTTTTTCTGCATAAAAGTTTTGAAGGACTTCAGTTAATTCAG
rs1559354 64 AACATAAAAGTGGGTCATGAAATAA
TATATACTCTTTAGTACAGATATACTAAATCCCATTTATATGTAATT
CACTGCTGTACTTTAGATCAAAAGTCAAGGAAAGATTAATAACAGCC
ATCAACAATATTAATGTTGTTCTTGAAAAATGCAGTCTTAAAGAGCA
TATGAAATATCTTTAAGACTAACGGAAAAGAAGCATGCAGCTTAGGA
AAAAATAGAGCAKATATAAGTCCCACTACTATAAAATCATCAATGCG
ATTTAGAAGAAAAGTCATTCCCACATTTGAAGTGCTAACGAATACTA
LNPEP ATCTTTATTAGCGCTAATTTAGTTTTTGATTGTGTTATGTATACTTG
Region TTTTTAATGTACTAGAATTAACCAGTATTAACTCCAGACAATGTAAT
rs1559355 65 TATAAGCCAAGTGACTTGGTTCATT
TTTATATGTAATTCACTGCTGTACTTTAGATCAAAAGTCAAGGAAAG
ATTAATAACAGCCATCAACAATATTAATGTTGTTCTTGAAAAATGCA
GTCTTAAAGAGCATATGAAATATCTTTAAGACTAACGGAAAAGAAGC
ATGCAGCTTAGGAAAAAATAGAGCAGATATAAGTCCCACTACTATAA
AATCATCAATGCRATTTAGAAGAAAAGTCATTCCCACATTTGAAGTG
CTAACGAATACTAATCTTTATTAGCGCTAATTTAGTTTTTGATTGTG
LNPEP TTATGTATACTTGTTTTTAATGTACTAGAATTAACCAGTATTAACTC
Region CAGACAATGTAATTATAAGCCAAGTGACTTGGTTCATTTCAAACTTT
rs1559356 66 TAAAAAATTATCTTTTTTTCCAGCT
TTATATGTAATTCACTGCTGTACTTTAGATCAAAAGTCAAGGAAAGA
TTAATAACAGCCATCAACAATATTAATGTTGTTCTTGAAAAATGCAG
TCTTAAAGAGCATATGAAATATCTTTAAGACTAACGGAAAAGAAGCA
TGCAGCTTAGGAAAAAATAGAGCAGATATAAGTCCCACTACTATAAA
ATCATCAATGCGRTTTAGAAGAAAAGTCATTCCCACATTTGAAGTGC
TAACGAATACTAATCTTTATTAGCGCTAATTTAGTTTTTGATTGTGT
LNPEP TATGTATACTTGTTTTTAATGTACTAGAATTAACCAGTATTAACTCC
Region AGACAATGTAATTATAAGCCAAGTGACTTGGTTCATTTCAAACTTTT
rs1559357 67 AAAAAATTATCTTTTTTTCCAGCTA

AAGAATATGATGTTATTTCTCAAAGGTACAATCTAGCTGAAATCATA
TACAAGTAAGTAGGTGTGGACTTTTACTGTTGAGCTAAGGTTTATGT
TTATATATGTTTTATTCTTTAAGCTAAACAAACATTCAGATAACATT
CTATGCATTTTTTGAAGCATAGGGTTAGTAATGAGGACTTAGATTTT
TTAATTAAACAAYTCAGTAACTATATAAAAAGAAAAGGAGTCCCTTA
TGAATAAATATTAAAA.TTAAAAGAAATAGGCAACTATAAAAGTAAGT
LNPEP ATTTTTAATAATGGCATTGATTTTAGTAAGAAATCAATTAGGCTGGG
Region CTGGAAAGAAAAACTGGCTTAATATAAAGTAGTTTTAATATGTCAAA
rs17087165 68 TATTCTTCTTAAAATTGTGGCCCTG
GCCTTTCTGGGGGAAAATGCAGAGGTCAAAGAGATGATGACTACATG
GACTCTCCAGAAAGGAATCCCCCTGCTGGTGGTTAAACAAGACGGGT
GTTCACTCCGACTGCAACAGGAGCGCTTCCTCCAGGGGGTTTTCCAG
GAAGACCCTGAATGGAGGGCCCTGCAGGAGAGGTGGCTGCTTTTCTT
CTTTAGGTCTAGYTTACCTCATCTCAGTTTCCTCGTTATTTCCTTAG
CTTTCTCTCAGCTCATCTGGCAACTTTGTAGGATGCTAGTTCCATAT
LNPEP AAGAATCAAAGGCCTAAAGTAGACTTGATAAGATTTAAAGAGCTTCA
Region TATAACCCGGACTTCTTTGTTCAGGAGCACCATTCTTAGTGATTCCA
rs171647 69 TCAGCCTTGAGAACTTCAGTTCTTG
TTGAGCCTCAAGAGATTCAAAAAATAGTTTCACCTGTAAAATATTGA
AGAAAAAAATTACTAACACTTTGTCTTGGCCGAGTGTGGTGGTTCAC
ACCTGTAATCCCAGCACTTCGGGAGGCCAAGGTGGGCAGATCAATTG
AGCTCAGGAGTTCAATACGAGCCTAGGCAACATGCCAGAACCCCTGA
CTCTACAAAAAAYAACAACAACAACAACAAAAATTAGTCGGACATGA
TGGTGCATGCCTGTAGTCCCAGCTACTTGGAAGGCTGAGGCGGGAGG
LNPEP ATTGCTTGAACCCAGCAGGTGGAGGTTACAATGAGCCAAGATGGTGC
Region CACTGCACTCCAGCCTGGCTGACAGAGCGAGGCAGTTTCAAAAATAA
rs 1820148 70 AGAAACAATAAAACCACTTCGTCTT
ATGTAGCATTGTTTCCAGGTTCTCTTAAAGGTTTTCTTTTTATCTTT
AGTTTTAAGCAGTTTTGACCATGATGTGCTTAAGACATTATTATTTG
TGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTATTTATCTTT
TTGGGGGTTTGCTGAACATTTTGGATCTGGTAAGTGGTGTTTTTCAT
CAAACTTAATAAWATTTTAACTATTATTTCTTCAGATATTTTCTTCT
GCTGCATTCTCACACTCCTTCTGTGGCTCCTGTTAGATACATGTTAG
LNPEP ACTGTCTGATACTGTCCCCCAGATCCCTGATGCTGTGTTTATTTTTC
Region TTCAATCCTTTGTCTCATTGTTCTTCAAATTGGTAATTTCTAATGAT
rs1820149 71 CTGTCAAGTTTATGGACTCTTTCTT
TTGAAAGGGGTCAGGAAAGAGACTCCAGTCTCAACCTCCTTTTCACT
GGCTTTTCCTGCCATGTATTCACCCTACTATATCCTGTATATATCCC
TCAATTCAAGTAATTTGCAGAGAGCAGCCCTGGGATAGCCATCCCTA
ATCCAGTTGCCTGGATTACCCTTCCCTGAGATACCAGTCCGAGTCTT
CTGTTCCCCAAGSCTTGTTTCTGGCATCCAAGGAGATGGAAGTTTCT
GTCCCTCTGTCTTTGGATTGTCTCCTCTCTCTTGAGTTATCATAGTC
LNPEP ACCTGTCATTTCAGCTCGCCTTTCTGGGGGAAAATGCAGAGGTCAAA
Region GAGATGATGACTACATGGACTCTCCAGAAAGGAATCCCCCTGCTGGT
rs 187265 72 GGTTAAACAAGACGGGTGTTCACTC
CAACACGGAAGAATCTATCATTTGGTGTGCATACTGGCAGTAGAGGG
TGGGAGTTAAAAAGAAAATTTGGCCAGCAATTACCAGATCATTTTAG
GCCAGCAGTGTAAATTCCTGTGTTATTTTTTGTCACATCATGCTTAT
AATCATCTCAAAAGATAAAGTAATCATCATTACTCTGTGTTTATAAG
TGAGAAAACTGAYACTAAGGGACAGATTTGCCCAAAGTCACCAAGTC
AGTGAGAAAATCAGTACTTAAAATTTGTCTTCTAAGTCCAATAGTTA
LNPEP TTCAATTATATCACAGCTAGTTCCTAGTTTTAAGAAAAGTCCCCCAT
Region CAATCTTCCCCTAAAGGTCCTAGATTTTGACCAACTCTCTTCTGACA
rs193993 73 CCAAAGGGCCCTGTAGTATTAAAAT

TTTTTCGCCTCTTGCCCTCAACTCCAATGCATTTTCCTTACATAAAT
TAAAAGGGACCATCAATTGGCATACAGTTCCAGGCTTAAAAAAATTA
AAAGCTATATCCAGGGACTTATTTCGATAGTTCCTGAGTCTTACTCT
GCTATTATTGTGCAGGTTCTATATACTCTTTAGTACAGATATACTAA
ATCCCATTTATAYGTAATTCACTGCTGTACTTTAGATCAAAAGTCAA
GGAAAGATTAATAACAGCCATCAACAATATTAATGTTGTTCTTGAAA
LNPEP AATGCAGTCTTAAAGAGCATATGAAATATCTTTAAGACTAACGGAAA
Region AGAAGCATGCAGCTTAGGAAAAAATAGAGCAGATATAAGTCCCACTA
rs1974871 74 CTATAAAATCATCAATGCGATTTAG
CCGGAGGGTGAGGCATGAGAAGCTGAGGCATGAGAATCACTTGAACC
CGGGAGGCGGAGGTTGTGATGAACCAAGATCACACCACTGCACTCCA
GCCTGGGCGACAGAGCAAGACTCCATCTCAAAAAAAAAAAAAAAAAA
AAAAAAGACGTGGTTTTGTATAAGAAGTAAAAATAGTAAACAAACGA
AATGTTTCAGAAKCCTACCTAGGAGCAAAAGAATAATAATGAAGTTT
GTTTTGTTTCAACGGATACTGTTTTACATTTGACTTCATAGAGCCTT
LNPEP TTTGAGGGAATATGATATCACAATTTCACAACCAAAACCCATTATGT
Region TTTTATCTTTAACACCCGCCTATCCTCCCACACAGAACTTCCTCTTT
rs1981846 75 AGTTTAAGAATATGACAGTTTAAGT
GACAGAGTGAGACTCTGTCTTAAAACAAAACAAAACAAACAAACAAA
CAAAAAACATATAAAGATGCTCTTTACTATCCATTTCCATCACCCAC
CGTCAGTGGTCCAGACACACTTTCTCCATGCTTCCGCTTAAGCTTCT
CAGCACCAAGTATTGTGTTGCTTCTGTCTCTCATCCCTCTCCATTTC
CCTCTCCCTTGCYATGTGTGTGTGCATGTATGTATATTTGTAGACAT
CAGTTTAGCTCCCCTCCAACACGGAAGAATCTATCATTTGGTGTGCA
LNPEP TACTGGCAGTAGAGGGTGGGAGTTAAAAAGAAAATTTGGCCAGCAAT
Region TACCAGATCATTTTAGGCCAGCAGTGTAAATTCCTGTGTTATTTTTT
rs2042383 76 GTCACATCATGCTTATAATCATCTC
CTGAGGCAGGAGAATGGTGTGAACCCCGGGGGGCGGAGCCTGCAGTG
AGCCCAGATCGCGCCACTGCACTCCAGCTTGGGCGACAGTGAGACTC
CACCTC GAAAAGAAAAGAAAAAAATGCCTTC
AACTTGGTGATAAAAAAGCATCAAGTAATCATCTTTAAAAAAAAAAT
CTTATAGCACCARTAGTGGCCACTAAATGATAGAATTTATATAAACC
AGTAGTTTTGTATTTCAGAAAGCTTTTATATTTGTTGATTACATCAA
LNPEP CTTTCTATTTTCACCTCAGAGTAGGTTAAAATTTTATGCTTATTTTC
Region TTGCTAACATTTTATCATCAGTAGGAGATAAAACACAAATAATTTGC
rs2042385 77 AGAGTAAAAGCACATAAAATATTTT
CCACCACCCCTGGCTAATTTTTTTTTTTTTTTGTATTTTTATTAGAG
ATGGGGTTTCACTGTCTTAGCCAGGATGGTCTTGATTTCCTCACTTC
GTGATCTGCCTGCCTCAGCCTCCCAAAGTGCTGGGATTACAGGCATG
AGCCACCGCGCCCGGCCTCTTTTTTGACTTTTTAACAATAATCATTC
CGGCTGGTATGARATGGTATTTCATTGTGGCTTTAATTTGCATTTTT
CTGATGATTAGTGATGCTGAACATTTATTCATGTTCGTTGGCCACTT
LNPEP ACATGTCTTCTTTTGAGAAGTGTCTGTGAGACGGCATATTCTATAAG
Region CAGTTGAGAATATCAGAGTACTAAGAAAATAATTCTGGAATAAGAAT
rs210687 78 TATAAGGCCTCTCACAGCTGTAATC
ACTGAATTAAATAAGATGTTTATACCATTGAGTCATCCATTAAAAAC
TAAAACATAAATAAAAGTATACCACAGTTATGAAACAAGAAAGCTAA
ATAAACAGGCTATTATATTTTTAAAAAGTTAGCTGAGATAATATACT
AATTTCCTTAATATACTCCTGCCCCACAACCTGGGACCCTGCCCTGG
GCTTGAGAGGGCMCTGTTTTGGCATTCCTCTGACTATGTCTGTCCCC
ACCAGGCGAGGAGTCAGTAGGATCAAAGGGATGTGCCCACCTACAGT
LNPEP CCACGGTTCCCCTTCTAGGGTTTGGGCACTGCAATCCCAGAATTTCT
Region GTCCAACAGGCCTCAAATCTGCTTCCAAGGTATTTGTGGGTCTCATC
rs2113050 79 CCTGAGTCTCATTCTCTCTAGGGAG

TTTTTTAATGTGATAGCACCTAGCATATGTTGATCTTATAATAGTGA
TTAATAAGCAGTTAATGATTGATTAAAGAACTTATGGTCTGTCTTTG
GGATTCATGTAGATAATAGGAAAGGCAAAGCAGAAAAATTCAGTTAA
TTCAGATGATTCTAATAATTATTAAAATATTTTAAAATTTCCAACTG
CAAAGAAAATAAWTTTTTATAGAACCATTAGACCCAGAGAACTCATA
CCTGTAATTAGAAGAACCCTAAGTCATTGTAGACAGAAGAGATCCTT
LNPEP TCTTTTTTACAAGCACTTGTGTCCCAGGGACAGTAATAATATTGTTT
RegiOn AATATTTCTGCAGCAGTTTACAGTTTAAAGACACTTTCATGGCCGGG
rs2113189 80 TACAATGGCTCACGCCTGTAATCCC
CCCCACTGCTAGCTAAAAATATCTCAGCGCAAAATGTTTTTGAGTGG
TTACTACTGCATTGGCATCCCTTAAGCTCTGAAAAATGCCAAAATAA
GTATGCTGTTAGGTTTGGAAATACAGTATATGTTTTTCTTTTTCCTT
ACCTCTGGGAAGTTATAGAATCACTACAGGAAAGAGAAAAGAAAGTC
ATCACAGGGGAARAAAGGAAAACTTTTTATTTAAACAAAGAGTCATG
CTAATCCCCTGAATATATATATACATAAATTTATATTTATTTATTTT
LNPEP AGACAAAGTCTCACTCTGTTGCCCAGGCTGGAGTATAGTGGCACAAT
Region CTCAGCTCACTGCAACCTCCACCTCTCTGGTTCAACCAATTCCTCTG
rs2113190 81 CCTCAGCCTCCCAAGTAGCTGGGAT
AAGCCTGAAATCAGTTTTAG CTTAAAAAAAAACCTT
TTAAATCTATTATTCTCTTCTTTTTGTTTCTGTTTCAATGGGTTGTA
TGAGTGAAGCTAAAATGTAAACATCCTACTGCCCTATACAAAATAGA
ATACTATTATTTCATCTTTATGCTAGTTACAAGAAAGATAATCTTAA
CCTGCAGTAACCYACCTACAGTAGATATAAGTGTTCAACATGTTGAA
TATACCTATGAAAATATTCTAGGTAAACTTATTTATGCTCACAATCA
LNPEP AAAATATGTGATTAAATATTGTTGGTTTTTTCTAAACTCCAAGATTG
Region CTAGTATGAATTTTAATGAAGAATTTCTTTACATAGATTAATTGATT
rs2113191 82 ACTTCATTCATTTGTGGATTTGAAA
GTTCATACTTGCTTTCCTTTGTACATTGTTATCTCCAGTGTTTGAAA.
TTCTCTTATCCCCAGTTAATTTGTAATTGTCTTGAACACTACTTGAT
AAAGTGTTCAACTTTAGTATTTCAGAAAGGAAATATACTCTCCAGTG
AAAGAATAAGCTTCAAGTTATTCAGCATAGATAGAACAGGTTATAAG
TATTATCAAGCARCAGCCTTCTCAAAGGGATTTTTATGTGAGATAGT
TATGATTGGATCTCTTAACAACAGTTTAAGGCTTTTTCGCCTTAGTG
LNPEP TGTTATGATCTAATTTTTATCCAAAAGTGGTGGGTCTCTCTTGTATG
Region AATAGTAGGGATAACATCAAACTTTATTCCCTGGTCCCTTATGCTTC
rs2161548 83 TCTTCCAAA.ATCTTCTGTTAACTAC
TCTAGAAAGTAACAGAATAATTGTGAATGTTTATAAATAGCTATATA
TTGTCAGTCAACCATATTTATTCTGCTTGCTATGTTGTCATGGTCTA
TAGAAGGCAGCACTTCCCTTTTTCCTCTAACACCACACTAGGATGTC
ACGCTGGGGTGGCCCCAGGGGCTCACTATTTGACCTGACTTTCTTTG
GTTTCTCTTCTAYGACTAATCCTACACTTTTATGTTCCCTTGATCTA
AAATCTTTAAAATGTTGTAATTTCTACCATATAACACCTAATCTCTG
LNPEP GCAAATTTTAAGGTTGTCAACTGTATTCCCCAATGTGTATATATTTG
Region TTGAGCAAAACTAATCTTCTCTCTTATAAGAAGAAATCTTGCTCAAT
rs2161657 84 CTCTAGATCATTGTGCCTATATTTC
TATAATTGTAATCCAATATTTTAAAATGTGGAGAACTTTACCTAAAA
ATCCTGACCTCTGGAATCTCTTAAAAATGATATTTGGCAACTGTGGG
TCTTTATCCTGTGGGCCACAGGATAGCTATAAAGGAGAGTGCAGTGG
GCCAAACTCTCTTTAGGCCAGGCCTACTTTCTCCCAAGCACCAAAGT
CCCAAATGGCCTSTTTCATTCACTTAGTGTGGACTCTCTAAGTATTT
GAGCTTTCGACCCCACATTTAAAATGTATTTATGTTATTAGCTGCTA
LNPEP CACCAAATACCGGTGTAATCTCTTAAGGAAAAGTACAAATATAGTCT
Region TAACTTTTATAATTTTAAATGGGTTGTTATGAAATCTATTCATTACT
rs2161658 85 TACACTGGAGAAATTAGTATGACGT

AACTGATTCTAGCCACTTTACCAGTTAGCAAGACTAGTTTATTCATT
CATTCAGTAAATACCTACGGAGAACCTACTGCGTTCCTGGCACCATG
CCATATGTTAGAAATACAAAGATGTATATAATATAGCCACTGCCTCA
ATACAAATGATGGAGGTCAACCAGTAGACAAATAAATACAGTAAAGC
AGGTGCTAAGATMAATGTCTTTGCCAGGGACAGAGGGGATTCCAGGA
GGAAATAATCAGTTTTGCCAGGACAGTGTTCATTTCCTGAGCCTTGT
LNPEP AAATAGTACTCAGGTATGCTGAATATCAGGTAGTAGGAGCAAAGGCA
Region GAGTGATACAACCTGGCATGTTCAGAAAATGGCAGGTAATCTTGGAT
rs2247650 86 GGCTAAAGCTTAGGTGTAGGCAAGA
TTCATTATCATGTCTGGATGAATTATTTCATATAGCTCTTTTAATAA
ATGCCTGCATCCATGGCTAATGTGCACGTTCAGCCAACTAATGATGC
CTACATTGCAGTGCTCTTTTGTTCTTGTTTTGTAGAGTTGTTTAGAA
AGTGATTTTACATCTGGTGGAGTTTGTCATTCGGATCCCAAGATGAC
AAGTAACATGGTRAGGATAAAGAGAGTCACAGAGTAGAAGAGATCTG
TGGAATAGCCTGACCTAGAGTGAGTATGACATACAGAGTAGCCCACC
LNPEP TGTCCCTTTTAAAAGCTGGAGAGAAAGAGAGCCCCCACGATTTTCTC
Region TAAAACAAAACTGAAGGGGAAATGCTTGGGGTATTTAGGGGGACAAT
rs2248374 87 GCTGTTGCTACTATATTTTTGTTGT
TTTGGGCTAGGGAGTTTCAAAGTTGACTCCACTGAACTATTTGGATA
CAAATGGTATTATTTATATGCTTTGAGAAACATTTGATTACACTTGG
TTTGAGGCAACTGAGACATCTGCATGGAAGAACAAACATTGGATGAA
AATGAATACCAACTTTTTCAGAAGATGGGTCCAATTTTCTCTTACAA
AATCCCATGCTARTTGCTGCCCCTTTGGACGTCTGGCAATCGCATGA
AGGAGAGCTGCCAAGTTCTGTGTCTTGATAACCTTTCCTTCCATTCC
LNPEP TAGTTCAATTAACCTGAAGAAAGAAAAATAATTTGTTTCTAAATAGT
Region AGGTATTATGTACATGGACATTAACTCAAGCCACCAATATATTAAAA
rs2255546 88 GAATAGAACAGAAAGAGGCATGATA
GCCACATATGTGTGATGCACTATACAAGGCATCTTGGGATTCTTCTG
GGCTGAGGAGAGAGCCAAGAAGGGATGGTGGGAGGGGGCTGATGACT
GCATTTAATTCAACTCGGACTTGATGCCAGTGGTTTCTTGCCTGGAC
TGAATGAGAGAAGGCTGTTTCCCATTCCCTTATTCTCATGTCTCTCC
CTTACTCCTGGAYAGGATAATTTGGGCTAGGGAGTTTCAAAGTTGAC
TCCACTGAACTATTTGGATACAAATGGTATTATTTATATGCTTTGAG
LNPEP AAACATTTGATTACACTTGGTTTGAGGCAACTGAGACATCTGCATGG
Region AAGAACAAACATTGGATGAAAATGAATACCAACTTTTTCAGAAGATG
rs2255633 89 GGTCCAATTTTCTCTTACAAAATCC
CCAGTACAAAACTGCATTAACAAATGAGGCCACATATGTGTGATGCA
CTATACAAGGCATCTTGGGATTCTTCTGGGCTGAGGAGAGAGCCAAG
AAGGGATGGTGGGAGGGGGCTGATGACTGCATTTAATTCAACTCGGA
CTTGATGCCAGTGGTTTCTTGCCTGGACTGAATGAGAGAAGGCTGTT
TCCCATTCCCTTWTTCTCATGTCTCTCCCTTACTCCTGGACAGGATA
ATTTGGGCTAGGGAGTTTCAAAGTTGACTCCACTGAACTATTTGGAT
LNPEP ACAAATGGTATTATTTATATGCTTTGAGAAACATTTGATTACACTTG
Region GTTTGAGGCAACTGAGACATCTGCATGGAAGAACAAACATTGGATGA
rs2255634 90 AAATGAATACCAACTTTTTCAGAAG
TCTTACCAAAATTCCTGAGATTTTCCCCCAGTACAAAACTGCATTAA
CAAATGAGGCCACATATGTGTGATGCACTATACAAGGCATCTTGGGA
TTCTTCTGGGCTGAGGAGAGAGCCAAGAAGGGATGGTGGGAGGGGGC
TGATGACTGCATTTAATTCAACTCGGACTTGATGCCAGTGGTTTCTT
GCCTGGACTGAAKGAGAGAAGGCTGTTTCCCATTCCCTTATTCTCAT
GTCTCTCCCTTACTCCTGGACAGGATAATTTGGGCTAGGGAGTTTCA
LNPEP AAGTTGACTCCACTGAACTATTTGGATACAAATGGTATTATTTATAT
Region GCTTTGAGAAACATTTGATTACACTTGGTTTGAGGCAACTGAGACAT
rs2255637 91 CTGCATGGAAGAACAAACATTGGAT

TGATAGCTAATTTCTTTGGGGGAGCCATTGAACATATTTGAGCATTT
CTTAGTTTAAAGCAAGCTTGACAGAGGGCGGATCCAATAAGTTCTTC
ATGGCTTCCCACATAGGTCTAGAAGAAACCTATGTTTTATTTGAATT
GTGTTTGTGGTCATCATTTTGGAAAGCTAGTTGACAAGTGTTAAAGT
ATATCATAGAGAYGAACTCAAGTGGGTTCCTCTCTATGATATACTTG
GATTATGATACAATGGGTTAACATGATTTGAAAGTTACAGATGAGCA
LNPEP CTGAGGAAATGGATTGTAACAGAAGATTCAGGGTGTTTGTAATTTTC
Region AAGACTGACTTTTGCTTTAATACTTCACAGAACCTCTTATCCTTATT
rs2278018 92 GACAACATGCTTAATGGTATCTTAA
AAACTTGCTTTGATCTCTTCCCTCTTTCTCTTTCTATGTGATTTAAA
TGAGCACTGAGGAATTCAGTTAGCTCAGGAAAAAATAATTTGTTCCT
CAGAGATGATTCTTGAGTGTAGAAAATAAAATATTTATGACATGCCC
CAACAGTGTGGATCATTTCTCTATTCTTTTATCAGGTTTAACGTTAA
CATATCTGCATCRAACTCTTTCCCAGGCTGATCAGAAAGGGCACACA
CTGGAGGCTGGGACGGAAGCCAGGTAGAGGGTCCAGGAAAGAGATGG
LNPEP GGAGAAAAAGAAGGAACACAGTGACTGCTCTGTTCAAAATAGGGGTC
Region CACATGTCCAAGATGCTGTGGCTCCCTGTGGCGGACATCAACGCTCT
rs2278019 93 CATCCATTATGCTCCTCTTCTGTGG
CATCCAAGGAGATGGAAGTTTCTGTCCCTCTGTCTTTGGATTGTCTC
CTCTCTCTTGAGTTATCATAGTCACCTGTCATTTCAGCTCGCCTTTC
TGGGGGAAAATGCAGAGGTCAAAGAGATGATGACTACATGGACTCTC
CAGAAAGGAATCCCCCTGCTGGTGGTTAAACAAGACGGGTGTTCACT
CCGACTGCAACARGAGCGCTTCCTCCAGGGGGTTTTCCAGGAAGACC
CTGAATGGAGGGCCCTGCAGGAGAGGTGGCTGCTTTTCTTCTTTAGG
LNPEP TCTAGCTTACCTCATCTCAGTTTCCTCGTTATTTCCTTAGCTTTCTC
Region TCAGCTCATCTGGCAACTTTGTAGGATGCTAGTTCCATATAAGAATC
rs2287988 94 AAAGGCCTAAAGTAGACTTGATAAG
GGGAAAGGGGCCATTATCTGGTATTTTACTTAAAAGCACAGAAGTTG
AATTGATGCCAGTGTTGGAAATTATTGCATTTTAAGAAAATAGAAAT
ATGTAATATTTTTATGCTTTCAATCAACAAAATGAGATTTGGCATTT
TTGTGCTTTGGGGATCTCAAAAGCAGGGCTTTTTGTTTTCAACAGAG
TGTTGGGGTAAARGCAATGGAGGTAAGAGAGGCTACAGAATACTAGG
AGAGGCCATTGCCCCCCTAGGAGGTCATCGATTGTCCTTCAGAGTAT
LNPEP GAGGCTTGCCTCTAACTCACCTGCCATAAGTCATAGGCATGGTTATG
Region AAATACTCCAGTTTTCAAGTACTGATTATTCCTTTTCCTTTCTGTAG
rs2303208 95 GTTAAGACAATTGAACTTGAAGGAG
GAAAGGGGCCATTATCTGGTATTTTACTTAAAAGCACAGAAGTTGAA
TTGATGCCAGTGTTGGAAATTATTGCATTTTAAGAAAATAGAAATAT
GTAATATTTTTATGCTTTCAATCAACAAAATGAGATTTGGCATTTTT
GTGCTTTGGGGATCTCAAAAGCAGGGCTTTTTGTTTTCAACAGAGTG
TTGGGGTAAAAGYAATGGAGGTAAGAGAGGCTACAGAATACTAGGAG
AGGCCATTGCCCCCCTAGGAGGTCATCGATTGTCCTTCAGAGTATGA
LNPEP GGCTTGCCTCTAACTCACCTGCCATAAGTCATAGGCATGGTTATGAA
Region ATACTCCAGTTTTCAAGTACTGATTATTCCTTTTCCTTTCTGTAGGT
rs2303209 96 TAAGACAATTGAACTTGAAGGAGGT
CGAGTTATGCTTGGTATAGCTATTAGGTAATTCAATTAACTTGCAAA
ATAGATGAAGAAAGCAATTCTGAGAAGATCAGCTGAAATCACTGGAA
AAACTCAAAAAGGCAAGCCACTAAAATTGTTGTTGAATTAGGTAGGA
GACAACTCTAAAAGACTGGGGAAAA.AAATTGAAAGTCTAGACAAATT
TTGCACTCGGACYGCTTCACAGGTGTCCACATTTTCATTTCACTTTA
TAATAGGTTATAGGGTCAAAAACTTGCTGAAGCAAAACACACAGGGG
LNPEP TGAGTTTCTGTTTTAATATTGTTCCATTTCCTTTCTCTACTTTGCCC
Region TGAAGGCAGGCTTTGGTCACAGAGTGGTGTGGAAATGCCAACAGGTA
rs2351010 97 AAATTCCAATGAGTCCCATATTTCT

TCAGCTCACTGCAACCTCCGCCTCCTGGGTCCAAGTGATTCTTCTGC
CTCAGCCTCCCAAGTAGCTGGGACTACAGGTGCGTGCCACCACATTC
TGCTAATTTTTGTATTTTTATTAGAGACAGGGTTTCACCATATTGGC
CAGGCTGGTCTCGAACTCCTGACCCCATGATCTACCTGCCTTGGCCT
CCCAAAGTGGTGKGATTACAGGTGTGAGCCACTGTGCCTGGCCAAGT
GTCAGGTTTTAATCCTGTCCCTTCCATTTACTTGCTATATGGCATTG
LNPEP GACAAACAACTTTTTTAAAAACTAAAATGAGAACTTCAAATCAGATT
Region ATATCTAAGTTTACTTTCAATTCCACAATTTGAACATTTATTTTGAA
rs2351011 98 ATTGTTAAAAACAGAAAGTCACAAA
ACATTTTAATGTATATAAATATTTGCTACATTCTGTGTGTTATATAA
TGTGGTACCCAGTCCTCTGCTGGGACATGGATGTACATAATGAAACA
TGGAGGTCCAGACGTATGATAACTCTCCTGTTTCCCTTCCCTCATTG
CCTACAGGGGCAATAGTTTCATATCTTGGGTTTTTTATTGTTTAATT
TTTTTTTATGGGRAGGGGTTCTTTGGGTGGGTAATAGTCAGGGGGAA
AGGACAGTGTCTATACTTTTTAAAGATGTATATAAATGTTTCATGTT
LNPEP ATTGGTTTTGTACCTAGTCCTTTGCATGGATATATAGGTACCTAATG
Region AAAATCGAGGATCAGTGTATGACAAATCTCCCATCCTCCCCTTTCCT
rs248215 99 TATTGCCTGTGTCGGCAATAGGAAG
ATCATTACTCTGTGTTTATAAGTGAGAAAACTGATACTAAGGGACAG
ATTTGCCCAAAGTCACCAAGTCAGTGAGAAAATCAGTACTTAAAATT
TGTCTTCTAAGTCCAATAGTTATTCAATTATATCACAGCTAGTTCCT
AGTTTTAAGAAAAGTCCCCCATCAATCTTCCCCTAAAGGTCCTAGAT
TTTGACCAACTCYCTTCTGACACCAAAGGGCCCTGTAGTATTAAAAT
AATAAATTACTGAAAATATCTTGCCCACCATTGTGTCACATAAAGTC
LNPEP AATTCTAATACATGTCAATAGCAACTTGAGAATGAGAAGAATTAGTT
Region GCTGTTATTTTTCATAAGATCATTTAAAGGCATTTGAGAGCCTTAGC
rs251339 100 ACATTCTTCATTTTTTCTCATTTGC
GTATGCTGTTAGGTTTGGAAATACAGTATATGTTTTTCTTTTTCCTT
ACCTCTGGGAAGTTATAGAATCACTACAGGAAAGAGAAAAGAAAGTC
ATCACAGGGGAAGAAAGGAAAACTTTTTATTTAAACAAAGAGTCATG
CTAATCCCCTGAATATATATATACATAAATTTATATTTATTTATTTT
AGACAAAGTCTCRCTCTGTTGCCCAGGCTGGAGTATAGTGGCACAAT
CTCAGCTCACTGCAACCTCCACCTCTCTGGTTCAACCAATTCCTCTG
LNPEP CCTCAGCCTCCCAAGTAGCTGGGATTACAGGCACACACCACCATGCC
Region CGGCTAATTTTTTTGTATTTTCAGTAGAGATGGGGTTTCACCATGTA
rs251340 101 GGCCAGACTGACCTCAGGCAATTCG
ACAGGCATGATCCACGGCGCCTGGCCCTAAATTGTGTTTTCTAAAGG
AAGGTTCAGCATCATCCAGTGATCAGAAACCCATACTAGCAGTGCAG
CAGCCAGAGGTTTTGTTCTCCATTCACTACACCTCTATTGATATTAA
ATTGTTCTGTTGAAATATTTAAAGCTTCCCTAAAGACAGATATTTCC
CTCGTAAACCACYCCTCCTGGATTCTACTGTTATTTGAGGGTTTTGT
TTGTTTGTTTGTTTGATTTTGTTTGTTTGCTTGTTTTTGAAAGGGGT
LNPEP CAGGAAAGAGACTCCAGTCTCAACCTCCTTTTCACTGGCTTTTCCTG
Region CCATGTATTCACCCTACTATATCCTGTATATATCCCTCAATTCAAGT
rs251342 102 AATTTGCAGAGAGCAGCCCTGGGAT
AGAATAAATTGTCTGTGAAAATACTGAAAACATACAAAGGACATTTT
TTTCTCAGTTTTAAAACTGTATTCCGCTTTAAAAACTGTTTTCTAGG
CCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCG
AGGCGGGCGGATCACAGGGTCAGGAGATCGAGACCATCCTGGCTAAC
ACGGTGAAACCCYGTCGCTGCTAAAAATACAAAAAATTAGCCGGGCG
CGGTGGCAGGCTCTTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGG
LNPEP AGAATGGCACGAACCCGGGAGGCGGAGCTTGCAGTGAGCCGAGATCA
Region GGCCACTGCACTCCGGCCTGGGCGACAGAGAGAGACTCCGTCTCAAA
rs251343 103 AAAACAAAACAAAAAcAAAAA.AAAc AGCTGGAGTGTCACGATCGTAGCTCACTGTAACTTTCAGTTTCTGGG
TTCAGGTGATCCTCCTGCTTCAGCTTCCCACGTAGTTGTGACTGAAG
ATGTGCACCACAATGGCTGTCTAATTTTTATTTTTTAATTTTTGTAG
AGATGGGGGTCTCACTATGTTTTCCACACTGGTCTCAAGCTCCCGTC
CTGCCGCCTTGGSCTCACAAAGGGCTAGAATTACAGGTGTGAGCCAC
CACGCCAGGTCCTGGCTGTTTGGATTTTAAGACCAAGGGAAACATAC
LNPEP TATTTGTTGACCCCTCGGTCTCACTGAGGACCTGGAAAGAAATAACA
Region GCAACAGTGCTGGCCTTGCAAATCCAAACCTAAAACGTGCTGTCTAA
rs251344 104 AAAAAGAAACTTCAGGCGGGGCGTA
GACATGTTTTGCTGAGTGTGGTTGGTTACTTCAGGTACAGTATCACA
TTAATAGGGGCCACAGTCTATATCCCTGTTTAGTTTGTTAGTTACCA
CTCAAGAGCAGACAGATATTGTCCACTTTATCCCAAATCCCAGCCAG
ACTTTGTTGTATGCTGTGCTTCATTCATGGGGCTGTGAACTACTGAT
TATATTCTCCCTWTTCCTAATGTAGAATGCTTTATTCTACTGCCATC
TTTCTGTCTGCACTGTTTAATTAGGCTTACTGATAACAACTTTAATT
LNPEP CTGAATTTTCTTTCTCATTCAGGTTCTATTTGTAATTACTAAGACTT
Region AAAGAATAGTCTGGTGAAGTTACTCGAAGAATTAAGGAAGGTTTGAG
rs2548225 105 CTAAAATGAACTAGAGACCATCTAG
CACATTTTTGAGAAGTGATGCTAAAAATTTTTTTTTAAAAAGACTCA
CATATCTATAGAACAATTGTTATTTGTAAGATTAAAAGATGGAATCA
CAATTTTATACTGTATTACAACCCACAAATATCTCATTTGTTGCCCA
GACTTCCCATTTTTGAAGTTGAAAAATACTTTCAACTGGATACCAAT
CTGAACATGAAARCAAAAATAATTTTTTAAGACAACTAAGTCCTCCT
TGTTTGATTATGCACCACACTGCGGTAATAAAAGTGATTCATAGGAC
LNPEP CTACATTCATATGAAAAAAAAAACTATTTATGTTTTCAGTTCTGGGA
Region CCTCAAAATGCCAAAATACCAACCTTTAGATATACTTTAGAATATAT
rs2548516 106 CACAAACTAGAAAGTATATATACTT
ACTATAAAATGAAAATGTAGATACAGCTTCTTTGGGAAATATGGTTA
GTTATTCAGCAATGTTTATGTTTAATTTTATGTTTCTGTTTAAAGCA
GTGTTCCCTACTTTTTTTGTTACTACATACTCCAGTCAGTAAAGATT
TTTTGAGCAAGAACTTCCCAATATACATATTTTTATTTATAAATTAT
ATGGGCTGGGCGYGGTGGCTCACACCTGTAATCCCAGAACTTTGGGA
GGCCGAGGTGGGTGGATCACCTGAGGTCAGGAGTTTGAGACCTGCCT
LNPEP GACCAGCATGGAGAAACCCTATCTGTACTAAAATACAAAAAAATTAG
Region CTGGGCATGGTGGTGCATGCCTGTAATCCCAGCTACTCAGGAGGCTG
rs2548520 107 AGGCAGGAGAGTCACTTGAACCCGG
TATGTTTCTGTTTAAAGCAGTGTTCCCTACTTTTTTTGTTACTACAT
ACTCCAGTCAGTAAAGATTTTTTGAGCAAGAACTTCCCAATATACAT
ATTTTTATTTATAAATTATATGGGCTGGGCGCGGTGGCTCACACCTG
TAATCCCAGAACTTTGGGAGGCCGAGGTGGGTGGATCACCTGAGGTC
AGGAGTTTGAGAYCTGCCTGACCAGCATGGAGAAACCCTATCTGTAC
TAAAATACAAAAAAATTAGCTGGGCATGGTGGTGCATGCCTGTAATC
LNPEP CCAGCTACTCAGGAGGCTGAGGCAGGAGAGTCACTTGAACCCGGGAG
Region GTGGAGGTTGCAGTGAGCCAACATGGCGCCATTGCACTCCAGCCTGG
rs2548521 108 GCAACGAGAATGAAACTCCGTCTCA
ATAAATAATGTATTTATTTAACTTTTTATACTATATATCATTTATGT
TTATAAATTTATAACAATATAAAATTTAAAATTAGATAAGAAATAAT
AGACACTCTAATGTATTGCACTTCTTGCACACTTCCTCATCCCATTT
TGGATACCACTGTGTTTAAACATTGTGTTTAGTGGGGCAATGTTACT
TGGTTGAACTCTYATTCACGGCCACAGAATGCATCCTTCAACCCAAT
GTTTTATATATGGAAAACTTGTACTACAGGTCAAAGTGATTCATGTT
LNPEP GATAAAGCAGAGCACAGTTACAGCTCAGAA.AAAAATATGGTTCCAAG
Region TCTAGGCTCTGCACATGGTTGGGCAGGGGCATCATTTCCTGTTTAAA
rs2548522 109 ATGAAATCCACAGCATTGTAGATTA

TGATTTTTATTATCTTGAGGACATTAACCAGTTTTTATTCTAAGTGG
GCATATGACTTTTTAATCCCAAATGTCAACGGATCAATAAGAACTGT
TATTGATGTCTCAGAAA.AAACACAACACAGAGCATTGAGGAGGGAGC
CAGAAATTTGCATTTGTCACAAAGTGACCATATGGTAGAGATTGTAC
TAGTCTCCATACMTCTTATTTAACTGTCAAAAGCTACCCTCTGAGAT
AGTTATTATCCTGATTTTTTTAAGCGGAAATAAATCTCAGAAAAGTT
LNPEP AAGTAACTTGCACAAGATGACATAATTTGCCATTTGCAGATGGGATT
Region TAACCCTATGATTCTAATGCTTTGGCTACTTCCTCTATACTATATGT
rs2548523 110 ACTTAAATACCCCAAGTGACATTTG
ATTCTAATGCTTTGGCTACTTCCTCTATACTATATGTACTTAAATAC
CCCAAGTGACATTTGAATAATATAATAAAGATCAAATAATTATAATA
CATATTGTTTTCATTTTAGTGTATTTTGCTGAACAACTTTATAACAA
TTGGTAACAAACACATTGTAAGCTTCTTGAAGGTAGGCCACATGGTT
GTTTTGTTCACCWCTTTATCCTTAGCTCCTACAGCAATACCTGGCTG
GCATAAAGGAAATGTGCAACTAGTTACATTTCAAATCCACAAATGAA
LNPEP TGAAGTAATCAATTAATCTATGTAAAGAAATTCTTCATTAAAATTCA
Region TACTAGCAATCTTGGAGTTTAGAAAAAACCAACAATATTTAATCACA
rs2548524 111 TATTTTTGATTGTGAGCATAAATAA
TTTGCATTTTTAGTGCAGACAGGGCTTCACTATGTTGGCCAGGCTGG
TCTTGAACTCCTGACCTCAGTGATTCACCCTCCTTGGCCTCCCAAAG
TGCTGGGATTATAGGCGTGGGCCACTGCATCCAGCCAGCACCGGAAT
AATGGACACCATTACATTTCATGGTAGAGATTGTACTAGTCTCCATA
CATAGCACTTACRATGTGAGAGCATGAAACAGGGTTTGTAATGCCCA
GCATGTTTTTTTTTCTATCCTCACTAAAAGGTTTTAGACCTAATGTC
LNPEP TTGCTTGATCAAAGACTTTTACATCAAAGAGAAAAGAACAAAGGGTA
Region GGACAGAAGTCTACATCTACTTTAATTTTCCACTGGATTCCATCCAC
rs2548526 112 TGGGAGAAGAGTTCAGCAGCTTTCT
GTCCATCATGTGGTAAAACGATTCCAAGTAACTCAGACCTTCGAGAA
GTGCGGGGCTGCTTGTTTCATGTTGGAGGTAGTAAGTCATGTCAAGA
GCTTTGTCTAGGGTCAGTCTCCCTGCACTGAAGTATAAAACAAATGT
CAGTGGTTTGTGCATATCTTATAGTTTTTAATATTTTTAACATTAAA
ACAAATATGAAAKAGAGAACAATAACAGAAGTAGGTCATTATAGCTG
GGCCATTCAGTTTAAATCTTAGCTCTGCCACTGACTAGCTGAGTAAT
LNPEP CTTGGACAAATTACCAAACCTCTCTGGACCTATTGCCTTCTTTATAC
Region AATGGGGATAATAATACTATCTTCCTCATAGGCTTGTTGTGAGGATT
rs2548527 113 AATGACCTAATATTTTAAAAAGCAT
TTTTCCAAGTCTTGCATTGTTAATCTATCTTCTCTTCAATCTACTCA
GAGCTTCTCCTTTGAGCAGGCAAACCTCCTTCAACTAGCAATAGCTT
GCTTCTTAGCTCACCTTTCATGCATTCACTCATATGTAGGATGGTGT
TTTTCCTAATTTTGGCCTCCAATGAGCTATGCCTCCAAGATGTTCCT
GAGACCCACGGGRCTGAGGATTAAGCCTCACTTCCTCTTTTCTTTCT
AACTAGAGGATTTTAGTGTACCGAGAAACTTTGTCTCAGAGATGTCC
LNPEP TGCTGGTCACTTTCACTCAATTTGACCTAAATAAGCTCCTGAAAGAA
Region AATTATATGTCACATTGAGTAAAGTGAGTGCATCACAGTAATTCTCA
rs2548529 114 GAATAGGGAAAGCTTGCAATGCACA
TTCACTCAATTTGACCTAAATAAGCTCCTGAAAGAAAATTATATGTC
ACATTGAGTAAAGTGAGTGCATCACAGTAATTCTCAGAATAGGGAAA
GCTTGCAATGCACAATATACTTCCTGGTCCTCAATTCCCTCCAGCCA
TTGGTGATCTTGTGACCTGATTCATTCCACACATTATTCTGTTCATG
ATACATAGAAAARGAAAGAAAACACTTTGTCCTTCCAGGAAAGTCTA
GAGAGGAATGAATGCAAACAGCCATTTATTACTTCATTTCCCTACAA
LNPEP ACGTCATACTAATTTCTCCAGTGTAAGTAATGAATAGATTTCATAAC
Region AACCCATTTAAAATTATAAAAGTTAAGACTATATTTGTACTTTTCCT
rs2548530 115 TAAGAGATTACACCGGTATTTGGTG

GGAATTTGGCTTAATTTGATGATGTCCTTGTCTCAAGGTTTAGTCAC
TAGTCATTGAAATATGTATGTGTAAATAGGTGATCCATTTGTTCATT
TTAGTAAAGAAGGACTCCAGGTTAAGCATGACTTTGTGACGGAAAAC
CTCTCAAATTTTATTAAAGTGTTTAGAAGAAAATTAAAATTATACTA
TGTATTTTTAATRTGGCATATATTATACTAGAGGGTAAAATTACATT
ATAATATTCTCTCAACAACTCTGTGAGGTTTAGTCTTTATTCAACAT
LNPEP AAGATGAAAAAATTGAAGCTCAGGATGAGTGTGTACATTTTCTTAAG
Region GTCACACATCTAATAAGTGAGAGAGTGAGGACTTGAATCCAGAAGCA
rs2548532 116 ATCAATTTTAAAGTATGTGCTTTTT
AAATTATACTATGTATTTTTAATGTGGCATATATTATACTAGAGGGT
AAAATTACATTATAATATTCTCTCAACAACTCTGTGAGGTTTAGTCT
TTATTCAACATAAGATGAAAAAATTGAAGCTCAGGATGAGTGTGTAC
ATTTTCTTAAGGTCACACATCTAATAAGTGAGAGAGTGAGGACTTGA
ATCCAGAAGCAAYCAATTTTAAAGTATGTGCTTTTTTCCACTGAACA
TTTTTTGCCTTATCCATAACCTGTAAAAATAGATTAGTGGGTATTAT
LNPEP AAGACATAAGATAGATTTCTGTTATTTCTTGATGTAAATAATCTGTC
Region TCTAAATGATAAAAGCGCAAGAGAACTTCCCACTGAATGAAAAATCC
rs2548533 117 AGATTTTCTTACTAAAAGAGTTATT
CCTGCCTTAGCCTCACGAATAGCTGGGATTACAGGCAAGCACCACCA
TGCCAAGCTAATGTTTGTATTTCTAGTACAGACGGGGTTCCACGAAT
TGGCCAGGCTGGTCTCAAACTCCTGACCTGAAGTGATCTACCCACCT
TGGTGTCCCAAAGTCTTGGGATTACAGGCGTGAGCCATTGTACCCGG
CCATGAAAGTGTYTTTAAACTGTAAACTGCTGCAGAAATATTAAACA
ATATTATTACTGTCCCTGGGACACAAGTGCTTGTAAAAAAGAAAGGA
LNPEP TCTCTTCTGTCTACAATGACTTAGGGTTCTTCTAATTACAGGTATGA
Region GTTCTCTGGGTCTAATGGTTCTATAAAAAATTATTTTCTTTGCAGTT
rs2548534 118 GGAAATTTTAAAATATTTTAATAAT
CTTAAAATTTGCCAGAGATTAGGTGTTATATGGTAGAAATTACAACA
TTTTAAAGATTTTAGATCAAGGGAACATAAAAGTGTAGGATTAGTCG
TAGAAGAGAAACCAAAGAAAGTCAGGTCAAATAGTGAGCCCCTGGGG
CCACCCCAGCGTGACATCCTAGTGTGGTGTTAGAGGAAAAAGGGAAG
TGCTGCCTTCTAYAGACCATGACAACATAGCAAGCAGAATAAATATG
GTTGACTGACAATATATAGCTATTTATAAACATTCACAATTATTCTG
LNPEP TTACTTTCTAGATTAAATAACAGTCTATCGTTACCCAACATATGACT
Region TACATTTGACAGACTGCTCCACAAGTCATCATTCTTAGCATTTCTAT
rs2548535 119 AGCTGAACTTCTTTAAGTACTGAAT
AATAACAGTCTATCGTTACCCAACATATGACTTACATTTGACAGACT
GCTCCACAAGTCATCATTCTTAGCATTTCTATAGCTGAACTTCTTTA
AGTACTGAATTATTCCTTTCTGGAATTTCTCCTCACCCAGAAAATCC
TTGAGCATATTCAAAATACAAGCTCCCTTTAAAAAAAAACAAAAGAG
TTGAAAAAAGAGWTAAAGAAAATGGTAGTATGGTATGTTTTTAAAGG
AAGCTTAAATTTTACGGAACATGTGTGATGTCTGAAAAGTGAACAAA
LNPEP TAAAAAGTGAAACAAGTAGCAGGAACTGGCACCAGTGACTTAAACTG
Region CTGATTCTATAGTCATTATTACACTTCTGAAAGCAGAGCTTCCACCT
rs2548536 120 GCACCTGATATTTACTACCTTGTTA
CAAAAGAGTTGAAAAAAGAGATAAAGAAAATGGTAGTATGGTATGTT
TTTAAAGGAAGCTTAAATTTTACGGAACATGTGTGATGTCTGAAAAG
TGAACAAATAAAAAGTGAAACAAGTAGCAGGAACTGGCACCAGTGAC
TTAAACTGCTGATTCTATAGTCATTATTACACTTCTGAAAGCAGAGC
TTCCACCTGCACSTGATATTTACTACCTTGTTATAGGAAACTTCATC
AAACATTTCCTGTATTTGAGTCGGGGTTTCCGCTGGTTTGGAGATAG
LNPEP GGCGGGATGAATTCAATGAATCTTTTGTAATTACTTCAAAACACACA
Region TTCAAAAAATAGTCATCCTAAACAGGGAGAAAAATGTTTAGTTTTAG
rs2548537 121 TTTCTATTTGACACTGTAAAAGCAA

TGATGTCTGAAAAGTGAACAAATAAAAAGTGAAACAAGTAGCAGGAA
CTGGCACCAGTGACTTAAACTGCTGATTCTATAGTCATTATTACACT
TCTGAAAGCAGAGCTTCCACCTGCACCTGATATTTACTACCTTGTTA
TAGGAAACTTCATCAAACATTTCCTGTATTTGAGTCGGGGTTTCCGC
TGGTTTGGAGATWGGGCGGGATGAATTCAATGAATCTTTTGTAATTA
CTTCAAAACACACATTCAAA.AAATAGTCATCCTAAACAGGGAGAAAA
LNPEP ATGTTTAGTTTTAGTTTCTATTTGACACTGTAAAAGCAATAGAAAAC
Region ATAGTAGGTTTAGTAAGATGTTCTTAGAGGTAAGATTTCAATCGATA
rs2548538 122 TTTCTTGGGAGATGTTTCTTTTCTT
TAAGAATATATAAAGCTTTGGCATTAAGCCACAAATTCAGTACATAC
ACAGTAACAAGAAGAGCCTAACTTTGAATCCATGTCTGTCTATAGTG
TACTGGACTAAATATATATCCCAAAGACCTAATTAACCATTACTAAC
CACCTTGATATGCAAATTTGTGTAGTGTTCAGACCACTATATTCGTT
TTTAAAAAAGACRTACCTGAAGAAATCCCTTCACACATTTTGGGGAA
GCCAGCAGACCCTTTGGAAATTCTAGAAAAGTACACCCCCAATGATG
LNPEP TTGATTTCAGGTTACATGCCGAGAACTCTCTATAGTACCTAGTAGCC
Region ATGAGCATTCCTGTGCAGATGTATACAAACAGTGATGTTCTTTCCTC
rs2548539 123 TCAACCCACATACACAGTTCTACAT
GTCTAAGATTTAAAAAATATATAAATCAAATAAAAAGGATGCATAAA
TATAATTGACATATTTACCCTTTACCTATATTTGATCTGTATTATGC
ATTTTAAATATTACTATTCTTTTATGTGCTTTTATGTTTTATTTATT
TAGTCTATATGCCTAATACTGCACATCTAGTGTATGTCTCTAAGATT
AAAATCTCTAGAYGGACCAAAGCTTCAACAATAAGATTCTAAGATTC
AGAAGAGCCTGGTTATAGTTACAGAACAGAAAATTATAAGTCTGTAG
LNPEP CTTCTAGAAACAGTTTAAGCACTATTCCTTTTCTGACAGTCTTCAGA
Region TTACTTTACAAGTGGGCAGCAATCTTCTGAAGGGCATTCATGGAAAG
rs2548540 124 GGAGAGGTGTTTCCTCAATTTGAAA
GCTAACTGGTAAAGTGGCTAGAATCAGTTTATCCTGTACTTCTTATA
TTCACCGGTTTTCAAATTGAGGAAACACCTCTCCCTTTCCATGAATG
CCCTTCAGAAGATTGCTGCCCACTTGTAAAGTAATCTGAAGACTGTC
AGAAAAGGAATAGTGCTTAAACTGTTTCTAGAAGCTACAGACTTATA
ATTTTCTGTTCTKTAACTATAACCAGGCTCTTCTGAATCTTAGAATC
TTATTGTTGAAGCTTTGGTCCGTCTAGAGATTTTAATCTTAGAGACA
LNPEP TACACTAGATGTGCAGTATTAGGCATATAGACTAAATAAATAAAACA
Region TAAAAGCACATAAAAGAATAGTAATATTTAAAATGCATAATACAGAT
rs2549781 125 CAAATATAGGTAAAGGGTAAATATG
AGAAGAAAATTGTACAGAGAGAAAAGGGTAGCAAAGAGAGAAGAGAG
ATCCTAACTAATAAAAAAAAAGTTAGTAACTATTGTATTTTTTGCTA
AAGTTAATAATTTTTATTTGTTTAACTTCTAATAATATTGAGTTTTT
ACCTCCTAGTGGTTTGGCAACCTGGTCACAATGGAATGGTGGAATGA
TATTTGGCTTAAKGAGGGTTTTGCAAAATACATGGAACTTATCGCTG
TTAATGCTACATATCCAGAGCTGCAATTTGTAAGTTCACAATTCTGT
LNPEP GTATCATACTATATGGTGTAAAGAATCATCAATTCACTATTAAAATT
Region TCAAGTGAATGTTAAACAGAAAAACTACATAATGTTGTGGTTTTTGA
rs2549782 126 ACATATGGCATTTTGTTTGATACAC
TTGAACATATGGCATTTTGTTTGATACACGAAACAGATCACAGAACT
GGATGAAACATTGAAGGTTTTAGAAAACAATCAACATAAATCTGTCA
CCCCAAAGTCTGTAAAGAGAGAAGGCAAACTAATACAAATGTAGAAC
TGTGTATGTGGGTTGAGAGGAAAGAACATCACTGTTTGTATACATCT
GCACAGGAATGCYCATGGCTACTAGGTACTATAGAGAGTTCTCGGCA
TGTAACCTGAAATCAACATCATTGGGGGTGTACTTTTCTAGAATTTC
LNPEP CAAAGGGTCTGCTGGCTTCCCCAAAATGTGTGAAGGGATTTCTTCAG
Region GTACGTCTTTTTTAAAAACGAATATAGTGGTCTGAACACTACACAAA
rs2549783 127 TTTGCATATCAAGGTGGTTAGTAAT

GTGGGTTGAGAGGAAAGAACATCACTGTTTGTATACATCTGCACAGG
AATGCTCATGGCTACTAGGTACTATAGAGAGTTCTCGGCATGTAACC
TGAAATCAACATCATTGGGGGTGTACTTTTCTAGAATTTCCAAAGGG
TCTGCTGGCTTCCCCAAAATGTGTGAAGGGATTTCTTCAGGTACGTC
TTTTTTAAAAACKAATATAGTGGTCTGAACACTACACAAATTTGCAT
ATCAAGGTGGTTAGTAATGGTTAATTAGGTCTTTGGGATATATATTT
LNPEP AGTCCAGTACACTATAGACAGACATGGATTCAAAGTTAGGCTCTTCT
Region TGTTACTGTGTATGTACTGAATTTGTGGCTTAATGCCAAAGCTTTAT
rs2549784 128 ATATTCTTATTTGTAAAATGCATAT
TTTTTGAATGTGTGTTTTGAAGTAATTACAAAAGATTCATTGAATTC
ATCCCGCCCTATCTCCAAACCAGCGGAAACCCCGACTCAAATACAGG
AAATGTTTGATGAAGTTTCCTATAACAAGGTAGTAAATATCAGGTGC
AGGTGGAAGCTCTGCTTTCAGAAGTGTAATAATGACTATAGAATCAG
CAGTTTAAGTCAYTGGTGCCAGTTCCTGCTACTTGTTTCACTTTTTA
TTTGTTCACTTTTCAGACATCACACATGTTCCGTAAAATTTAAGCTT
LNPEP CCTTTAAAAACATACCATACTACCATTTTCTTTATCTCTTTTTTCAA
Region CTCTTTTGTTTTTTTTTAAAGGGAGCTTGTATTTTGAATATGCTCAA
rs2549785 129 GGATTTTCTGGGTGAGGAGAAATTC
AATGGCCTGTTTCATTCACTTAGTGTGGACTCTCTAAGTATTTGAGC
TTTCGACCCCACATTTAAAATGTATTTATGTTATTAGCTGCTACACC
AAATACCGGTGTAATCTCTTAAGGAAAAGTACAAATATAGTCTTAAC
TTTTATAATTTTAAATGGGTTGTTATGAAATCTATTCATTACTTACA
CTGGAGAAATTARTATGACGTTTGTAGGGAAATGAAGTAATAAATGG
CTGTTTGCATTCATTCCTCTCTAGACTTTCCTGGAAGGACAAAGTGT
LNPEP TTTCTTTCTTTTTCTATGTATCATGAACAGAATAATGTGTGGAATGA
Region ATCAGGTCACAAGATCACCAATGGCTGGAGGGAATTGAGGACCAGGA
rs2549787 130 AGTATATTGTGCATTGCAAGCTTTC
AGAAAGAAAAGAGGAAGTGAGGCTTAATCCTCAGTCCCGTGGGTCTC
AGGAACATCTTGGAGGCATAGCTCATTGGAGGCCAAAATTAGGAAAA
ACACCATCCTACATATGAGTGAATGCATGAAAGGTGAGCTAAGAAGC
AAGCTATTGCTAGTTGAAGGAGGTTTGCCTGCTCAAAGGAGAAGCTC
TGAGTAGATTGARGAGAAGATAGATTAACAATGCAAGACTTGGAAAA
AATGGAGAATATTGACAATTCAGCAAATTAATCTTTTAGGTAGTTGT
LNPEP GAAATCTTTTTTGCTGTTTCTAGCCTATCCACTTAGATTGTCTAAAT
Region TTAGTAGGAGGAAATTTGCAGTTATTGATGCATTGGTGGAAAACTAA
rs2549788 131 TCATCTTTTCTTCACTAAGTAGACA
AAGCGATCCTCCCACCTCAGCCTCCTGAGTAGCTGGGACTACAGGCA
CACACCACCATGCCCAACCAATTTTTAAATTTTTTGGCAGAGATGGC
GTCTGCCTATGTTGTCCAGGCTGGTCTCAAACTTCTGGGCTCAAGCA
ATCCTCCTGCCTCGGCTTCCCCAATTGCTGGGATTACAGGTGTGAGC
CACTGCACCCAGMATGGAGAGAGAATTTGATGCAAGAATTGATATTT
ATTTTAGTTCGGTTTTCATACATTTTAAATGTAATTTAAAGACAGGG
LNPEP GTCTTGGATAAGTTGAGTGGAATTGAAATGACAACTTCAATTTGCCT
Region ATAGAAAAAGCTATATTTGTTTCTTTTAGTCCCACACCTTAAAGAGA
rs2549789 132 AAACCCCACATTGGGCGCAGTGGCT
TCCTCCTGCCTCGGCTTCCCCAATTGCTGGGATTACAGGTGTGAGCC
ACTGCACCCAGAATGGAGAGAGAATTTGATGCAAGAATTGATATTTA
TTTTAGTTCGGTTTTCATACATTTTAAATGTAATTTAAAGACAGGGG
TCTTGGATAAGTTGAGTGGAATTGAAATGACAACTTCAATTTGCCTA
TAGAAAAAGCTAYATTTGTTTCTTTTAGTCCCACACCTTAAAGAGAA
AACCCCACATTGGGCGCAGTGGCTCACGCCTGTAATCCCAGTACTTC
LNPEP GTGAGGCCAAGGCGGGTGGATCACCTGAGGTCAGGAGTTCAAGACCA
Region GCCTGGCCAACATGTTGAAACCCCGTCTCTACTAAAATTATAAAAAT
rs2549790 133 TAGCTGGGCATGGTGGTGTGTGCCT

GATTACAGGTGTGAGCCACTGCACCCAGAATGGAGAGAGAATTTGAT
GCAAGAATTGATATTTATTTTAGTTCGGTTTTCATACATTTTAAATG
TAATTTAAAGACAGGGGTCTTGGATAAGTTGAGTGGAATTGAAATGA
CAACTTCAATTTGCCTATAGAAAAAGCTATATTTGTTTCTTTTAGTC
CCACACCTTAAARAGAAAACCCCACATTGGGCGCAGTGGCTCACGCC
TGTAATCCCAGTACTTCGTGAGGCCAAGGCGGGTGGATCACCTGAGG
LNPEP TCAGGAGTTCAAGACCAGCCTGGCCAACATGTTGAAACCCCGTCTCT
Region ACTAAAATTATAAAAATTAGCTGGGCATGGTGGTGTGTGCCTTCCCA
rs2549791 134 GCTACTTGGGAGGCTGAGGCAGGAG
TATTAACCTTTTGCTATGTGGTAGACATTATTCTAAATGCTTTTTAA
AATATTAGGTCATTAATCCTCACAACAAGCCTATGAGGAAGATAGTA
TTATTATCCCCATTGTATAAAGAAGGCAATAGGTCCAGAGAGGTTTG
GTAATTTGTCCAAGATTACTCAGCTAGTCAGTGGCAGAGCTAAGATT
TAAACTGAATGGYCCAGCTATAATGACCTACTTCTGTTATTGTTCTC
TATTTCATATTTGTTTTAATGTTAAAAATATTAAAAACTATAAGATA
LNPEP TGCACAAACCACTGACATTTGTTTTATACTTCAGTGCAGGGAGACTG
Region ACCCTAGACAAAGCTCTTGACATGACTTACTACCTCCAACATGAAAC
rs2549794 135 AAGCAGCCCCGCACTTCTCGAAGGT
TAGTATTATTATCCCCATTGTATAAAGAAGGCAATAGGTCCAGAGAG
GTTTGGTAATTTGTCCAAGATTACTCAGCTAGTCAGTGGCAGAGCTA
AGATTTAAACTGAATGGCCCAGCTATAATGACCTACTTCTGTTATTG
TTCTCTATTTCATATTTGTTTTAATGTTAAAAATATTAAAAACTATA
AGATATGCACAARCCACTGACATTTGTTTTATACTTCAGTGCAGGGA
GACTGACCCTAGACAAAGCTCTTGACATGACTTACTACCTCCAACAT
LNPEP GAAACAAGCAGCCCCGCACTTCTCGAAGGTCTGAGTTACTTGGAATC
Region GTTTTACCACATGATGGACAGAAGGAATATTTCAGATATCTCTGAAA
rs2549795 136 ACCTCAAGGTTTGTGTTGCTTTTAG
ATAAGAGAAATACGAAGATACACTGTTTGGGGAAAGATTGGGAAAGA
TGCAGAAAGTTTAGAGTTGAGCCCTTTAGATGGGCAAGAACTGTGTT
AAGGACTAAATTTAGCCTCTCTGTTAACCATCTCATATTTTCTGCAG
CGTTACCTTCTTCAGTATTTTAAGCCAGTGATTGACAGGCAAAGCTG
GAGTGACAAGGGYTCAGTCTGGGACAGGATGCTCCGCTCGGCTCTCT
TGAAGCTGGCCTGTGACCTGAACCATGCTCCTTGCATCCAGAAAGCT
LNPEP GCTGAACTCTTCTCCCAGTGGATGGAATCCAGTGGAAAATTAAAGTA
Region GATGTAGACTTCTGTCCTACCCTTTGTTCTTTTCTCTTTGATGTAAA
rs2549796 137 AGTCTTTGATCAAGCAAGACATTAG
ACAGGCAAAGCTGGAGTGACAAGGGCTCAGTCTGGGACAGGATGCTC
CGCTCGGCTCTCTTGAAGCTGGCCTGTGACCTGAACCATGCTCCTTG
CATCCAGAAAGCTGCTGAACTCTTCTCCCAGTGGATGGAATCCAGTG
GAAAATTAAAGTAGATGTAGACTTCTGTCCTACCCTTTGTTCTTTTC
TCTTTGATGTAARAGTCTTTGATCAAGCAAGACATTAGGTCTAAAAC
CTTTTAGTGAGGATAGAAAAAP.AAACATGCTGGGCATTACAAACCCT
LNPEP GTTTCATGCTCTCACATTGTAAGTGCTATGTATGGAGACTAGTACAA
Region TCTCTACCATGAAATGTAATGGTGTCCATTATTCCGGTGCTGGCTGG
rs2549797 138 ATGCAGTGGCCCACGCCTATAATCC
CCCACGCCTATAATCCCAGCACTTTGGGAGGCCAAGGAGGGTGAATC
ACTGAGGTCAGGAGTTCAAGACCAGCCTGGCCAACATAGTGAAGCCC
TGTCTGCACTAAAAATGCAAAAATTAGCCAAGTGTGGTGGTGCACGC
TTGTAATCCCAGCTACTTCGGAGGCTGAGGTGGGAGAATTGCTTGAA
CCTGGGAAGCAGMAGTTGCCGTGAGCCAAGATCACTTCACTGCACTG
CAGTCTGGGCAACAGAGAAAGGCCCTGTCTCAAAAAAAAAAAAAAAA
LNPEP CTTTTCCTGTGCCAAATTATTATAAGATGGTATCATAACTTCTCTCG
Region CTATAACTAAATCTGTGAGCTTTTTGAAATCCTTTCTTGAATTCTTC
rs2549798 139 TTTTTAA.AAAAGTAATTCAAGTTTT

CTATAATCCCAGCACTTTGGGAGGCCAAGGAGGGTGAATCACTGAGG
TCAGGAGTTCAAGACCAGCCTGGCCAACATAGTGAAGCCCTGTCTGC
ACTAAAAATGCAAAAATTAGCCAAGTGTGGTGGTGCACGCTTGTAAT
CCCAGCTACTTCGGAGGCTGAGGTGGGAGAATTGCTTGAACCTGGGA
AGCAGAAGTTGCMGTGAGCCAAGATCACTTCACTGCACTGCAGTCTG
GGCAACAGAGAAAGGCCCTGTCTC CTTTTCC
LNPEP TGTGCCAAATTATTATAAGATGGTATCATAACTTCTCTCGCTATAAC
Region TAAATCTGTGAGCTTTTTGAAATCCTTTCTTGAATTCTTCTTTTTAA
rs2549799 140 AAAAGTAATTCAAGTTTTCTTCTTT
ATCAGCCCCCTCCCACCATCCCTTCTTGGCTCTCTCCTCAGCCCAGA
AGAATCCCAAGATGCCTTGTATAGTGCATCACACATATGTGGCCTCA
TTTGTTAATGCAGTTTTGTACTGGGGGAAAATCTCAGGAATTTTGGT
AAGAGCTACTCCTCACCCCTAGAGCCCCTGTGGAGGTGGCACAGTGG
AGACCTTGGTTCMGGTGAAAGAAACCTAGTCAGGAGTGTTTGGGGAG
CCCTCCCTCCAAATTGTTTTGGTTCTGAGTCTTTTCTGGGGTTTCAA
LNPEP CTTTGGGGAGAACTGGAGCTCATTTCAATATGTTCCTGGATCTAAAA
Region TATCCCTCAGAAATAACCAATAATGATTAGATTTTGTTGGAATGGAA
rs2549800 141 TGTATAAGACAGCATTGCTTTCTGT
CTCACACAGCTTTGCGTAAGCAAAAAGCACATTTCCACTCCTCTCCC
AAATGCTCAAGGAGTTGACGTCCACATGAGACCAAATAGAAACTGCT
TTAATATGTATGTTTGTGTATGTTTCCTTTAAAACTCTACTTGAGCC
ATTGATTTGTCTGTTTTCATGATTGTCATTTTCCTCCTGAAATGATC
AGCCTTAATCTAMAATGCTGTGGATTTCATTTTAAACAGGAAATGAT
GCCCCTGCCCAACCATGTGCAGAGCCTAGACTTGGAACCATATTTTT
LNPEP TTCTGAGCTGTAACTGTGCTCTGCTTTATCAACATGAATCACTTTGA
Region CCTGTAGTACAAGTTTTCCATATATAAAACATTGGGTTGAAGGATGC
rs2549801 142 ATTCTGTGGCCGTGAATGAGAGTTC
TGATTTTCTGGCGCAGTGCGGGTGTCTCGGCGTCCGGGATCGGGCGG
GTCGCAGTAGGGCTCCACATTTGTTGAGTGACTGAACACCGTTCCCG
GCCGGGGAGAGCGCCGCAGCCGGGTCCACTTCAGGTAGGGGCTGGGC
TTTCCCGGCCCCGCCTAGGCCCCGCCCCCAGCGCGAACCCGCTCCCA
CCTCGCCTGTCCRCGGAGCAGCAGGGGGTTTGACTGTGCTTTTCCCT
CTTGCTTCCCTCGCTCTTTCTGCAGCTGCCACGAAAACCCGGAACGG
LNPEP CGGAGCGGCGCCGCCCCTCGCGGCACCTCCCTGGCAGCCCTTGGAGG
Region CCGCGCTGGGCATGCTCAGTCAGCTGGGCCGCCTCAGCTCTCGGAGT
rs2617434 143 AGGAAGCTCGGGCGCTCCGGCTGTA
CAGTAAGGAAGTAAGTAGAGGCAGGTGGTAGGGTGGCAGTAAGAATT
GATTCCCCCAAATTAACTATGCTGTTTGTCCTAATTTTATATGTGTT
GTAGCTTTACCCTTCAAAAAGAAAGAAACTTAGTTCTATTTACAAAG
GTAGTAAATTCAGTTTGATTTAATTGTGCTTTCAAAAGTAGTGTAAA
GGGAAAAGAACCRAACCTTAAAAAAATTCTGTAAGAATATTATAAAC
TCAAAATTTATTTCCATGGCTTTTGACATATTGAAAATAAACTGGGG
LNPEP ATAAATACCTACCTTGACCAGCAACCTTTACACCAGTAGCCATAAAA
Region TGAGGCCATTCAGATAATGTTATTGAAAGAGGTGAAGTTCAATGCCA
rs2617436 144 TTCGTAGTAATAATAATATCTGGTA
TAATTAGTAATGTTTGAAGTTGTATCAAATCAAGAAATGTTTAGAGC
ACAGAAGAAAGCAGAATAATTATCTAATAAAGTTCAAGTAGAGCTTA
GGCATTAGCAAAA.AAACGCAGCCAAATAAAGTGAAAGGTTATTATTT
GGAAAGAACAGTGATATACTAGTTCAGATTCCTTGGGCTACAAAAGA
CAAAACTCTGAGYAAAACTAGTTTAAATGATACAGACATTTATCATT
TCATATAACAAGTCCACTGATAAGATAATCTTCAATCACAGCTCACC
LNPEP AGCCTCATCAAGAGCCCAACTTCTCTCTCTCCACTCTTCAGTCCTCT
Region ATATGAGCAATTCCCCAAAGCCCAGACTACCATATGGTCAAAAGTTG
rs2617447 145 GCTGCAGCAGGGGAGGAAGAAGGAA

AGGAAGGGCATATAGTAATTAAAATATTTATCATGTGCCATTCTCTG
CTCTTGCCTTTTTTTCCCCTAATAAAGGAGAAAGAAAGGGGTATTAG
AGAAGGGAATGCTTTTGAACAGGAGTGATAAAGTTCAATAGCATGTA
TGATGCTAGCCCTCTGGAGCAAACTGTACAGGAAATTTTGTAACTTT
GTAGTAAAAACGKGTTTTTTAGTTTCAGAACTTTAGTTTTTTTGTAA
AACAGTAGTTGATTTTCGTAGCTCATTGACAAATGGTTTTTAAAAAT
LNPEP CACTGTTAGATTACTTCATCTGGGCTTCTGCCATTTAATATTGCAGT
Region TGCTCACTCTTTTTTGCTACTCAATAGACTGAAAATTGAAGTGTTAA
rs27289 146 TCTGTTGATGACTATAGTAAATTAA
CATTGGTTTTGAGGGACATCTCTGATGGCTGGAGCCACCTTATCTGT
ACTGCTTGCCTCCCCAACCACCTCATGCATTATAGAATCCCAAAGCC
AAGGATGACAGTGACCTCATGTAAACATATTCTCTGAATAGAATATT
ACCAATTTAGATTGATGATAGGCTTAAAAACACTGACGTGTTCCTTC
TCATCTCCCTGGRCATTTCCATTTTGTCTCGTTTTTTATGAAGTGCC
CTTCTTACGTCATCCTAGCCATTGCTGCTGTGATTCCTATAAAATGG
LNPEP TTAATTTTAAAAATGTACTCACTGTAAATTCACAATAGACCTTGTCA
Region TAACAAGTTTGAAAAACAAATTCCCATTAAACCAACAAATAAAATTA
rs27290 147 AAAAAAGAAATCAGATACTCTCTAT
TCCTTCTCATCTCCCTGGGCATTTCCATTTTGTCTCGTTTTTTATGA
AGTGCCCTTCTTACGTCATCCTAGCCATTGCTGCTGTGATTCCTATA
AAATGGTTAATTTTAAAAATGTACTCACTGTAAATTCACAATAGACC
TTGTCATAACAAGTTTGAAAAACAAATTCCCATTAAACCAACAAATA
AAATTAAAAAAARAAATCAGATACTCTCTATGCTATACTCTCTTTCC
TGGCAAATATAACTAATTAATAAATAAAATTAGTACTATTCATCTTT
LNPEP TCTAACCCAAGATATTATACTTTTGCTGAGTTAGTAGCAATTTACAG
Region GAGACTTAGGAATAAAAAAAAATGAGCTATTGTTTATCTTTCTCTTG
rs27291 148 AAATGCCTCTTTAATCTTGGGCCTC
GATTGGATGATATTAATGAATAACTATTAGTTTTCTTCAGTGTGATA
AGGTATTATGGTTCTGTAAGAGAATGTTCTGATATCTGTGAGTTGCA
TGCCAAAGTATTTATAAATGAAATATCGTATCTGTATATCACTTTTA
TATTGTTCAGCTAAAACAAGAAAAACATGTGTGCGTATGTGTGTTAT
ACACACTTGAAARTGAAGCAAGTGTCAGAGTGTTAAAAAACTGTTGA
ATCTAGATGAACAGTGTATGGGTGTTGTACTATCTTTTTTTGTAGGT
LNPEP TTGAAAGTTCTTTAAATAAAAACTTAGGAGAAAAAATAAGCTATAAA
Region CAACTATTCTTCCCTGCAGGTCTCATTTTCTTGCTAATTTGGTTAAT
rs27292 149 TTGTTATAACATCAAACTAGTTAAT
AAATGAAGCAAGTGTCAGAGTGTTAAAAAACTGTTGAATCTAGATGA
ACAGTGTATGGGTGTTGTACTATCTTTTTTTGTAGGTTTGAAAGTTC
TTTAAATAAAAACTTAGGAGAAAAAATAAGCTATAAACAACTATTCT
TCCCTGCAGGTCTCATTTTCTTGCTAATTTGGTTAATTTGTTATAAC
ATCAAACTAGTTRATAATGTTAAATATACCTTTAATATTGGATTGAG
AAACATTTAAACATTAACTATCAATAAAGAAGTTTATTTTTCTTTCA
LNPEP TTGCTTTATAGGTTTATAGATTGTAAAGTCACAAGGTCAGGAAGTCC
Region TGACATCCTTCCAGCAGTGGTTATAAGTGATACTTTTTGGCAGGAAA
rs27293 150 ATAACTTCTAGCTGAGTATATGCAG
GTTTGAAAGTTCTTTAAATAAAAACTTAGGAGAAAP.AATAAGCTATA
AACAACTATTCTTCCCTGCAGGTCTCATTTTCTTGCTAATTTGGTTA
ATTTGTTATAACATCAAACTAGTTAATAATGTTAAATATACCTTTAA
TATTGGATTGAGAAACATTTAAACATTAACTATCAATAAAGAAGTTT
ATTTTTCTTTCAKTGCTTTATAGGTTTATAGATTGTAAAGTCACAAG
GTCAGGAAGTCCTGACATCCTTCCAGCAGTGGTTATAAGTGATACTT
LNPEP TTTGGCAGGAAAATAACTTCTAGCTGAGTATATGCAGCATAAAGGTT
Region CCCTACTGCACAGAAGTCATTAATTTTTTTCTGAGTTAACATCACTA
rs27294 151 AAAGTCCCCCTTAGCTATAGCAGCC

GGTTTATACCATACCCAGTGTTTTGTGACCATCTTTTTAGTGAATGA
TCAGTCTATGAGATTTTCCATGTCACTTCATGAAGCCTGCTTTATAT
ATAAAAAAAAACTAAAGTGTTTTATGGGTTCATAATATTCTGTAGTA
TGGCCCTATCATAATTTATTTAATCCATCACGTTTTGTTGGGCTTTT
GTTTTTTTCTCTYCTAAAAATACTGCCACAGTCTTGGAGTGGGGCGT
GGTTTCTCACTATAAACAGATAGTATAGCATAGTAGATGAGAACTGC
LNPEP TTTTGTTCAGATGTCGGGCTTTGGTATTTATTACTGTGTGACTGTGG
Region GTCAATTAGATAACCTCAGTTTCTTCAACTATAAAATTGAGTTAGGT
rs27296 152 AGTATTAATAAATACCTACTTTATA
CGGAAATTTTCACATTTGTTAACATAATTCCATAGCATGAATCATTT
AACAGTAGCATTCCATCTAAGTTCTAATTAAGCCTAGCCTTGCTTGG
CACCAGGTTACTTAGCTCAGCGTGGCTACAGACTATTTCATAGCAAC
CATTTAGCTATGCATATTGAAAAATACCTCTGTATGGCCGGGCGCGG
TGGCTCACACCTKTAATCCCAGCACTTTGGGAGGCCGAGATGGGCGG
ATCACGAGGTCAGGAGATCGAGACCATCCTGGCTAACACGGTGAAAC
LNPEP CCCATTTCCACTA.AAAATACCAAAA.ATTAGCCGGGCATGGTGGCGGG
Region TGCCTGTAGTCCCAGCTACTTGGGAGGCTGAGGCAAGAGAATGGTGT
rs27298 153 GAATCTGGGAGGCAGAACTTGCAGT
ATCGAGACCATCCTGGCTAACACGGTGAAACCCCATTTCCACTAAAA
ATACCAAAAATTAGCCGGGCATGGTGGCGGGTGCCTGTAGTCCCAGC
TACTTGGGAGGCTGAGGCAAGAGAATGGTGTGAATCTGGGAGGCAGA
ACTTGCAGTGAGCCGAGATTGTGCCACTGCACTCCAGCCTAGGCAAC
AGGGCGAGACTCYGTCTC CAAAAAGGAAAATACCT
CTGCATTGCCAAGGCATCAGTTAAGAACTCACATTCAGCTAGATGCA
LNPEP GATGTAGGTTTTTTGCTTCTTTCTCTCTTTTAAATCAATAATGGCAT
Region TTCTGGGTGTACAGTGTGATCTTCGACAATGTTAAGCGGATTAATTG
rs27299 154 TCTGCATGTTCTGAACTCTTCCCTT
AATGTTAAGCGGATTAATTGTCTGCATGTTCTGAACTCTTCCCTTTT
TCTGCCCACCTTTCCTTCCCACCGACAATAAGTATGCATAGGGCTAC
CCCGGTTTCCTCAGTTGCAGTTCCGGGAGGAGGATTCCACTCTGGCT
TTGGCATTAAAGACTTTTCCTTGCACTCAGGAACAACGCTTTACCAG
CAGCTGCCTAATYTTTTTGCTCTTGTTTTTGTGTTTCTTCAGGTTCC
CTCTGGGGTCCTATACCATACAAAATATTGTTGCTGGATCAACTTAC
LNPEP CTGTTTTCAACAAAGACACATTTATCTGAGGTTGGTTTTATAAAATG
Region ATAATACAGAGACTGGGCAACCCTCCGCACACCCGGACCAGGCTGCT
rs27300 155 CAGTTTTAGTGAGATGGTGGATTTT
GTTAAAACTTTGAGTGGATGCATAGGGCGGATAGCTAACAGTCACGG
GAGCTCCATCAGGACCATTATTTACTTTTTGGACTAAAGCAGTTCTT
GTAAACACTCAGGTCACCTAAGTAGCCAACTGATGCAGTAGTCATAC
AGTACCTAAATCAGTGTGAGAAATGTCATACGTGTCGTATGCCAGTG
AAACCAAGGAACRCTGTCTTACTTTGAAGGTGAGACATTGGATGTTA
TCAGGGAAATACCCCTTGCGTTGATTCACATATAAGTAGGAGTATGA
LNPEP GTGCACCTTTTTAGAGGCACACTGCCACGGTTACATTCCTGGTCAGG
Region TCTACAAAAGGAGTTTCTTGGTTCTGTCTGCATGAGTAGCCTTGAGG
rs27302 156 AAGAACTGAGAATTTCTTAGGCTTC
GAGATACACAGTTTGACCACTTGGTGGTGCCCAGAATGTGTAAAAAG
GTCTAATACATGTTCTAGGGGAGCTCATCTGCTGAGCTCTTAAAGAA
TTATTTCTGTTTAAGAGTTACATTTTATTTAAAACCGACCTCAGGTA
AGGGAAATGTATATTTTCTTAGTAGAAATTCTAGACTATATATAAGA
AATCAGCGTAAGRACCAGTTTTTGTTCTTTCTCTTTTTAAATTTCAA
GTTTCATTTAAAAAAATATATGCTAACCTTTTTAGAATATTCATCTT
LNPEP GGATACTCAGAGTTGGCATTTGTTTACTTTGGTAATAGATTCTTAAT
Region TTTCCCATATGCTGTTGTTTAGGAAATGCTAATTTTAATGTGGCCAG
rs27305 157 GTTATAATTGTATCTTTAAATTTAA

GTGATAACGGTGTCATTCACATTTATGTTGTGGGGAGGGATGAATGT
TATGGCTGTCAGACAAGATAGAGAAGAAAATACACAAAATGTGTGAG
ATACAGTCTATGTCATCAAGTAGCTGAAAGTTCAGATGGTTGGTACT
TGTGGAGCAATAAGAGAGGTAATATGTGCTGAGTGGGACAGAATTTT
TGCCTAGGATAAKGAAGAGAAACTTTTGGGAGGTAAATGGGAATTGA
GTTGGCTTAAATAATTAAAATATAGGTAAAGAGGAATGTGAAGTATA
LNPEP GGGTAGGGCAGGAATGGAACAATGAGGTCTGCAAAGAAAATGAAGTA
Region CTAATGGGCAAGTGATGTTTTTTCAGAGAGTCAGTGTTTGACCACAG
rs27306 158 TGGAAGCCACACGTGAAGAGGGAAA
GTGCCTACTATGTAGTGGGCATTGTTTTTGTCATTGGAGTTGAGTTT
TCACTTTTTCCTCTCAGCTTACTGCATAGATGAGGAAATAAATGTGT
AACAGATACAGGATGCCATATAAATTGTATTGAAGATGGAGAAATGT
GATTTCTATTTCAAACCGGGAAGGTCTTCACAGAGGAGGTGGTGCTT
ATTTCAGGATTGSGAATGATGACAAGCACATCAATGGATATAGTGTG
GCCTTAATATTATGCTCCCTGCCCTATACATTTGTTAGTTCCAAGCA
LNPEP TTTGAAGTGACTCTGCAGGAAGAAGAGAGATTCTGGTTACTTCACAA
Region CACAATATACTAAAATAAGAAATTAATGACCTACCTAGCAGGGAGAC
rs27307 159 TTTTGAGAGCCTTGTCAATTTATTG
ACTTTCTAGCTGTTAGTCTTTTGCCCAGAAGATATACCTTCCCTACT
CTCTGAATTCTCTTTGAGAACTTATTACCTAACAGTTGTTCCCAAAT
CATTGTTTTTTTCCTCTGATCATATAGTAGTATTTCAATTGAAAGCC
ACATTGTTTACTTTATACTTACTGTCTTAATCTGTTGGCATTTAGAA
CATATTTCTGCCKTTCTCATTGACTGCAACTTTTGCATCATGGTGTT
TTTCCATCCCAAACTAGTTCCTAACATTATCCTCAGGTTTTTCAGCA
LNPEP CCCACATCAAATTATGCATTGGCCTCTTCACTTCAATACTGCTTCGA
Region CACCCAAAAGCACCTTGGTTTTAGGCAAGCTTATTTTCTTCTAATCC
rs27397 160 TCTGGTTCAGAAATAAATAGGTCAG
TGCACCAGTGCACTCCCGCCTGACAACAGAGTGAAACTCCATCTCAA
AAAAAAATAGGTCATATAGATAAGATGTCTTTTGGGGGATCTCCTCT
AGGTCTGTTATTTCTGAAGCCACCCATCACCATTTGGGAGTATTTCT
CTGTTATTTCCTCTTTAGGACTTAGAAATCATCTTCCTCTGAAACAG
GTTTTAAAATAAYATCTTAGAAAAATGTTATTGTAATTCTCAAAGGT
GTTTTGTTTTATGCAGTAACCTCGTCCTTTCGCTGCTGATTTGAGAT
LNPEP AAGCCCAAGACCACACTGACCAAATTACATATTTTACAACTACTTTT
Region CATTTCAAGGATTTTTTTAGATACATTTTTTAAGGAGAATCTCCTAT
rs27436 161 TATTTTTTTCCTTTTTCTTTTCTTT
GTATTCTATTATTTTCTTTCTTTTTCCTCACTTTTTTTTTTAATAGG
GATCTTCTCTCTTGTTGATGTTGAAAACTTACCTTAGTGAAGATGTG
TTTCAACATGCTGTTGTCCTTTACCTGCATAATCACAGCTATGCATC
TATTCAAAGTGATGATCTGTGGGATAGTTTTAATGAGGTAAGTGACC
TGGGTAATTTATKTAGCTCTTACTGTAAAAAGAGAGGAGTTCGTCTA
TTTATACTTTTTAGCATGTGTGTAAGTTAATCTGTGGTACAAAGCAT
LNPEP AGTTATTTAAGAAAGGGGGGGATGGAGCTTGCTATATAAATATTTAT
Region GAATGGAGCACTAAATTTTATGTCAAGAAATGGGAGTGCTGTTCTTA
rs27613 162 GTTGTTGGAAAAGACGTGTGTGGGC
ATTCTATAAGAGAAAAGACACCAATTTTAAAACTTGAGAAAGTACTT
TAATTCTGTAGGCAAAGGTTCAGCAAATCAGCTAGCACTAATCTTGA
CCAAATGGGTGAGTCAGCCTCATCACAGAGATTTTTTTTTTAATTTA
GATGAAATTTCACATTTAAAAACATGGTAACTCCAAGCATTCTTCCA
AAAACAAAGAATRAACATTGGAATAGTCACTTACAAGGACTTAACGA
CTTGTATTAAACATATTTTACACTAAAGTACTAGATGGTCTCTAGTT
LNPEP CATTTTAGCTCAAACCTTCCTTAATTCTTCGAGTAACTTCACCAGAC
Region TATTCTTTAAGTCTTAGTAATTACAAATAGAACCTGAATGAGAAAGA
rs2762 163 AAATTCAGAATTAAAGTTGTTATCA

TAAAGTATTAGCCAGCCTCTGACTTAAGCAAATAGAGAAAAATCACT
GTTTTTAAACTATGCTAGTAATACACTAAGAATGCCCATGATAAAGA
ATTTAAACAGTACCTAAGAATATAGAGTAAAATATGAAAGTATTTCT
CATGATCCTTCACTTCCATTCTCGTTTTCTCTGTTAACAACAGTGTC
AGTCCTGGTCTTYGTATTCATCTGTGGGAATGGATATTTGTACATAT
GTACGTACATACATACACACATACCTACATATTTAACTGCATTTTAA
LNPEP AAACCATATTAGGTTTATACCATACCCAGTGTTTTGTGACCATCTTT
Region TTAGTGAATGATCAGTCTATGAGATTTTCCATGTCACTTCATGAAGC
rs27621 164 CTGCTTTATATATAAAAAAAAACTA
TTGTACTTAGTCAAAATCATTATGTATATATGATTTCTGTATCTTGC
CTTTTTTAACTTAACATATATAGTAATTGACTTAACCTACTTGATTC
ACCATTTGTTGTTATAAAATATTGCCTTAATTAAATATTTCAAATCT
TAAAGGTTTTTCCATTATATGAAATTTTTTAAGGAATGCTTTTCAAA
AATGAAGACTGCRGTACCTTTTGTGATTTGGTACATATAACCAAATC
GCCCTTTTTATTGTGTAGTTACAGTTGATAATGCCACCTGAAATACA
LNPEP TGAATGTGCCAGTTTCATTGCAGTTTTACCATAGTGGAGTGTTAAAG
Region CAGCAACAATCTAATTATTTAAAATCCTAGTGGTAGTTGGTAATGTC
rs27659 165 ATCATATCTTTGATAGCATAGCTGG
TTTTAAGTTAGAAAAATGTATCTGTGTGGGAGTAAAAAGATTTCCTT
TTTAAAATCATTTCAGATATCACCATACTTGATTGGGAACTCCATGT
AGATACCTTGAATATTAAAGTACTTCTTTCTACTGCTTTCAAGATAG
CAGCACAGCCATCACTAAGTTAAAGCTTATTTTAAAAGCTGGGGTTA
CCTGAGGTTTATYGTCCTTTTCTTCTTTTGAAATTCTTCTGTGTGAA
ACTTACAGGTTCAGGCATTCTTTGAAAATCAGTCAGAGGCAACCTTC
LNPEP CGGCTTCGTTGTGTCCAGGAGGCTTTGGAAGTCATTCAGTTGAATAT
Region CCAGTGGATGGAGAAGAACCTCAAAAGTCTCACATGGTGGCTGTAGC
rs27712 166 ATGCACAACCGCACCTCATTTTGTT
TACCGTGCATTATGGAGAGAAGATTCAAGCATCAGATGAAGAGTTGG
GGTGGAGGATTTGGATAACGTTTTGAGGTCTTTCCCAGCTCTGAGAT
CTTAATAAAGGCAGTAGACTGTGTTTTCTCCCTGCACCCCATTTACT
GCTATAGTTCTACCATGAAACTTATCACACTGAATTGTAATGCATAT
AGTTATTGCTCTRTACTTCGTAGTAGCCTGTGAGTTCTCAGAGGACA
GAGGCTCTCATTCCTTTTCCGCTCCCTAGTGTCCAGCCAGTCGCCTG
I,NPEP CCTGGTTCTTTGTGAGTACTCTGTGAATATTAAATTGAACTGATGTA
Region TCCATAGACACACTACTAGGAAGATAGCAGTCACTGAATTAAACTTT
rs27747 167 TTCTCAACCCTAAATTGTGTACTCA
TCAATGAGTATTGCCATTGTTCTTCACTGATTTTTTTTTTAAATAAG
ATTTCAAGCATGTGATTTTTTTTCTCACATTCTTCATTTGTTCCTAT
TTGACAGTTATGAGTAGGATTTGAATTTCTTTTGTTCTCCAGTCATT
TGGAATGGTTTTCTATCATAATGCTATTGAGAAGGTAAGGCCAGTGA
AGACACCACATARCAATGCAGTTAGGTATGTCAAGTGGGATCCCCTG
CATTGCTTGTCCGTTCCTTGCATCGTCAGCGTAGCAAGTATTTTTCT
LNPEP ACTTCATGTCCTCCCAGTGACTCAAAAGCTTTACCACTTACACATTC
Region CACAAGGTGTCTGTTCTGTGTTTCATTGCTTTTGAAACAAACACAAG
rs27993 168 CGAGTTGACATGTTATACAAACCTT
AAAAGAGAGGAGTTCGTCTATTTATACTTTTTAGCATGTGTGTAAGT
TAATCTGTGGTACAAAGCATAGTTATTTAAGAAAGGGGGGGATGGAG
CTTGCTATATAAATATTTATGAATGGAGCACTAAATTTTATGTCAAG
AAATGGGAGTGCTGTTCTTAGTTGTTGGAAAAGACGTGTGTGGGCTT
GGGTAGCCAGTTKTTTTTTTTTTTCCTGTACCTTAACTTCTATTCCT
ATTTTGTAGGAAAGTTGTCTTCTCCGTATTAATGAATATTACTATAT
LNPEP TTTCATTATTTGACTTTTTTTCCAGAAATCTCTTTTCCTATCCTTAC
Region CCTTTTAGTTTTTCTGCCTCTTTTGAATGATTCTGTACTCTGCTCTA
rs27997 169 TGAATCTCTTGCCTTTGTGACTGTT

GTCTCGATCTCCTGACCTCGTGATCCACCCACTTTGGCCTCCCGAAG
TGCTGGGATTACAGGCGTGAGCCACCAGCCTATCTTTTTTTTTTTTT
TAAAGCATTATAGTCTTTGCACCTTCTTTTCACAATAAATCTTGAAT
TTATTTACCCTTTAGGCAAATTCAGAATTCCTGAACTTAAATCCCAG
CTCACCATTTACYCTATGACTTGGGTAAATCATTTAACTTCTTTAGC
CACATTGTGGTCACTTGTAAGATGAGGATTTATAATTTTTGTCTTAC
LNPEP TTTACCTATTGTTTGAAAATAAAGTGAACAATTATGCAGAAAAGTAG
Region AAAATAACCTTTTAGAGGTTGGCAGAGAAATGCCTATACCTGTGTGT
rs2910686 170 ATGTAATTTGCAAGCTCTTTTGAAA
TCAAAATAAATGTTCAAATTGTGGAATTGAAAGTAAACTTAGATATA
ATCTGATTTGAAGTTCTCATTTTAGTTTTTAAAAAAGTTGTTTGTCC
AATGCCATATAGCAAGTAAATGGAAGGGACAGGATTAAAACCTGACA
CTTGGCCAGGCACAGTGGCTCACACCTGTAATCCCACCACTTTGGGA
GGCCAAGGCAGGYAGATCATGGGGTCAGGAGTTCGAGACCAGCCTGG
CCAATATGGTGAAACCCTGTCTCTAATAAAAATACAAAAATTAGCAG
LNPEP AATGTGGTGGCACGCACCTGTAGTCCCAGCTACTTGGGAGGCTGAGG
Region CAGAAGAATCACTTGGACCCAGGAGGCGGAGGTTGCAGTGAGCTGAG
rs2910688 171 ATCACACCACTGCACTCCAGCCTGG
ATTGGATTTTGTTACACGTTCATCCTCTTTTAATGGAATCTTTCCCA
CTTACACTTTTTCATGTATCCCTATATATGTAGAGAGGTGTATGAGC
TTAACAAAAAACAGTTTCAGTAATTTAGGACCACATATCTTTTAGTT
AAAATCTTGTCAGTGGTTCCATCTACTGACCTATGCATTTGTAAAGG
AAGTGAATTTAGYTTATATCTTGTCACTCTAGCCTTCAATACTCATC
TATTCCAGTACGTTTTTTTTGTAGTTTCCCTGTTTTCTGTCCAAAGT
LNPEP TGCCACTGGTATGACCTATTTTTGTTGGGCCCTGCTCTCTACCTGTT
Region GATAATTGGTTCATTTGATGAATATCCTATGTTAACCTGTTCAGGTA
rs2910787 172 ACATACTTCTGCAACCCATTTAAAA
AAGAGAAATGAATAGAAGAACCTAGTTTTGTTGTCATGCTAATATGA
AATATGGAAACACAGAAGAAATAAAAAAGCAATAAAGTTTTGTCTAA
GACAGTATTCTAATTATGAAATAAATGTACAGAAACTGTTCATAACT
GTTTGCATGTCTACTAATTTAGTGTAATACTCCTATTAGGAAACAGC
AGTATTAACCCTSTCTATGAAAACATTAGGAAATTGAGATTTGAAAG
AGTTTAGCCAAGATTACCCCAGATGTTGGGATGGACCTAGATGAGGC
LNPEP CTGTGGTTCTTGGCAGTCGAGGTGAGGTCAGTGCAGCTATGTTTTGT
Region CAATTAGTCACCTCATGACTTGAAAACTGTAGGGCAGCAGTCCCCAA
rs2910789 173 ACTTTTCGGGACCAGGGACCACAGT
CCTGGTCCCGAAAAGTTTGGGGACTGCTGCCCTACAGTTTTCAAGTC
ATGAGGTGACTAATTGACAAAACATAGCTGCACTGACCTCACCTCGA
CTGCCAAGAACCACAGGCCTCATCTAGGTCCATCCCAACATCTGGGG
TAATCTTGGCTAAACTCTTTCAAATCTCAATTTCCTAATGTTTTCAT
AGACAGGGTTAAYACTGCTGTTTCCTAATAGGAGTATTACACTAAAT
TAGTAGACATGCAAACAGTTATGAACAGTTTCTGTACATTTATTTCA
LNPEP TAATTAGAATACTGTCTTAGACAAAACTTTATTGCTTTTTTATTTCT
Region TCTGTGTTTCCATATTTCATATTAGCATGACAACAAAACTAGGTTCT
rs2910792 174 TCTATTCATTTCTCTTATTTAGGTA
AGGAGAATGGCGTGAACCTGGGAGGCGGAGCTTGCAGTGAGCCGAGA
TCGCAAGCCACTGCACTCCAGCCTGGGCAACAGAGCAAGACTCCGCC
TC GATAACTAGAATTACCAACAAT
AGTTTTGTTAAAAAGATCATTAAGTACGCTTCCAAACTTTAATATAA
TCACTCTTGCATYGTAATACAATATGAAAGAAATAATACAAAAGGGC
TCACCTCTCAAGTCTATTTTCATTTTGAATGCTATGAATACACGTAT
LNPEP TTTAAGTATTTTAAGAGTCAGGGGCTTTTTTTTGCTGTTGTTTTTTG
Region TTTTTGTTTTTGTTTTTTGTTTTTTTGAGATGGAGTCTCACTCTGTC
rs2927609 175 ACCCAGGCTGGAGTGCAGTGGTGTG

CTGGAGTCCAGTGGTGTGATCTCAGCTCATTGCAACTCCGCCTCCTG
GATTCAAGTGATTCTCCTGCCTCAACCTCCCGAGTAGCTGGGATTAC
AGGTGATCCACCAGACCTGGCTAATTTTTTTTTTTTTTTTTTTTGTA
TTTTAGTAGAGATGGGTTTTCACCATGTTGGCCAGACTGACCTCAGG
CAATTTGCCCACYTCGGTCTCCCAAAGTGATGGGATTACAAGCATGA
GCCACCGCACCAGGCCTATAAGTATTTTTGTAAGTAAAAACTATGTA
LNPEP TTTGAATATGTCTCAGGATTTTCAAGAAATGCAAGTAAAAAATAGGA
Region GCTGTGAAATAATTTTTGATTGTTGGATTTTGTTTCTTTAACCACAA
rs3096167 176 AATCACACATCAGTTGGACCATAAG
GGAGTCCAGTGGTGTGATCTCAGCTCATTGCAACTCCGCCTCCTGGA
TTCAAGTGATTCTCCTGCCTCAACCTCCCGAGTAGCTGGGATTACAG
GTGATCCACCAGACCTGGCTAATTTTTTTTTTTTTTTTTTTTGTATT
TTAGTAGAGATGGGTTTTCACCATGTTGGCCAGACTGACCTCAGGCA
ATTTGCCCACCTYGGTCTCCCAAAGTGATGGGATTACAAGCATGAGC
CACCGCACCAGGCCTATAAGTATTTTTGTAAGTAAAAACTATGTATT
LNPEP TGAATATGTCTCAGGATTTTCAAGAAATGCAAGTAAAAAATAGGAGC
Region TGTGAAATAATTTTTGATTGTTGGATTTTGTTTCTTTAACCACAAAA
rs3096168 177 TCACACATCAGTTGGACCATAAGTG
CCACTGCATTCCAGCCTGGGCAACTGAGCAAGACTCCATCTCAAAAA
CAAAAAAAAGAATACCTAAAAACATTTTTTATATCAGAATTTTTATT
CTTTCTAGTGGTATTCATAAAAGCATATTGCATATGATGCTTTTTAA
AATATCATGTGCCCTCACCCCCCACCCGCCATGCACAACTTGCAGAA
TGGAAATACTTCRACATGGTATTAACAGGTTTGGTGTTTTTATTTTG
GAGAGAGATGAAAAAGGCGTCTGTTAGTACCTTAATACCGCAAGTAT
LNPEP ACGTTTAGCAATGACAGCCAATACCAATGGACTAGATTGGATGATAT
Region TAATGAATAACTATTAGTTTTCTTCAGTGTGATAAGGTATTATGGTT
rs31398 178 CTGTAAGAGAATGTTCTGATATCTG

TACTCATTAATTCTTTTTCAAATCCTTTAAAATAATTTTAAGACAGT
TGAACACAGTCCACATCTATATGAGACTAAGTAGCAGTATATTATAA
CTAAGTTCTACATATGAAAGTAAATTTTTAGAATGACTGTAGTTTGA
ATTTTAGATTCCCAATTCGATAATCTATAGTATTCTATTATTTTCTT
TCTTTTTCCTCACL-TTTTTTTTTTAATAGGGATCTTCTCTCTTGTTGATGTTGAAAACTTA
CCTTAGTGAAGATGTGTTTCAACATGCTGTTGTCCTTTACCTGCATA
LNPEP ATCACAGCTATGCATCTATTCAAAGTGATGATCTGTGGGATAGTTTT
Region AATGAGGTAAGTGACCTGGGTAATTTATTTAGCTCTTACTGTAAAAA
rs3214461 179 GAGAGGAGTTCG

TTGGCCAGCAATTACCAGATCATTTTAGGCCAGCAGTGTAAATTCCT
GTGTTATTTTTTGTCACATCATGCTTATAATCATCTCAAAAGATAAA
GTAATCATCATTACTCTGTGTTTATAAGTGAGAAAACTGATACTAAG
GGACAGATTTGCCCAAAGTCACCAAGTCAGTGAGAAAATCAGTACTT
AAAATTTGTCTTT/-CTGACTAAGTCCAATAGTTATTCAATTATATCACAGCTAGTTCCTAG
TTTTAAGAAAAGTCCCCCATCAA.TCTTCCCCTAAAGGTCCTAGATTT
LNPEP TGACCAACTCTCTTCTGACACCAAAGGGCCCTGTAGTATTAAAATAA
Region TAAATTACTGAAAATATCTTGCCCACCATTGTGTCACATAAAGTCAA
rs33912722 180 TTCTAATACATGTCAAT

CAAAAACCAAATTTTAAAAATTAGTAGTTTTATCACCTAGGCAGAAA
ACTTTTCTATTAGAAATTATACAGTCTCTCATCTCAAATACCATGTT
TTACTGTTCTAAGAATCAAATAGTGCTATAGTGAAAA.AAAGAGAGTA
GTTTTTTTCTGAAACTATCTACTATACTGTATAACATGAGAAATTTC
TCAAAAAATATGT/=
TTTTTTTTTCCATAATCATGTCTGGTCTCTTTTTTGAGACCAAGATG
AAACCATGTTGCTTGGTCTTCAACCATCAGCTTATCTGTTCTCTAAT
LNPEP GATTTTTGTTGTTCTGGTTTGGTCTTAAAGTTTTGAGAATTCATTTT
Region ATTATAAATGTGAAAGTTCATTTAAATATTGTGTTCTTTTTGTTCCT
rs33918743 181 GTAAAGGAAAAA

AGGTTGCAGTGAGCCAAGATTGTGCCATTGCACTCCAGCCTGGGCAA
CAGGAGTGAAACTCCATCTCAAAAACAAAACAAAACAAAACAAAACA
GAAAACCCAAATTGGTGCTTCAAGAATATGATGTTATTTCTCAAAGG
TACAATCTAGCTGAAATCATATACAAGTAAGTAGGTGTGGACTTTTA
CTGTTGAGCTAARGTTTATGTTTATATATGTTTTATTCTTTAAGCTA
AACAAACATTCAGATAACATTCTATGCATTTTTTGAAGCATAGGGTT
LNPEP AGTAATGAGGACTTAGATTTTTTAATTAAACAACTCAGTAACTATAT
Region AAAAAGAAAAGGAGTCCCTTATGAATAAATATTAAAATTAAAAGAAA
rs33934033 182 TAGGCAACTATAAAAGTAAGTATTT

GGCAAAAAGAAACATTCCACTTGAATCTAACACTCTTTACAAAGATT
TCCCACCCAATGACTTCAGCTAGACCAGAATGAGTCATAGCCTCACC
AAGTCACAAGGTAGCCTGTAAGAAGTAACTCTCTTATCTGGACTTGT
TGCCTTCCTGAATAAAATCAGGATTCCACTGGAACCAAGGAAGGGAA
ATGGGTATCAGGA/-AGTGACTAGCTGTGTCTACTACATCCTGCTCTTCCCTTCCCCACTTG
GGTGCTCACTGCACAGCCTGCAGCCATCCACCTAGGACAACTCTTCC
LNPEP CCAGGCTCCTCTCTTTCCACATTCCCTTGGTGACACTTCCCCTCATT
Region GCAGCCACAATCCTCAGGGGCTTGTTTTCAGGCTCAGCACAGTATTG
rs34037881 183 GATAGGAAAAGT

TTGATGGGATTGTTTTATTTTCTTGCTGATTTGTTTGAGTTCCTTTT
AGATTCTAGATATTAGCCTTTGTCAGATGTATAGATTATGAAGATTT
TCTCCCACTTTGTGGGTTGTCTGTTCACTCTGCTGATTGTTGAATAA
GATGTCCTTTCCCCACTTTATGTTTTTGCTTTGAGAAATTGTTGACA
GTTTTAAAATCAV_ TAATGAGAAACTAAAATTGGAGTTAAGAGTTCACCAATGTGCTTTTT
CCAAATTATGAATTGTTCAAAAAGTTTCCATTTTCCACCTGTTGAGA
LNPEP TCTTCATTTTGAGGTTTTTATTTTCTACTGTGTCTAATCTACATCCC
Region ACTTTTCCAGGTGAGTATAGAGGGCTTTTTAAAATCAATTAGAAAAA
rs34323164 184 AATAAATACTGTT

AACTAAACATTTTTCTCCCTGTTTAGGATGACTATTTTTTGAATGTG
TGTTTTGAAGTAATTACAAAAGATTCATTGAATTCATCCCGCCCTAT
CTCCAAACCAGCGGAAACCCCGACTCAAATACAGGAAATGTTTGATG
AAGTTTCCTATAACAAGGTAGTAAATATCAGGTGCAGGTGGAAGCTC
TGCTTTCAGAAGA/=
AAGTAATAATGACTATAGAATCAGCAGTTTAAGTCACTGGTGCCAGT
TCCTGCTACTTGTTTCACTTTTTATTTGTTCACTTTTCAGACATCAC
LNPEP ACATGTTCCGTAAAATTTAAGCTTCCTTTAAAAACATACCATACTAC
Region CATTTTCTTTATCTCTTTTTTCAACTCTTTTGTTTTTTTTTAAAGGG
rs34701361 185 AGCTTGTATTTTGA

CTCTTATCAGAACGTAAAATGTGCCAGACTCTTAGTTAAATCTCTCC
TGGATCAA.AAAAAGACCTGGGGTGGTGCAGTGGCTCACACCTGTAAT
CCTAGCACTTTGGGAGGCCAAGGCAGGAAGATTGCTTGAGGCCAGCA
GTTCAAGACCAGCCTGGGCAACATAGTGAGAGCCTGTCTCTACAAAA
AAATTAAAAATTA/_ AAAAAAAAAATTAGTCAGGTGTGATGGTATGCACCTGTGGTCCCAGC
TGCTTGAGAGGCTGAGGTGAAAGGATCACTTGAGCCTGGGCAAAGTG
LNPEP GAAGTGAGCTGTGGTCATGCCACTGCACTGCAGCCTGGGCAAGAGAG
Region TGAGACCCTATCTC GAGATCAGAAAGGT
rs34815125 186 CTTTTTCTATAG

CAGATGCCTTGGTTATGTGCGGATTCTACCGTCATTTATTTCAGCCC
TAGATGGTCCTAAAGTAGAGAGAGACAGATTTTTCTTAAACTATTGC
CTTTAAAAATCATTTATTTTTATCCCCATTTTTTTTGTTTATATCCA
AAGGGTTTTCAACAAGCTGCCCCTTTCCCAACACCCCAGCCCCTCAA
CGAAAACATAATAG/_ GAGACACATCATTTAATTTCTCAGCCCTTTCATGATCTCTTAGACTA
ATCTTAGTTTTCATAAATTAAAGGCCTACTTGGCTAAGTTCATTTAC
LNPEP TTTTTTTTTCTCCTACTTTTCTTGATCTCTGGACCCAGGAATCCCAG
Region ATGATACAAAACCCTTTGTTTCATACCTGCCCTGCCATAGAATGATC
rs34962665 187 TAGACCTTTAAG

GAAGTAAGTAGAGGCAGGTGGTAGGGTGGCAGTAAGAATTGATTCCC
CCAAATTAACTATGCTGTTTGTCCTAATTTTATATGTGTTGTAGCTT
TACCCTTCAAAAAGAAAGAAACTTAGTTCTATTTACAAAGGTAGTAA
ATTCAGTTTGATTTAATTGTGCTTTCAAAAGTAGTGTAAAGGGAAAA
GAACCGAACCTTA/-AAAAAATTCTGTAAGAATATTATAAACTCAAAATTTATTTCCATGGC
TTTTGACATATTGAAAATAAACTGGGGATAAATACCTACCTTGACCA
LNPEP GCAACCTTTACACCAGTAGCCATAAAATGAGGCCATTCAGATAATGT
Region TATTGAAAGAGGTGAAGTTCAATGCCATTCGTAGTAATAATAATATC
rs35199417 188 TGGTATCCAAAG

GTAGGTTACTGATTTGCCCAAAGTCATGTGGTTAGTAAATTATAGAG
TCTGGGTCTTCTGACTCCAAATCTCATACTCTTTCTTTTCTCCTTAT
CTTCTAGTAGTGGAAACTAAGCCCAAAATGAGAGAGGCTACCACCTC
CAAGTGGTGGTTGTATATGTGCTATATTGATTGGTACCTGAAATATG
CACACCAGGGCCAT/-TATATTTGCCGTGATTATAGCCACGCTGGGATGATCTCCCAAGTTCA
GATCTAGTTATTCTTTTACTTAACTGAAAATCTGCATTTCTCCTTGT
LNPEP TTCTTTTTATGCTTTTCCACCAACCTGTAATCGAGGACTTTTCTTTT
Region TTTTTCCCTTGAGACAGCATCTTGCTCTGTCGCCCAGGTTGGAGTGC
rs35304156 189 AGTGGTGCAATC
ACTACCTCATAGAAGAAAATATTTAAAGCTCTTTCTGACTTCATTTG
TTTATATATGCCATCTTTTTTTTTTTGTTTTTAAAGAAACAAGATCT
CACTCTGTCACCCAGGCTGGAATGCAGTGGCATGATCATAGCTCACT
GCAATTTTGAACTCTTAGGCTCAACTGATCCTCCCGCCTCATCCTCC
CGAGTAGCTAGGMCAACAGGCATACATCACCATGCCTGGCTTAATTT
TTTTGTAGAGACAGAGTCTCTCTATGTTGCCCATGCTGGCTTGAACT
LNPEP CCTGGCCTTAAGCAATCCTCCTGCCTTGCCCTCCTAAAGCACTGGGA
Region TTACAGGTGTAAGCCACGATGCCCAGCCTGTATATGTCAACTTAGTC
rs35475916 190 TTAAGGAATGTTGTTTGAATTCTGT

GTCTCACTATAAAAATTTCTAGGAAAAGAACATGCAAAGCCTGATAA
AATGATGTTTTCTTTTTCTCTTCCTCTTCTTAGTAAAGAGGAATATA
CAAAATTCACTAGAATATAATTGATTTAATCTAGAGCTGGAACTGGG
CCAATACATGATGAAAGTAGTGTCTGTTACTTCCTCTTCTCAACTGT
GTTATTTCCCTTGCT -CTGCTGCTGCTGCTATTTTAATTCCTGCCATTTCGGGTTTAGAGAGT
CCACATGAAAACTTCTGTCCTTACGTTTGACCCTGAGGACAGCTGAG
LNPEP CCTTCTTGGTTCCTAATGCTCCAGTGAGAATTACTCTTAATTTAACT
Region GCATTTTTATTTTTTCTATTCTCAAAAGAAAGGTAGCAGAGAGGGTG
rs35562078 191 ACTTCAGGCTTC

AA.ATGAGGTTTCACCATGTTGGCCAGGTGAACTCCTGACCTCAAGTG
ATCCGCTCACCTTAGCCTCCCAAAGTACTGGGATTACAGGCATGAGC
CACCGCGCCCAGCTGAAAGTATATATACTTTCTAGTTTGTGATATAT
TCTAAAGTATATCTAAAGGTTGGTATTTTGGCATTTTGAGGTCCCAG
AACTGAAAACATT/-AATTAATAGTTTTTTTTTTCATATGAATGTAGGTCCTATGAATCACT
TTTATTACCGCAGTGTGGTGCATAATCAAACAAGGAGGACTTAGTTG
LNPEP TCTTAAAAAATTATTTTTGCTTTCATGTTCAGATTGGTATCCAGTTG
Region AAAGTATTTTTCAACTTCAAAAATGGGAAGTCTGGGCAACAAATGAG
rs35929998 192 ATATTTGTGGGTTGTA

AACCCTTTGTTTCATACCTGCCCTGCCATAGAATGATCTAGACCTTT
AAGAGGACTAGAATCAGCCCTCTTTTTCTGGGCTTTCTGGGGCCAGG
AATGACTAGGATTGATCTGCTTTCTCAAGCTTTGCCCCGGGCCTAAC
CAGGTCAGCCTGGGACCAGCCCGTGGGGTTTGACTATACCTGGAACA
GATGGTTAATCTA/-TTGGCTTGCTATAATGTAATTTCCATTTGGCTGGCAGTAGGGAAAGG
AAGGTACTTCCTGTAAGCTACACACTGATTTTCATCCAGGTGTTCAC
LNPEP ACATACCGGGTTTTATGAAAGAGAGCTTGACCCTCGCATTCCTGATT
Region AGCATTTTGTTAGTGTGAAAGTAAGGTATAGACACAGAGACAGGTAT
rs36019589 193 AATCACAAAATG

CCCAGGATCATCAACCCATCAAATTTCACTTGAAGTATTTCATTATG
GCCATGTAAGCACAGGTTCCAACTGAAGGAAGAGTGATTTTGCCCTA
GATTGGAATGCCAGAGTACCAGGGGATATAAGGAGAAATATTTTTAG
TAGAAATCTTTATTTGTAAGGTTTCCAATTCTGTGCTTCATGTGTCT
GTATAGTCACTTYCCTTCTTTTCCCAAATGACATTTGAAGGCTTTGC
TTTGAAAGGTTTTAGAGGATAAATTTAATGGCTACTTCTCGTAATAA
LNPEP AATTCCAGTATGCACACCACAGTTCAGAGACTGAGTACTGTGCTACT
Region TGACGTTGTGTTAGGTTTAGTAGTCTCTAAGTTCCCCTCTAGAGGTA
rs3734015 194 AATGAGATGATTTATTTTGTTTCAG
TCAAAGCCATTTTTTTGTCTTTCTCTCTTTTAATTTTGCTTAGTTCT
ATTAGAGAAGCTTTTATAAATTTTTCTTCTCTGAGGTATGATTAGAA
TACATATTTATACTGGTAGATAAAGTAATTAAGGGATGTATTTCTTG
TTTTTACACATAGCTTACATTTCCTGGGGATAATAGGCATTATAGAA
GGAGAACTAAAGRCAAGAACTTTCAAGTTCCCATTGCAATTATACAT
TTGTGTTCAATCCCAGATCTCACGCAAGAATTGAAATGCAGGGCCAG
LNPEP TATGCCATTTATTTTAAAAGTATTACATAGAGGGAAAATAAAATAAA
Region AATTATTTATCTGAATAGAATTATGGATCTTGCTTGGTCTCTTTCTC
rs3797796 195 CATTTAAGAAGGATCAAAAAGTTTC
CGTCTGCCTTTTTCTTGTTGATTTGTAAGAGTTCTGTATATATCCTA
GATATGAATCTTTTGTTGGTCATGTATATTTGCAAATATCTTCTCCC
ACTCCATCTTGCTTTTTTTTACTCTCTTAATGATTTTTTATTAATAT
GAGTTTTAAATTTTAATGTAATCTAGCTTATGAAATCTTTTCCTACC
CCTAGATATTCTSTGTTCTCTTCTGAAAACTTTATCATTTTATCCTT
TACATTTAGATCTGTGATCCATCTGGAATTGATTTTTGTGGATGGTG
LNPEP TGAGGTAGACACCAAGATTCATTCTTTTCAGTATGGATATCCAGTTA
Region TCCCCAGGACCAGTATATTTTATTGCATAGAATTATGTTTGAGGTAA
rs38029 196 TTAGTATGATATCAACACCATTTGG

ATAACAGAAATTTATTCTCTCATAGTTCTGGAAGCCAGAAGGCCAAA
ATCAAGGTATTGGCAGAGTAAGGTTTGCTCCTTCTGAGGAAGAATCT
GTTCCATTCCCCTCTCCTAACTTCAAGTGATTGCCAGTAATCCTTGG
TATTCCTGGGCATGTAGGTGACTAACCGTGGCCTTTGTCTCTGTCAA
CACAGTGTTCTCY/-CTGTGTTTCTGTGCCCAAATTGCCCCATTCTTAGATTAAGGCCCACC
ATAATCCAGTATGACCTCATCTTAACTTGATTGTACCTGCAAAGACC
LNPEP CTATTCCTAAATGAGGTCATATTCATAGGTCCCAGGCAGACACAAAA
Region TTTGAGGGGATACTATTCAACCTAGTACAGGTAGCAATAAATAAGAT
rs38030 197 TAGTGCATATCA
TCATATGGAGACTAACTAGTAAAATTGCTCCCTGTAATTCGGTGGTG
TAACTGCTCAGGAATTAGCCACAGCCATCTTCAAGTGTCAGATTTCC
TTTGCTTCCAGGACTTCAAGTGCCATTCTTTCCATTGCTGCCTTTGT
GTTTTAGTAAACTCTCAATGAGTATTGCCATTGTTCTTCACTGATTT
TTTTTTTAAATARGATTTCAAGCATGTGATTTTTTTTCTCACATTCT
TCATTTGTTCCTATTTGACAGTTATGAGTAGGATTTGAATTTCTTTT
LNPEP GTTCTCCAGTCATTTGGAATGGTTTTCTATCATAATGCTATTGAGAA
Region GGTAAGGCCAGTGAAGACACCACATAACAATGCAGTTAGGTATGTCA
rs38031 198 AGTGGGATCCCCTGCATTGCTTGTC
CCTACTTTAATTTGTGGTTGGAAAATTCTATAAGGTTGCCTACATTC
CCTCATTTTGTGTCTGCTGCAGACTTCTCTAATGACTTACTACTGAC
TTTGTTCCCACTAAGCTTTCTTGGGGGTCCTCAACATGGCACCCCAT
GAAGCCATTTCAGATCATTTGAAGGGATGTCGCAGCTAGAGCTCCTT
CTGTGGATGTATYTGTAGCAGTAGAGTGGAGCAATCCCAGGTCATAA
GGAAGGATTTTGGTTTTGGAGGTGTTCTAATGGGAGAAGCAGAACCA
LNPEP ATGTGACTATCTTTAACTTAACATTTATTTGGTCATCTTTGGGACTA
Region AAAACTCCTTGAGGAGTTTCACTGTGCTCCATATGTCCTCAGGATGA
rs38032 199 AGGATGGTACAACAGACTGAGACTA

TTTGGAGGTGTTCTAATGGGAGAAGCAGAACCAATGTGACTATCTTT
AACTTAACATTTATTTGGTCATCTTTGGGACTAAAAACTCCTTGAGG
AGTTTCACTGTGCTCCATATGTCCTCAGGATGAAGGATGGTACAACA
GACT-SAGACTAGGAGCCATGCTCTTTGCAGAAATTCATACTGAGAGG
TTATAATATGCTRGCATCTTTACCATTTATTTCCTATTTGAA'PTTTC
AGTTTCTCAGTTTGTTTGTTATTGCCATTTATTCCTATAGTTACAGA
LNPEP ACTGTCTTTTCCCCTTTGCTTGTAGAAGTCATCAGTCGTTCTAGATG
Rec,ion ATGG_ACTTGTTCAGGATGAGTTTTCTGAGAGTGTGAAGATGAGCACT
rs38033 200 TACTTGGTTGCTTTCATTGTGGGAG

TGGA~TTGTTCAGGATGAGTTTTCTGAGAGTGTGAAGATGAGCACTT
ACTTSGTTGCTTTCATTGTGGGAGAGATGAAGAACCTGAGTCAGGAC
GTAAATGGAACCCTGGTATGTTGATGTGGTAATTGTCTGAAAGCCTG
TGTCACAAGAGGYTCAGAGGACCTCTTGCTTTAACGATTCCTGGTAT
TTGCTGTGTGAAATAAATAAGCTTTTAGATCACACTCTGACATTTTA
LNPEP TACCAGAAATGCTACTTTTTTGCTTAGCTGTTATTTACTGTTACTAG
Region TTTAATAGCTGAAAGTCAATAATTTTCAAGTTTTAAAAAATTTTACT
rs38034 201 TTTAAAGAGAATTTTAGTAAGACAC
AAACAATTATTCTTGATGATAGAAATATGATAGAATGTCTTAGTTTC
TGTTTTCGTATTTTTGAGCTCTACCAGGGAATATACTGCTAGTTTTG
GGTTT'CCT'i'TCTAGACTAAAGAGCTTTATATTAATCACAGGATACTT
GGATCTTATCATTTTGCTACTTCAAAAGGGTATATGTTTCCT.kTTAG
AAAASACTI-TCAYGTCTATCCCATACCTTTCAGAGATAAGGACAGAG

LNPEP ATGATGCTACTCAAAAAGTAAACTAAGTTTTTAATGGTAAGTGTAGA
Re~ion CTGTAATATTAAGCGCTAAATAATGGTTCACTCACCTTTGGATTGAA
rs38035 202 AGACTTTATGTCAAGGATTTTTCAG
ATAASGACAGAGATAAGGATTCTCTGGTGATTTATCAGTAAT.kATAC
TGTATGCCTTTAATGATGCTACTCAAAAAGTAAACTAAGTTTTTAAT
GGTAAGTGTAGACTGTAATATTAAGCGCTAAATAATGGTTCACTCAC
CTTTSGATTGAAAGACTTTATGTCAAGGATTTTTCAGAATCCTTTCA
AAAGSATATTATRACTGGCTTAAATCTGAAATAATTCAATTA7~TTCC
ACTT~:AGGTGTTGCACTACATATTTAGCCTTTGATTTAGAGTTTGCA
LNPEP GCCTTGATAAAGCCTAAGAAGCCCAATCTAAAAGAGTCAGGTTTGCT
Reoion GCTGLTTCAAGACTCAGCTGAATACTACGTTCTCCATGAAGC.yTTTC
rs38036 203 TTTCTTTCCCCAGCTGGAATTAATC
TCTGTTCACTC-7GCTGATTGTTGAATAAGATGTCCTTTCCCC.z~CTTT
ATGTTTTTGCTTTGAGAAATTGTTGACAGTTTTAAAATCATAkTGAG
AAACTAAAATTGGAGTTAAGAGTTCACCAATGTGCTTTTTCC.Z~AATT
ATGAATTGTTCAAAAAGTTTCCATTTTCCACCTGTTGAGATCTTCAT
TTTGAGGTTTT'T'RTTTTCTACTGTGTCTAATCTACATCCCACTTTTC
CAGGTGAGTATAGAGGGCTTTTTAAAATCAATTAGAAAAAAATAAAT
LNPEP ACTGTTTTGTAAAACCCATTGCTTTGAACATGGCTGTTTAACACTTG
Region CCTTTTGATACTTCCTGAATAAAATGTTTATAGTTTGTCGCAPCATA
rs38040 204 TATGTTTAATTTATTCATTTAGCCA
T'TAT2TAGTATCCCACTTCTC`?'TAATTACACAGAATATTTTTGCCAA
ATTC2CAATTCTGAAACAAGTAGTTACCATGTTGACAGGGGT'PGACA
ATGATATGGAAACTACATATTCAGAAGACACTGAATTCTGGGTTTAG
AGGGTTTGGGTCAGTGGCAGACAGAACTCTGTTATGACTCTG'rTCTG
TTATTATATAATRAACTTAGAGCATTTTAAGCAGGTTTTCAAATCCT
GAAATAACTGCTCTAAGTTTGGTATAATAACAGAACCTCAAGTTTTA
LNPEP AATTTTCTTTATTGACAGGTCCACTATGGTCTTCAAAAATCACACCA
ReQIOn GTAG:~TCTAATTGGAATAGATTTAATA"'AGCTAACTGAACTCCTGAT
rs38042 205 TTTCTT'GTTTGTTAATAGTACCTGT

ATACGAGATTGAGATAAAAGGTTGCTTTGCATGTTCAAGCACCAGCA
AGGATCCAGTGTTATCTGAAGTAGAGTAAGCAGAGGAGAAAGTAGTA
GATGAAGTTAGAGGGACTGTAAGAGGCCAGATTATTATAGGGTCTGC
TAAGCCATAGTAAGGACCTTGATTTTATTCTAAGTGAAACGAAAAGC
AATTTGATCAGGRAAGTACCGTGATATGGCTTATTTTGTAA.AAGATC
ACTCTAGTCTTCAACAGTACATGGAGTAAAGAGGACTAGTTP.GGAAG
LNPEP TTATTGTAATAGATGGGTGGCGAGATAATGGTAGCCTGGACAAGGGT
Revion GGAAGTTGTGAAGGTGATGGAGGTACAACTGGACTTGGAGTGTGTTT
rs38043 206 TAAAGATTGATCCAGTAGAATTTGT
TCCCAGCACTTTGGGAGGCCAAGGTGGGTGGATCACCTGAGEITCAGC
AGTTCAAGAACAGTCTGTCCAACATGGTGAAACCCCGTCTCTACTAA
AAATACAAAAATTAGCTGGGCGTGGTGGTGGTGCCTGTAATCCCAGC
TACTCAGGAGGCTGAAGCAGGAGAATCGCTTGAACCCAGGAGGCGGA
GGTTGTAGTGAGYGGAGGTCGCACCACTGCACTCCAGCCTGGGTGAC
AAGP.GTGAGACTTCATCTCAAAATAAATAAATAAATAAATAAATACT
LNPEP TACAGTAGAGTGATGATTAGAAGATGGCTCF.AGAGAAAATGCAAAGA
ReQion GAGCAAATGGAGATGGCAAATTGAGGACAACTCTTTTGAGGAGTTTT
rs38044 207 ACTACAATGGGGGAACAAAAAAACA
ACTCGGGAGGTTGAGGCAGGAGAATCACTTGAATCCAGGAGGCGGAG
TTGCAATGAGCTGAGATCACACCACTGGACTCCAGCCTGGTGACAGA
GTGAGACTCTGTCTTAAAACAAAACAAAACAAACAAACAAACAAAAA
ACATATAAAGATGCTCTTTACTATCCATTTCCATCACCCACCGTCAG
TGGTCCAGACACWCTTTCTCCATGCTTCCGCTTAAGCTTCTCAGCAC
CAAGTATTGTGTTGCTTCTGTCTCTCATCCCTCTCCATTTCCCTCTC
LNPEP CCTTGCCATGTGTGTGTGCATGTATGTATATTTGTAGACATCAGTTT
Region AGCTCCCCTCCAACACGGAAGAATCTATCATTTGGTGTGCATACTGG
rs3849749 208 CAGTAGAGGGTGGGAGTTAAAAAGA
AGTTGCAATGAGCTGAGATCACACCACTGGACTCCAGCCTGGTGACA
GAGTGAGACTCTGTCTTAAAACAAAACAAAACAAACAAACAAACAAA
AAACATATAAAGATGCTCTTTACTATCCATTTCCATCACCCACCGTC
AGTGGTCCAGACACACTTTCTCCATGCTTCCGCTTAAGCTTCTCAGC
ACCAAGTATTGTRTTGCTTCTGTCTCTCATCCCTCTCCATTTCCCTC
TCCCTTGCCATGTGTGTGTGCATGTATGTATATTTGTAGACATCAGT
LNPEP TTAGCTCCCCTCCAACACGGAAGAATCTATCATTTGGTGTGCATACT
Reaion GGCAGTAGAGGGTGGGAGTTAAAAAGAAAATTTGGCCAGCAATTACC
rs3849750 209 AGATCATTTTAGGCCAGCAGTGTAA
GTTGACCATACCAGTTAATCTTATTTACAGAGGATGTGGAGA~3TAAT
GATTAATATGTTGAGCTGATGAAGTAGACAAGTGGCTGCTGTATGTA
GAAGTAATGTTGGAACAAATAATACGTCCCAGAATAGTTTCT~-,TAAG
GCTGATTTTACTCTGAAATTTTAATTAAT'T'TATAGTTAATAT.kACTA
CCTCTGTA'~'TTTKTTGTAGTCTTTTGTGGGTAGAGTTGAGGA..kGAGA
TAGGaATGGGATTATTTTGACATGGCTCATGATCACCAAAATGTGAT

Reaion TAATAATTTGCTGAAATCTTCCTTATTT-TTACTTTTTATGA.AGCTT
rs3909451 210 TTAGCCATTTATATTAGATGGTGAT
TCATTTTGTTGCCCATTCAGAGAGCTTGTAAGCTTGGGCTCTGCCGC
TTTTGCAAAAGCCAAGGTAAAGCCAGGATCGCTGCCAAGTTGTTTGC
ACTCTTTGGAGTTCTAGTTAGCTCAGGGCCTGACTGTATTTTTCATC
CATCTTTTCTGAAGTGTCTTTGGGCAGTATGTAGTTATTTATTACAA
AATTATATTCACSTAAATGCCAACCATCTACAAAAACAATGAGTAAT
TTTTCTACTTTGAAGATACACAGATGGGGACAAAAACCCTGTTTTGG
LNPEP AATTCTGTTCTATTCCTCAGTATCCAGAAAGTTACTGACACAGTAAA
ReQion ACAAGGAA-zsGTTCTACCCTAAGAGCCGCCATCACTTCAGGCCGCTGG
rs39602 211 TTTGTCAGCCATCTGTTGCTTCTTA

TTGACATGTATTAGAATTGACTTTATGTGACACAATGGTGGGCAAGA
TATTTTCAGTAATTTATTATTTTAATACTACAGGGCCCTTTGGTGTC
AGAAGAGAGTTGGTCAAAATCTAGGACCTTTAGGGGAAGATTGATGG
GGGACTTTTCTTAAAACTAGGAACTAGCTGTGATATAATTGAATAAC
TATTGGACTTAGG/-TCAGAAGACAAATTTTAAGTACTGATTTTCTCACTGACTTGGTGACT
TTGGGCAAATCTGTCCCTTAGTATCAGTTTTCTCACTTATAAACACA
LNPEP GAGTAATGATGATTACTTTATCTTTTGAGATGATTATAAGCATGATG
Region TGACAAAAAATAACACAGGAATTTACACTGCTGGCCTAAAATGATCT
rs3985004 212 GGTAATTGCTGGCCAAA
GAGCAGGTGATCAGTTATATCAAATGCTATCAATAGGTTGATAAGAT
GAGC:CTGAGAATTCACATTTGTATGGCACCAGGAAGTTTACCAGTGA
CCTTGATAAAAATACTTCCGGCCGGGCATGGTAGCTCACGCCTGTAA
TCCC:AGCACTTTGGGAGGCCAAGGTGGGTGGATCACCTGAGGTCAGC
AGTTCAAGAACASTCTGTCCAACATGGTGAAACCCCGTCTCTACTAA
AAATACAAAAATTAGCTGGGCGTGGTGGTGGTGCCTGTAATCCCAGC
LNPEP TACTCAGGAGGCTGAAGCAGGAGAATCGCTTGAACCCAGGAGGCGGA
Region GGTTGTAGTGAGTGGAGGTCGCACCACTGCACTCCAGCCTGCiGTGAC
rs42983 213 AAGAGTGAGACTTCATCTCAAAATA
TACCTCATAGAAGAAAATATTTAAAGCTCTTTCTGACTTCATTTGTT
TATF,TATGCCATCTTTTTTTTTTTGTTTTTAAAGAAACAAGATCTCA
CTCTGTCACCCAGGCTGGAATGCAGTGGCATGATCATAGCTC'ACTGC
AATTTTGAACTCTTAGGCTCAACTGATCCTCCCGCCTCATCC'TCCCG
AGTAGCTAGGCCMACAGGCATACATCACCATGCCTGGCTTA,~.TTT'TT
TTGTAGAGACAGAGTCTCTCTATGTTGCCCATGCTGGCTTGP.ACTCC
LNPEP TGGC'CTTAAGCAATCCTCC'i'GCCTTGCCCT'CCTAAAGCACTGGGATT
Reg1011 ACAGGTGTAAGCCACGATGCCCAGCCTGTATATGTCAACTTP.GTCTT
rs430827 214 AAGGAATGTTGTTTGAATTCTGTTT
TTGTTTTGGCTGGCGATCACCCTGCTCAGGTTCAGACCTTACTTCTG
TTTCACCATCTGTGGCCAGTGGCTCCAATGTTAGTTTAGTTCTCCTA
GCCTTTGTATGGTAGGCAGAATAATGGTCTCCAAAGATGTCCATTTC
CTA~.TCCCTGAAGCCTTGGTAATATTTTAGGTTACATAATGAAGAGG
AGTTAGGTTGCARTTAGAGTTGCGGTTGCTAATCAGCTGACCTTAAA
ATAPAGAGGTTATCCTGGATTATCTAGTTAGGCCCAGTGTACTCATA
LNPEP AGG`ITTTTAAAAGTGAGAAAGTGAGGCAGAAGAGTCAGTATCAGAGT
Re~ion GACAAAGTGTGAGAAAGATTCAGCCTGCACTTGTGGCTTTGATGATG
rs4360063 215 GGACGGGGGCCCAAGCTAAGGAATG
CTCTTATTTAAAACATTTTAACTTTAT'CCTTTATCGTCACCACAATA
ATGAGCTGTTGTTCTTTAAAGCAGTGAACTAAATACTCTGTTACACA
GAGAGCCATGCTCAACACTGTGCTTCGAGAACACATGGGCTGCTTCC
TTTGGTTCAAAATCTCCCCACTGGCGCATTTTAGGTGTTTTGATCAT
GAGTCACCAGGAKCTCTAAAGCACTTAACTGAGTCTGGGGATTTCTA
ATCTTTCTGCCAGTTGTTTGTAGGGAAGTGCTCTGTGAGCTCTACCT
LNPEP CTGAGGCTCCATGCTCCCTCTGGCCCTCCCTTTAATAGCTTCTCTTC
Region CACGGAGATGCAGTCAAGTGCTGAAGCAGCAAACAGCACTGGAATTT
rs4869314 216 TTGCCCCCACTTTTTTGTCTTCCCA
ATGAGCTGTTGTTCTTTAAAGCAGTGAACTAAATACTCTGTTACACA
GAGAGCCATGCTCAACACTGTGCTTCGAGAACACATGGGCTGCTTCC
TTTGGTTCA-AAATCTCCCCACTGGCGCATT'PTAGGTGTTTTGATCAT
GAGTCACCAGGAGCTCTAAAGCACTTAACTGAGTCTGGGGATTTCTA
ATCTTTCTGCCARTTGTTTGTAGGGAAGTGCTCTGTGAGCTCTACCT
CTGAGGCTCCATGCTCCCTCTGGCCCTCCCTTTAATAGCTTCTCTTC
LNPEP CACGGAGATGCAGTCAAGTGCTGAAGCAGCAAACAGCACTGGAATTT
Re.giOn TTGCCCCCACTTTTTTGTCTTCCCATTGATTACCATGTTAACATGTC
rs4869315 217 ACTCTGTGCATAACCCTGGCAAAGA

TAGCACCTAGCATATGTTGATCTTATAATAGTGATTAATAAGCAGTT
AATGATTGATTAAAGAACTTATGGTCTGTCTTTGGGATTCATGTAGA
TAATAGGAAAGGCAAAGCAGAAAAATTCAGTTAATTCAGATGATTCT
AATAATTATTAAAATATTTTAAAATTTCCAACTGCAAAGAAAATAAT
TTTTTATAGAACSATTAGACCCAGAGAACTCATACCTGTAATTAGAA
GAACCCTAAGTCATTGTAGACAGAAGAGATCCTTTCTTTTTTACAAG
LNPEP CACTTGTGTCCCAGGGACAGTAATAATATTGTTTAATATTTCTGCAG
Region CAGTTTACAGTTTAAAGACACTTTCATGGCCGGGTACAATGGCTCAC
rs4869316 218 GCCTGTAATCCCAAGACTTTGGGAC

TGCCACCCAACTTTTAAGATCCAGCTGAGATTTCACCTCCTCCTTAC
AGAC:TGTTCCAGCCCTCATTCGTTTGCCTGTCTGCTAAATTCTTAGC
AGTGCACTTATAA.TCTGTTCCACATAATAGTACCCTCTTTTATTGTT
TTTATTAGTTCAA.TAATGATAATGTGCTTAAGAACAAAAATTGTGTC
TATTCTTTTTTTT/-ATGTGATAGCACCTAGCATATGTTGATCTTATAATAGTGATTAATAA
GCAGTTAATGATTGATTAAAGAACTTATGGTCTGTCTTTGGGATTCA
LNPEP TGTAGATAATAGGAAAGGCAAAGCAGAAAAATTCAGTTAATTCAGAT
Revion GATTCTAATAATTATTAAAATATTTTAAAATTTCCAACTGCAAAGAA
rs5869737 219 ApTAATTTTTTA

GAA.F,TGCCTATACCTGTGTGTATGTAATTTGCAAGCTCTTTTGAAAA
TTTTTGGAAGACGAAGTGGTTTTATTGTTTCTTTATTTTTGA.AAC'PG
CCTC'GCTCTGTCAGCCAGGCTGGAGTGCAGTGGCACCATCTTGGCTC
ATTGTAACCTCCACCTGCTGGGTTCAAGCAATCCTCCCGCCTCAGCC
TTCC'AAGTAGCTG/-GGAC'TACAGGCATGCACCATCATGTCCGACTAATTTTTGT'PCTTGTT
GTTC~TTATTTTTTGTAGAGTCAGGGGTTCTGGCATGTTGCC'IAGGCT
LNPEP CGTP.TTGAACTCCTGAGCTCAATTGATCTGCCCACCTTGGCCTCCCG
Re-ion AAGTGCTGGGATTACAGGTGTGAACCACCACACTCGGCCAAGACAAA
rs5869740 220 GTGTTAGTAATT
GAT`ICTCATAAGGAACACGCAACTTAGATCCCTCACATGCGCAGTTC
ACAA.TAGGATTCATGCTCCTATGAGAATCTAATGACACCTCTGATCT
GGCAGGAGGCGGAGCTCAGGCAGTCATGCTCTCTCGCCCACCGCTCA
CCTCCTGCCATGCAGCCCAGTTTCTAATAGGCCATTGACAGGTACTG
GTCCGCAGCCCTRGGGTTAGGGACCCCTGTTGTAGAGCATATAAAAA
CTGAAGAAAGTTTCATAGCATATAAAGATTAGTGCTTGGGGTTTCTG
LNPEP ACAGTGACAAAACAATTTTTTTCCTTTGGAATTTAGGATATACTTCT
Region ~ TATCCTGTCCTTTTTCGCCTCTTGCCCTCAACTCCAATGCATTTTCC
rs6556942 221 TTACATAAATTAAAAGGGACCATCA
TCTTGAAAATCCTGAGACATATTCAAATACATAGTTTTTACTTACAA
AAATACTTATAGGCCTGGTGCGGTGGCTCATGCTTGTAATCCCATCA
CTTTGGGAGACCGAGGTGGGCAAATTGCCTGAGGTCAGTCTGGCCAA
CATGGTGAAAACCCATCTCTACTAAAATAC AAAAA
AAATTAGCCAGGYCTGGTGGATCACCTGTAATCCCAGCTACTCGGGA
GGTTGAGGCAGGAGAATCACTTGAATCCAGGAGGCGGAGTTGCAATG
LNPEP AGCTGAGATCACACCACTGGACTCCAGCCTGGTGACAGAGTGAGACT
ReuiOn CTGTCTTAAAACAAAACAAAACAAACAAACAAACAAAAAACATATAA
rs6859160 222 AGATGCTCTTTACTATCCATTTCCA
TCCTGAGACATATTCAAATACATAGTTTTTACTTACAAAAATACTTA
TAGGCCTGGTGCGGTGGCTCATGCTTGTAATCCCATCACTTT--~GGAG
ACCGaGGTGGGCAAATTGCCTGAGGTCAGTCTGGCCAACATG:~TGAA
AACCCATCTCTACTAAAATAC TTAGCC
AGGTCTGGTGGAKCACCTGTAATCCCAGCTACTCGGGAGGTTIAGGC
AGGASAATCACTTGAATCCAGGAGGCGGAGTTGCAATGAGCTGAGAT
LNPEP CACACCACTGGACTCCAGCCTGGTGACAGAGTGAGACTCTGTCTTAA
Region AACAAAACAAAACAAACAAACAAACAAAAAACATATAAAGATICTCT
rs6859168 223 TTACTATCCATTTCCATCACCCACC

CP.CTTAGACATGGATGTCTATGCATAGACATGGATGTGCAGGAGGTG
AP.TGGCACTTCAGAGGACAGGTTCCTGTCAGCCTCTTTGGATTCACG
TCCCAGCTCTACAACTTTCAGCCTGGGTGATCTGGAGCAAGTTACTA
AATCATTATGTGTTTTTATTGCTTCACCTATAAAATGGCACCTGCTT
CATAGAGTGGGCRCAAGTATTAAATTAGATTTTATACGTAAGCATTC
AGCACAGTGCCTGGTAAACTGTCAAAAAATGGTGGCCGTTTACATTT
LNPEP TTTCTGCATAAAAGTTTTGAAGGACTTCAGTTAATTCAGAACATAAA
Region AGTGGGTCATGAAATAAAAGTAGCTCTATACTTGGAAGGCAAGAAAA
rs6868302 224 TTrGAATCTAATTCTATTTTTTCTA
CCTTGGCCGTTCAGTCAGAGGGGTCCATTCGGTCAGTTGAGGGGCCT
AGAATTTTATTTTTGGTTTACAAAATCATTCCAAGATCCTCTTTAGA
GGAAAAATTTATAGAGATTAGTGGGAATGATGAGGAGAACTCAATCT
TGAGAGCTCAATCAAAAGGAGATGTTTAAATATCTTTTTAAGTTGGT
ATTGGTAAAGTGMTTTGAAGACAGAAAGAATGTAATACATGTCTGGT
GTCTGCTTGTCCTATAATTGTCGGAAGGGCCTCAATGATGAAATAAG
LiVPEP GGAGGCTGCCATGACACT^'GAGTCTTGGTGAGAGGAGCTAGTGTGTC
Region CACATTTATCAAGATCACCTGCAGGAGTTTGGGCTGGCCCCCTCTTA
rs6871162 225 TTAGTAGTTTCTCTGTTTTTTAAAC
AARATACTTATAGGCCTGGTGCGGTGGCTCATGCTTGTAATCCCATC
ACTTTGGGAGACCGAGGTGGGCAAATTGCCTGAGGTCAGTCTGGCCA
ACP.TGGTGAAAACCCATCTCTACTA.AAATACAAAAAAP,AAAAAAAAA
AAAATTAGCCAGGTCTGGTGGATCACCTGTAATCCCAGCTACTCGGG
AGGTTGAGGCAGRAGAATCACTTGAATCCAGGAGGCGGAGTTGCAAT
GAGCTGAGATCACACCACTGGACTCCAGCCTGGTGACAGAGTGAGAC
LNPEP TCTGTCTTAAAACAAAACAAAACAAACAAACAAACAAAAAACATATA
Region AAGATGCTCTTTACTATCCATTTCCATCACCCACCGTCAGTSGTCCA
rs6873441 226 GACACACTTTCTCCATGCTTCCGCT
GTGGCTCATGCTTGTAATCCCATCACTTTGGGAGACCGAGGTGGGCA
AATI'GCCTGAGGTCAGTCTGGCCAACATGGTGAAAACCCATCTCTAC
TAP.AATACAAAAAAAAA TTAGCCAGGTCTGGTGGAT
CACCTGTAATCCCAGCTACTCGGGAGGTTGAGGCAGGAGAATCACTT
GAATCCAGGAGGYGGAGTTGCAATGAGCTGAGATCACACCACTGGAC
TCCAGCCTGGTGACAGAGTGAGACTCTGTCTTAAAACAAAACAAAAC
LNPEP AAACAAACAAACAAAAAACATATAAAGATGCTCTTTACTATCCATTT
Re2ion CCA~,CACCCACCGTCAGTGGTCCAGACACACTTTCTCCATGCTTCCG
rs6874656 227 CTTAAGCTTCTCAGCACCAAGTATT
CTTTGTGGCTTCATCTCCAGCCACACTGGACAGCCACCCCCAGTTTC
TGCACATGCACTGCTCTCTTGTGTTCCCGGACCAAACTGAGGGTCAG
GCTC;CTATTTTTTGCTGCCCCAAAACGAGATGCAGATGAACTGGGAA
GAGP.CTT'TTTATTTCTATAACCAGTTATATAGGGAGAAGGCCTGGAA
A'TTP.TTGCCAGAMCAACTCAAAATTACAAAGTTTTCCAGAGCTTATA
TACCTTCTAAACTATATGTTTACGTGTAAGTGTGCATTTCTCTAAAG
LNPEP ACATAAGTGATTAACTTCTTTTAATCCATAACTAAGGTCCGAGTCTT
Revion GAAGACCTTCCTCTTGAGCCTCAGTAAATTTACTTAATCTAAATGGG
rs6879678 228 TCCAGGTGCTGGGGTGATTACCCTT
ATTGGAAGAGGAGAATCAATGATGAAGATGAAAGAAATGTGG.?~GATT
GGGGGTAAAGGAAGAAGCTGATAGGCAGAGATTTTAAAAATGGTCAT
GCCTTGATCCTTGCAAGTCTTTGGTTCAGAAATGAGCTTCAGTTGGA
GAGC.L,GGACACTGTTGTATGAGGTTGAAGACAGAGTCTAGGTPGGAA
GGGG.kCAGGTAGRTAGGTCTGGTTGGATTAATGGAATTGGGGGCTCA
GGGGACAAATGAGTTAAGATTGGCATTTGGGAGCCTTGCCAAGAGAT
LNPEP AGAAAACATTTGCCAGAAATTTAAGCATACTGTCTTTTTTATAGTCA
Region GAAA.t~TTCAGTCACTCGTAAGTTGGGACTGTTCACTTGTCTGAATGT
rs6887500 229 TTTAGATTTAAAGAAAAAATATAGC

AAAGAAAGGAAGGAAGGAAGAAAAAAAAGGAAGGAAGGAAGGAAAAG
AAAAGAGGGAGGGAGGGAAGGAAGGAAAGAAGGAAGGAAGGAGAAAG
AAAAGTAGATCTAACTTATTTTGGGCATGTGTATTAGTTTACTAGTG
TTAGCAATGGCAAATCCGTCGGGTCTGCAGAAACTCTATTTTTGCCT
TCTTGGAGGAAAKAATTCTGCTGAGGGGCATAAGGCAGAG.?~GACTGA
GGCAACTTTTAGAGCAGGAGTGAAAGTTTATCAAAAAGTTATAGAGC
LNPEP AGSAATGAAAGGAAGTAAAGTACACTTGCAAGAGGGCCAAGTGTACC
Region TGAGAGATCCAAGTGCACTGTTTGGCCCTTGACTTGGGGGTTTTACA
rs716848 230 CA'TTGGCATGGTGCCAGGATTTCTG
ATTGAACCTTTTTCTCCTAGATTTTTCTTTTTTCCCTCTCATTTAGT
TCTTTTTTAGTCTTGATTTCCCCACGGAGAGTCTCATCTATTCACAT
AT`CCTCATTTTTTCCTTTTTAAAATACATCTTCCTGCTTAATGATGG
GGATACAATTGAAA.AATAATAAAACACGTCTTCTTCAGGGATTCTTT
TTI'ATTTATAATRGCTACTCTAAAGACTCACTAAATACAAGCAATA
TC~'GGACCACCTTAAGATTGCTTTCTAATGATTTTGTTTACTTAGGG
LNPEP TTCACATTTTCTTGTTTCATTAAATGTCTAGTAATTTTTTATTACAT
Re~ion ATTGAATAGTGTCAATGGCACATGGTAGAGATGCTGAATTAAAAAAA
rs7700332 231 ACTCTGTAAAATGTTGATTTTTCTC
AAAATACCTTGAAATACTTACTGACATTATAGAAATTTAGC'.CCTTCA
CTC'TGCTGATGTTTATAGTTAAGTGTCAGAAATACTTTTATACAGAA
GAC'CTTGTATGGTTCCTTTGTGTGAGTGGACAGAATTTGTCGAGCAA
AG;~.CCTGGAATCCAGCATATGAGAATGTGCAATAATTGTTCAAATGA
ATAAGCTTCTCARATTTGGCCTTTGTATAATTAAAATCAGAGTGCTG
AAGTGTTGCATATTCCTCATTCTTCTCATTCTTGCAAGTCTCTCTCT
LNPEP CTCTCTCTCTCTATATATATATATACATATATACATATATACATATA
Re2lOn TACACATATATACATATATACACATATATACATATATACACATATAT
rS7703341 232 ACATATATACACATATATATACATA
AGAATACAACTGGATTTTCAGATTTGCTTCTGCATTCAGTC.AGTTGT
AATAGCACAA.GTCATGTAGCCTGTGGAAAACTCTGCTGTACACTCAT
GAG?1GAAGTGGAGTGAAAATGGCATATAACATATTATGATGAAATAG
TTTTGACTCTGAAGGCCTCCTGCAAGGGTATCAGGGATTTC'PAGGTG
TACCCATATCACRTCTTGAGAACATTAATCTTGCGTTTTTCAGGAAC
TGGAGAGGAATAGTTTAGGAGTCCACAGAAGGTAGAAAGTGGAGCTG
LN PEP TTGGAATTGGGCAGCAAGTTTCTTAAGATAGATCTAGGTCACAGGAG
Region GGGAATGTTCTGGCCAGGCATATTTGACTGGCCACATTATCf~GATGC
rs7713127 233 CTTGGTTATGTGCGGATTCTACCGT
TTCCATCATCTGGTGATTGCGTTTTCCATTGAGGATTGTTTACATTT
TCTGGTCCTTTGTATTTCAAGTAGTTGTGGCTTGCATCCTGGACAT
TATGGGTGTTATATTGTGTAGACTCTTTTATCCTCTGAAGP.ATGTTG
ATATTTTTGTTTTGGCTGGCGATCACCCTGCTCAGGTTCAGACCTTA
GTTCTGTTTCACMATCTGTGGCCAGTGGCTCCAATGTTAGTTTAGTT
CTCCTA.GCCTTTGTATGGTAGGCAGAATAATGGTCTCCAAAC;ATGTC
LNPEP CATTTCCTAATCCCTGAAGCCTTGGTAATATTTTAGGTTAC,~.TAATG
Re-ion AAGP.GGAGTTAGGTTGCAATTAGAGTTGCGGTTGCTAATCAGCTGAC
rs7716222 234 CTTPAAATAAAGAGGTTATCCTGGA
AGACCCACAAAAACAATTCCCAAGCCP.ATTAAATTCAACTTTTAAAA
AGGAATTTCCTAATATACCATAGAGTTGGTGAGAAGGCAATGAATGG
GTCCCACAAGCTTTCATGTAGCCTTATGGGAAGAGTAAAGGTTAAGC
TGTGTCATGGTTGTCAACTGGGCAAAGCCACTGAAAGGCAGGACTCT
CTATTAGTiGACRTAACAAAATATTAATAACTAGTGTTATGAATTAG

LNPEP TATCCAGGAGGGAAAAAAGTGGATGTTTCTGTACTGATGTTA.~TCAA
Re-ion AGGTTAAAAATCAAATGACATTTTGAGGAAAACAAACCTAAACAACT
rs7719705 235 CATTAATGGCCACACAACTTAAATT

ACGCATGTGCTACCATGCCTGGCTAATTTTTATATTTTTAAGTAGAG
ATGAGGTTTCACCATGTTGGCCAGGCTGGTCTCAAACTCCTGATCTC
AAGTGATCCGCCCACCTTGGCCTCCCAAAGTGCTGGGATTTCAGGCG
TGAGCCACCTGGCCTGGACTGTAATTGAGGATTTTTCTGTGTCATAT
TCTCAACTGTTGYTGGTGTGCTACAGAAAGAGGAGGAAATTTTTTTT
AATCTCTGAGGCGAGTAAAGGAAACCAGAATACTACAGGACACCTAA
LNPEP TTTTTTCAATCTTCATGAAAATGCAAGCTGTGAATTTGAGGTTTGGT
Region ATCGTGAAGCCAGAGTCTGTACAGATAATTCGCAGCAATTAATGACC
rs7722694 236 AC'--CTTCTTAATAATCTTCCATCAG
GTAATCCTAGCACTTTGGGAGGCCAAGGCAGGAAGATTGCTTGAGGC
CAGCAGTTCAAGACCAGCCTGGGCAACATAGTGAGAGCCTGTCTCTA
CAAAAAAATTAAAAATT TTAGTCAGGTGTGATGGTA
TGCACCTGTGGTCCCAGCTGCTTGAGAGGCTGAGGTGAAAGGATCAC
TTGAGCCTGGGCWAAGTGGAAGTGAGCTGTGGTCATGCCACTGCACT
GCAGCCTGGGCAAGAGAGTGAGACCCTATCTCP.AAAAAAAZ~AAAAAA
LNPEP AAI~AGAGATCAGAAAGGTCTTTTTCTATAGAATGTTCCACACAAGAG
Region ACAGCTTTGCAGGGCCATTTCAAAATAGGTCTAAGAAATATATTTTG
rs7726445 237 GGGTAAAATACCTTTATTTCTTTCA
GGATTGATCTGCTTTCTCAAGCTTTGCCCCGGGCCTAACCF,GGTCAG
CCTGGGACCAGCCCGTGGGGTTTGACTATACCTGGAACAGP.TGGTTA
ATCTATTGGCTTGCTATAATGTAATTTCCATTTGGCTGGCr?.GTAGGG
AAF.GGAAGGTACTTCCTGTAAGCTACACACTGATTTTCATCCAGGTG
TTC'ACACATACCRGGTTTTATGAAAGAGAGCTTGACCCTCGCATTCC
TGATTAGCATTTTGTTAGTGTGAAAGTAAGGTATAGACACAGAGACA
LNPEP GGTATAATCACAAAATGGTTGGAGTCTTTTATTGTGTCCTTTTCTTA
Region GAGCAAATTTAATAGAGGAGTTTGATTAGCACCTAAGACTTGCTTAA
rs7731592 238 AACTGAGTTACTAATTCTTTTTCCA
TCCTTCCCTCCCTCCCTCCTTTCCTTTTCCATCCTCCCCCT^ACCTT
TCCTTTTTCTGTAAACTTTTCCATAGCAAATAGAGTAATTCCAAATC
ATTTTTTGGAACATTCTTATTAGTGTTCATTCAGCTTCCCTTTCCAC
TGAAATGAATTTATTGAGTACTTGGAGTATTTCAAACCCTATGCTTT
GTACAGAGAAGASAGTGCTAAATAGGAAACCCTCTCAGTGTTAGAGG
GA.AAGGAAGATGATGTGGAGGGAAGGAGTCTCTTACTCTGAAGCATT
LNPEP TTC,kAAATCAACATTAAAGAGTGAACCAACATTTACCTCCTTTCTTC
Region TTTCATCTTCTTATTTCATAGCTAGAGAGCTGCTGTGCGTTTGAGAC
rs77333 12 239 CTAAGTGGTGCAATTAAATCAATTT
TTTTGTTTTTTACTCCAGATGTGTTGATAGAGGTTAATATAt'1GAAAT
GTTTGTGTTGGCATAATGCAAAGGTTATTTTTGATTCTGAACCCATA
GCAGTTTCTAACCGGTGTTCGTCAGTTTGTGCTTGCTTTTATCCTTG
AGG",TAAGGATTGCTCACCAAGCCTTTGATTACTAGGTACA'ITGCAG
AATE~AATP.AAATSGTTGCTAGTGTATACTCTGTATTAATCTGTCCAC
AGCAGCATTGTCAGTGATCTCAAGGTTCTCTGTAGACATTAC;TATTG
LNPEP GGTTATGGCATGCTAAAATAGAGATAATTGAGACTATAAAGTTCCAA
Region GTTGAAGTTATCAATAACAACCCTAAAACTATCTTCCTTTTCTTTCC
rs7736466 240 TTCTAAAATAAGACATATGGTAATC
TCATCCCCCACATGTGGCAAGACAAGTTGGCCCTTTCTTACCCAGAG
GTCTTTTGTGTGACTGCATCTTTCTCCTCCGTTCTCCATTGTGTGCT
TTCCATTTTGTCTTTAGTGCCTATACTGTTAGGTGTTTTCTTCACTG
GCATTCACAAATTTAAGCCATTGCTGCCTCATTAGCCTTGTATTTTG
TGTGCATATCATRTATCCAGACCTGTATGTTCGCTTTAAGCATTCTT
ATATCACACTGTCTCCTCATCTACCATATGGTAAATGTTAAAACTCC
LNPEP ACATTTGTCTGCATCAGGGAAAATGCATGGGCACACATCCTC~CCTCC
Region CTCCCTCTCTGCTCTCCTCCCTTCCTTCAGGCCTCTTAGCATTGTTT
rs9127 241 GTTTTCCCATTTCTGATACTACTAC

TGAAACAGTTGTTATGGAGGCCTGCGTTAGTGAGATCTGGCTTGCCA
CACTTGTGTTACCCACTCTTTCCAGAGTATACTTTCTTCCCTTCTTC
ACCTTTTCAAATACTCATCTTTTTAGGCCCTCTTCAGGTTTTCTGCA
TGTTTCCTTATAATATCTTCAACCTCTAGTCAGAATTTGTTTCCTTC
CCTTTGTTCCCAYTGCTTTATTTTCATTGTTAGGACATGA::TTACAG
CCTGATGTAAGTTTCTGTTCATTGTATAAACCTCTGCCTTTCCCAGT
LNPEP TTATTGCAGATCCTTTAGTAACTAGGATTGTAACATATTTATCTTAG
RegiOn TATACTTGGCAGGGTGCCTTGTACAGTAGGTGCTCAGTAACTACTGG
rs93 14181 242 ATTGAATTTGTGTTTGTTTTAGGTA
AGCAGCGTACTGCTGGCTCTGCACCGGACGCCGCGCAAGACGTCCCG
CA'PGCACCTCTTCATCCGACACCTCAGCCTGGCCGACCTGGCCGTGG
CATTCTTCCAGGTGCTGCCGCAAATGTGCTGGGACATCACCTACCGC
TTCCGCGGCCCCGACTGGCTGTGCCGCGTGGTGAAGCACCr'GCAGGT
GT'['CGGCATGTTYGCGTCGGCCTACATGCTGGTAGTCATGACAGCCG
ACC'GCTACATCGCGGTGTGCCACCCGCTCAAGACTCTGCAACAGCCC
GCGCGCCGCTCGCGCCTCATGATCGCGGCCGCCTGGGTGCTGAGCTT
AVPRIA CG`.'GCTGAGCACGCCGCAGTACTTCGTCTTCTCCATGATCGAGGTGA
rs1042615 243 ACAATGTCACCAAGGCCCGCGACTG
AACTGTGAA.AAATAAAATAAGGTGCTGCAACACATTTTTTTCTTGAC
TGTAAGCTGTTATTTGGCATAATATCTCAGGTCTTCTCTTTAGTCAA
GAPAAGGAAAACTTCCCTTCCCGGAATACTTTTTCAGTTTCTCTTCT
TCTGAAACAGACAGGCAGGTAGATTCCTTCCAATCTGAAATATTGTT
TTGAGATATGTGRCGTCCATTTCTGGGTACATAACATTGAGAAAATT
TACCAACCAGACAGATGAAACTTCTCAGCCTAAACCGCAGAGAATAA
GACCATGTATTTGCCTAGTGCAGAACTAGCACCCAGATCTCATGTTT
AVPRIA CCCCAGCCCATTTTCTACTGTCTCATCTCCCAATACATTTAAAAGGA
rs 10747983 244 GAAAATACAACTGGGTAGGGTGATA
TTGAGATATGTGGCGTCCATTTCTGGGTACATAACATTGAGAAAATT
TAGCAACCAGACAGATGAAACTTCTCAGCCTAAACCGCAGA:3AATAA
GACCATGTATTTGCCTAGTGCAGAACTAGCACCCAGATCTC.kTGTTT

GAA!l~ATACAACTSGGTAGGGTGATATGCACTTTTTTTTGTGAGCTGT
TCTCAGAAATAACATTCAAATTGAATTGTTTTGCTTGGGGG'PACATA
TCA.kCATTTTGAAGCAAGATCTATAGGTTCTGAGGTTCTTACTTTGG
AVPRIA AAATGGATTTAGAAAAAAATGGGTTCATCTTAGTTCCAAACCAAAAA
rS10784339 245 GCT'PTAGTTTTTGAACTATCA.A.AGA
AACCTCCCAAGTAGCTGGGACTATAGGCACACACCACCATGCCCAGC
TAATTTTTTGTATTTTTTTTTTCTTTTTAGAGTAGAGATAGGGGTCT
CCC'ATGTTGCCCAGGCTGGATTATACATGAATTTTTAAAAiiTGAAA
GTTACACTGAATGTGCCTGCCTGTCCTGCCTCCCCTTTCACCTCCTC
CACCCCTTCCACYCGAGACAGCAAGATCAACCCCTCTTCTGCCTCTT
CCTCCTCAGTCTACTCAACCTGAAGATGAGGGTGAAGACCTTTATGA
TGATCCACTTGCACTTAATGAATAGGAAGCACTTTCTATTATTTTTA
A VPRIA AATFACGTTTTCTTTTCTCTAGCTTACTTTATTGTAAGAATACAGTA
rS10877962 246 TATCATATATAATATGCAAAATATG
ATATGTATGCATCTGGCCATTCTATGTATCATGTGTCAATCAATCAT
CTATCTATCTGTCTATCTATCTATCTATCTATCTATCTATCTATCTA
TCATCCATCTATCTGTCTCTCGCTGGTTGTGCTGGATGCCATGGGGC
CTGGAAAGCAGGAAAAAAAAATGTTCATTGCAGATTGTAGAACCAGT
CCCTTTGTTTAAYCCATATAGTTTTAAACATGTTTTTGACTTAATTT
AACTGGTTTTATATACAAAGGAAAGCAGGACTATTACATATGAGGCA
CTACTCATATGCCTCACTGGACCTGCTATTAAATTACCCCATAGAGA
AVPRIA GTAAAATAATTGTGGTCTTAAAATATGAAAAAGAAAACACAAZAGAC
rs10877969 247 AATATTTTATGTGGCACCTTGTGCT

TTTACATGTCCATCCCTGTGGGCAGGAAAAGAGTGAAAACAGCCTTA
TGTGGATCGCATGAAATGGATTCCTCACAGGAAAGAATGCTCCTGTT
GCTAGAAAAGGAGGGTATGCTAAGCTGGCAAAAATAACAGATATTTA
CTTCACATATGAAAACCAACCTGTTGATCTCAGACTTGCAATGGATG
GCTGAATTTCATYCTAGCCTTTCTTTGCATAAGTGACCGG~3GAAGAA
GTACTGACTTTACTTTTATCATTTACAGTGATTTTTTTTCTGTATAT
GCTAGTTAATTAAACTGAATAAAAGGAATTCCTATATTATGATAATT
AVPR I A TASTCTCAGTAATAGCCAATAAATATTTCTGGAAAGAAGTACCCAGC
cs10877977 248 CC,--TGTGTGGGTGCTATTATTGAAT
TCCCTGTCTTAGAAGAAAAGTTTTCAACTTTTTACCATTAAGTATGA
TGTTAGCTATAGGCTAGTGATCTATGGCCTTTATTGTGTTGAGGTAC
ATTCCTTCTATACCTAATTTGTTGAGAATTTTTATCATGAAAGTGTG
TTGAATTTTGTCAACTTCTTTTTCTGCATCTATCAAGATGATCGATC
ATATGGCTTTTAYTTTTCATTCTGATAATATGGTGAATCA^TTTATT
GGTTTCTGTATGTGGAACCATCCTAGGCAAGTCAGATTTTGGATTTC
CTCCTTTATGTTCCATTCTGTAACATGTTAATGGGAACCGGAATTCA
AVPRIA GA",CAGAATAACAGCTTAGGAACCAAAGCAGGTATATATATATGTGT
rs 10877986 249 GTGTGTGTGTGCGTGTGTGTGTATA
TGTAACACTGATCAAAATACGTTTACAATGTCCAAGAGAAF,GTCCAG
AGTACCTTAAGCAATCCTTTTCTACTCTTTTAATAAAATTTGGCTTT
CCTTATACAAATCTGACTTTAAAACAACCTCGCAGTGGGGGAAAAAA
GATATTTTTGGCCAGTCAACATTTCCTCTCACCTTCAGCATCTCAGT
TTTCATGCTTTTMTTGACCAATAATATGTGAGGAACCAAAAGGAGGC
CACTGCCAGTTGTAAAGTTACCATTTTGAAATGCAAGGTGATTGATA
GCTTCTAATAGAACTCTAAACTGGCCACAATGAGCAGGAGCTCATTA

is 11174811 250 CACTGTTTAAGGCTGCATTTTCTGA
TTTTTGAGAATATTTTCTTTTTTTCCAAATTATTACATACTCAGATA
TACTCTTGAATCTCTCATTCAACAAGTCCCCA.AACTTTGTC,--ATGAA
ACCTTTCTTCTCTTTCTTTTCTCTATACCCCATCATTCTAATTTACA
TCACGTTAATCTTTTTGGATTATATTTACATATTTAATTTCTCTTCC
ACT'TTGCTCCAAYTCAAATTCTTTATAACAACCACAAGAACACGAAA
CTCCTGTAACTAGCCAATGTAGTAATTAGGGTAGGATAGGCTATGTC
CTG'PAGTAACAGAGCAATTCTGACACCTCAGTGGCTTAACAi~AAAAA
A VPRIA TTATTTCTCACTCATGCAAAGTCTAATGCAAGTTGAGCAGCTTTCCC
rs11832877 251 CCAaGCAGTGACTCTGAGGTCCATG
TTT'ATTTTGATCTAGATGTCTGAGAGTATGAATGTTCTTAGTGCAA
ATA.hTAAATTGAATGCTCTCGAGGATAAAATTTGAAAATAATTCTAT
CTT;,,AGATGTCTAACAAAATGAATAAAAATTATAAACTCTTATGAAT
GAGGTTGTACTCTCCAAGTGTTTCTTGTTAAGAACCATAGAF,GGACT
TCCCTTTTAGAARTGCTTTGGATATTCTAATACATTTAATGC'.CAGGG
CATF,AGCTAGTGGTTGTTAAGCTTTTCTCTCCCTCCCACAGC'ACCAA
GAGF.CCTAACATTCACCCATTTGTAGCAGTTGTTTTAGAACP.GTGAT
A V PRIA TGCC'AAGGAGGGGAAAAATGAGGAAGCATAGCAGAATTTCTCGGGAA
rs11835545 252 CTGTAGAAAGAGAGAGCATATTGGG
TTCCACAGCTTTGTGAACACAGAATAGTCCCATTGAAAAGAAAATCT
TTCCGAATTTGATAAATGAATAAGTATCTGATTGTTTTAATGTATTT
CGTTAGAAATATTTCATCGTTTTTGTCTCATTACTTACTTAATAATG
AGTTAAACATTTTCATAAATGTCTTATAACTTACAAACAGAATCTGG
GAGTGCTGAATTRTGATAAAGGAACTGCTCAAGTTAGAAATATTACT
TTTACTTTTCTTTGAACTGTTATAAATTATACAGAAAAAATAATACA
TGGTATATA.TGGACCATAAGTAGCAGGAGCTGTAATCCAGGTTTTGC
AVPRIA ATAC.3TIATCTTATTTAATCCTCACGAATCTAATGAGATGGATTAAC
1-s11836346 253 CACTATTTTACACATAAGGATGCGG

TGATGCCAACACTATAATTGCCAACCCCATTGAGAAAGGAAAGAAAC

TA~3CAAAGAGGAGGGATGTGTTGAGTCATCTAGTAAGTCCCTGTGAA
GAJTGGATCCTGGCCCATCTGAACATCTGACCAGAAACTAGTGGCAG
CAJTTGTAGAACKTGGTATATGCATGTGCTTCTCTTTTTATGGAATC
GGAATCAGGGTGCCCCAGAAAGAAAACGAGCCCAATTTTAAAGGGGT
TAATTGGGTATCGTCTTGATTCTTTGTAAGATTGGTTAGGTATTCAG
AVPRIA GAATCAGGCTGACCAGGCACAAGTACCTACCAACCTTTGTAAAATAT
rs16856 254 TC'PACACTCTACAATATCATTCACA
CA('CACCACGCCCGGCTAATTCTTCATATTTTTAGTAGAGACGGGGT
TT('ACCGTGTTAGCCAGGATGGTCTCAAACTCCTGACCTAAAGTGAT
CAGCCAGTCTCGTCCTCCCAAAGTGCTGGGATTACAGGCATGAGCCA
CCACACCCAGCAAAGTGGAACAGAATAGACAGCCGTAATGGTTCCAT
GTATATTTGGGTRCTTACTATACAA.TAAAGAGGTCTCCACTAAAACA
AGGGAGAAGGATGGCATAAAGGAGTTGGGAAATGCAGAAAl-..TTATGC
TAC>ATTCATCTTCTTATATCACATCTTAGTAGTAGACTCC?.AATAAA
AVPRIA ')TTAATGAAGTAAATGTGGAAGGTAAATTACAAACCTGATAC'AAGGAA
i-s~030106 255 AATGTTATTAGAGAACCTATATGAC
GAGCTGCCTAAGGCTGTGGGAGCCCACCTCTTGCATCAATGTGCCCT
GGATGTGAGACATGGAGTCAAAGGAGATCATTTTGGAATTTTAATAT
TTGACTGCCCTGCTGGAATTTGGACTTGCATGGTGCCTTTAGCCCCT
TCATTTTGGCCAATTTCTCCCATTTGGAATGGGTGCATTTATCCAAT
GCCTGTACTCCCRTTGTATCGAGGAAGTAACTAACTTCCTTTTGATT
TTACAGGCTCATAGGCAGAAGGGACTTGCCTTACCTCAGAT;,AGACT
TTGCACTGTGCACTTTTGAGTTAATGCTGAAATTAGTTAAG.kCTTTA
AVPRIA GGGCACTTTTGGGAAAGCATGATTGGTTTTGAAATGTGAGGACATGA
rs2201895 256 AATTTGGGAGGGGACCAGGGTGGAA
TCTTTCCTCTCTTTGAGATTGCCTCTTTCTTACTCCTGAGC,~CAGGA
GCCGGGCGGGTTTTCTGTCCCTTGCCCTGGACAGCACTGCCTGGATG
GCCGCTGTCCGGCAGCTGCTCTTTGTCCACCCAAAAAGATGTCCCCA
CGACTCAGTAGTA.ACCAGACGGTCCCCACGGACCACTGCGGCCAAAT
TTCCGCCATCCCYGCTGTGGGAATCAGGCTTTTCCCGCAGAAAACCC
CAGUAATCTAGAGAAAACTCCTTAAGTCCCTAGTCTCCATAGAGAAA
ACCE~GGAGACACTCCCCCCAAACCCCGCTGTGAATACAGGCACAGCA
AVPRIA GCCF~CTGGGGCTGCAAAGTGATGAGTGCGTTCTTCCCGTCGCAAACA
rs30?1529 257 TAGGGTAATAAATAGCATGCATCAA
AACATTTCAGTATGAATTTAACTTAAATATTCTTACTGACTF.TAATA
CTAGCGATAATGAAAAATACAATATAAACACTTTATTTTTGGTTTGC
TATTTCTTATCTTGCTTGATCTmAGAAGCCTCTTCATATTGTCCATC
AAATAAAGAAATTCAGTCTAATTATTGCTTTAGCAGAATTTACACTC
AAGTAATAAAAAYTTCAATTGTGCATAGATATGTTGGTAATTTTCAT
TCTTTGTGAATACCATCTTACCCATGGCTCCTGATCACCTTTGATAG
CAGCATCTTAGCACTAAGTATGATTAAATAATAACCTGTAATTGTTT

rti34462?14 258 AGGAAAAGTCAGTGTTTATTGATTA
TGTCTCTTAAAGGGTACTGTCCAATATAAGCCATAACTAAATTAATT
AATT~--ATTATTTGAGTTAGAGTAGCATCTCAGTAACCCAGCACTCGA
AGACTGTCAGTCCTTTTAACAACTCTTTGATAGTTCAAAAACTA.AAG
CTTTTTGGTTTGGAACTAAGATGAACCCATTTTTTTCmAAATCCATT
TCCAAAGTAAGAAl_ CCTCAGAACCTATAGATCTTGCTTCAAAATGTTGATATGTACCCCCA
AGCAi~,AACAATTCAATTTGAATGTTATTTCTGAGAACAGCTCE~CAAA
AAAAikGTGCATATCACCCTACCCAGTTGTAT`L'TTCTCCTTTTAAATG
AVPR I A TATTGGGAGATGAGACAGTAGAAAATGGGCTGGGGAAACATGAGATC
rs36014760 259 TGGG"GCTAGTT

TTCCAATTAAAGCAAAATATTCCCAATTTACATATGTGCAATGAGAA
GAGTTTTATGGTTAAATATGTTGGAGAAGTGCTGTGTATGCATCCCA
CCCTCTCCTGGTGATTTATACATAAAAAGGACCTGAGAAACTTCAGA
AAAGAAACTTACTTAACCTTGTTCATCAATGTTTTCCAAGGTTATTT
TACCATGGAAACYCCCCATTTTTTTACTTTCCCCATGGAATGGTGAT
GAACATGTCACAAGACAAGGTGACAGAGCAGGAGCATCACCATCCTG
CCATTTTAAAGTTCACCTTGATCAAAAACCACCTAAATCCAAAGGGC
AV PR1A ~ ATC.%GCCTAATGGCTAAGGCCAGAATGACCATGAGCCACAAATAACA
rs7_94536 260 TCTCTTACCAGAAACATTCCAAACC
TTA'PGCAGTCTTGTAGGACACGTTAAAGATATTGGGCTTGATCTACA
AGAAAGGGAAAATGTTGAAGGAATTTTAACAAGGGAAGGGCATAATC
ATTTTTGTATCTTTTAAAAGAGAATACTTTGGCTTTATGTGCAAATG
AATGGAGGAGGGTGAGAACAGATAGAGACTCAGTTAAGAGACCATAG
CAG.kGGACCCGAWAAGCTAGAGTATGGTAGGGAAGAAGACATGCAGA
GTC.kTGGTCTTGAGGATGAGTTTGGGAGTATTGGAATAATGAAGTTT
ACATCTCTATTGCCGAAATGAGGATTAGTCGTGACCACTCA;%GGCAG
AVPRIA GAGCCAGCCCCACTTATGAGGGAGAGAAGGCAGCAGAGTCTGGGGAC
rs7302323 261 AGGCTCCTAGACACCTTCTGGATCA
AAC.?~ACATAAATGAATTTTTTCCAATAGAAATGTAATTGATTTCTGC
CCCGTAGGAAAGAAAACTCCAAGCATTATGTTTTATGAACC,~-ATAGA
AAAATAATAATCAATCTTACATCTTTTAGCAAAATCATTTC,kGAATT
CTTGACTGCCTGTGTGTTACTCTTCTTCAGATTCTCCCCTG,~ACAGG
TCTTAACATCTCRTTGGTTCCATCCTTAATTAATAAGCTGA,%TAAAA
CTG'PAGCATGTGTTCATTTTACATTTGCAGGAGAGTCATGACTTTAT
CTT'PATAAAATTTATACATAGCAGCCCTGCGTGGTCTCAGGGGTCTG
A VPR1A CCTCTATCTTTGCCACATCCCATGCTGAGGTCCATAGCTAT'PCTAGC
rs7308008 262 TGGTCCTCACTAGTCCTCTGTTCTA
TTCTGGTTAAATGATTTTTAATAAGACGTTAATCTCTTTGTACAATA
AGAGTGCTTATACCCTTTTCATAATAATTGTGTAAAGACTTATGATT
ACACTAGGCACAGGAAGGTGTTTTCAATAAAACAAAGTGTCCTTCCA
GTTCCCTGCTTTGAAGTAGGGTCTTCAATCTTCCCATCTCCATTGTT
CAGTGCATATGTWTCACTTAGGATAAGCTAAGTTATGCmAA.%GTAAC
AAGCAAACAACAAATCTCAGTGGCTTAGAGCAATCAAGATC`PATTTC
TTATTCATGCTACTATTCATCATGCATAGCTGGGGCTTTACTCCATG
AVPRIA TGCTTCTCATTCAGGAACCTAGGTGAGGGGGCTTGATCATC'PGGAAT
rs7959001 263 GTC.ACCAGTCACTGTAGCAGGGAGA
AATTATAGATACTGAAATCTGAATTTTATACAATGTTCATGTGTCAG
AAATATTCATTTTGATTTTTCTCAATTATTTAAAAATGTAA.kAACTA
TTCTTAGCTCATAGGACAAACTAAAACATGGATGAGCTAGATTTGGC
TTGTGCATCATAGTTTGCCAATTCCTGTTCTAAAGTATGTTAACAAA
TCCkCATATCTTRAATATTACTATTTT'?'CATFATAGGTGAGAGCCTA
TTTTTAACTCCCGTTATGCTGATAAATAAGCTACTGATTTCACCATT
ATGPTAATTAACAAAATATCTATTGTCAATCAGAAGAAAAGGTCACC
AVPRIA AATATTCTTATAGTAGTCATCTCTGGTGGGTGGGGCTTTTC'PGATAA
rs7972829 264 P.ATTCTAGCTGCTTCCCCATTCCCT

An "allele" is defined as any one or more alternative forms of a given gene.
In a diploid cell or organism the members of an allelic pair (i.e. the two alleles of a given gene) occupy coi-responding positions (loci) on a pair of homologous chromosomes and if these allefes are genetically identica1 s the cell or organism is said to be "homozygous", but if genetically different the cell or organism is said to be "heterozygous" with respect to the particular gene.

A"gene- is an ordered sequence of nucleotides located in a particular position on a particular chromosome that encodes a specific funetional product and may include untranslated and untransci-ibed sequences in proximity to the coding regions (5' and 3' to the coding sequence).
Such non-coding sequences may contain regulatory sequences needed for transcription and translation of the sequence or introns etc. or may as yet to have any function attributed to them beyond the occurrence of the SNP of interest.

A"genotype" is defined as the genetic constitution of an organism, usually in respect to one gene oi- a 1'ew genes or a region of a gene relevant to a particular context (i.e.
the genetic loci responsible for a particular phenotype).

TABLE 1E. Genotype correlations for SNPs in vasopi-essin pathway associated genes with values representing an ability to recover from an inflammatory condition and an indication of responsiveness to treatment of an inflami-natory condition with a vaso ressin rece tor aQonist.
POLYMORPHISM Genotype Patient Outcome Responsiveness To Score* Treatment' rs 18059 TT I R
rs 18059 CT I R
rs 18059 CC 2 PR
rs27711 GG 1 R
rs277 I 1 AG l N/A
rs277 I 1 AA 2 PR
rs38041 GG I N/A
rs38041 AG I N/A
rs38041 AA 2 N/A
i-s 10051637 GG l PR
rs 10051637 AG 1 R
rs 10051637 AA 2 R
rs1410713 AA I R
rs1410713 AC 2 R
rs1410713 CC 2 PR
rs857240 CC I R
rs857240 CT 2 PR
rs857240 TT 2 N/A
i-s857242 CC I R
rs857242 AC 2 PR
rs857242 AA 2 N/A
rs10877970 TT 1 N/A
rs 10877970 CT 2 N/A
i-s 10877970 CC 2 N/A
r.53803 l 07 TT I N/A
rs3803107 CT 2 N/A
rs3803 107 CC 2 N/A
rs 1495027 CC I PR
rs 1495027 CT 2 R
rs 1495027 TT 2 R
good = 2; poor = I.

Responsive (R); Poor Response (PR).

A "phenotype" is defined as the observable characters of an organism. In gene association stLidies, the genetic model at a given locus can change depending on the selection pressures (i.e., the environment), the population studied, or the outcome variable (i.e., the phenotype). For example, the model at rs 1410713 changed between the risk of death claims (AA versus AC/CC) and the vasopressin IRP claims (AA/AC versus CC). This is a case of the same outcome variable (survival) following a different genetic model in different environments (i.e., no vasopressin treatment versus vasopressin treatment).

A siniilar observation would be seen in a gene association study with the hemoblobin, beta gene (HBB) with mortality as the primaty outcome variable. A mutation in the HBB
gene, which normally produces the beta chain subunit of hemoglobin (B allele), results in an abnormal beta chain called hemocylobin S (S allele; Allison A (1955) Cold Spring Harbor Symp. Quant. Biol.
1-0:239-1-55 ). Hemoglobin S results in abriormal sickle-shaped red blood cells which lead to anemia and other serious complications including death. In the absence of malai-ia, a gene association study with the HBB gene would suggest a codominant model (survivat(BB) > survival (BS) > survival (SS)). However, in the presence of marlai-ia, a gene association study with the HBB -ene would suggest a heterozygote advantage model (survival(BB) <
survival(BS) >
?U survival(SS)).

A"single nucleotide polymorphisni" (SNP) occurs at a polymorphic site occupied by a single nucleotide, which is the site of variation between allelic sequences. The site is usually preceded by and followed by highly conserved sequences of the allele (e.g., sequences that vary in less than ?5 1/100 or 1/1000 members of the populations). A single nucleotide polymorphism usually arises due to substitution of one nucleotide for another at the polymorphic site.
A"transition" is the replacement of one purine by another pui-ine oi- one pyrimidine by another pyrimidine. A
"transversion" is the replacement of a purine by a pyrimidine or vice versa.
Single nucleotide polymorphisms can also arise from a deletion (represented by "-" oi- "de1") of a nucleotide or an 30 insertion (represented by "+" or "ins" or "I") of a nucleotide relative to a reference allele.
Furthermore, a person of skill in the art would appreciate that an insertion or deletion within a given sequence could alter the relative position and therefore the position number of another polymorphism within the sequence. Furthermore, although an insertion or deletion may by sorne definitions not qualify as a SNP as it may involve the deletion of or insertion of more than a single nucleotide at a given position, as used hei-ein such polymorphisms are also called SNPs as they Qenerally result from an insertion or deletion at a single site within a Qiven sequence.

A"systemic inflamniatory response syndrome" or (SIRS) is defined as including both septic fi.e.
sepsis or septic shock) and non-septic systemic inflammatory response (i.e.
post operative).
"SIRS" is further defined according to ACCP (American College of Chest Physicians) guidelines as the presence of two oi- more of A) temperature > 38 C or < 36 C, B) heart rate > 90 beats per minute, C) respiratory rate > 20 breaths per minute, or PaCO2 <32 mm Hg or the need for mechanical ventilation, and D) white blood cell count > 12,000 per mm' or <
4,000 mm In the following description, the presence of two, three, or four of the "SIRS"
criteria were scored each day over the 28 day obsei-vation period.

"Sepsis" is defined as the presence of at least two "SIRS" criteria and known or suspected source of' infection. Septic shock was defined as sepsis plus one new organ failure by Brussels criteria plus need for vasopressor medication or vasopressin receptor agonist.

Subject outcome or prognosis as used herein refers the ability of a subject to recover from an inflammatory condition and may be used to determine the efficacy of a treatment regimen, for example the administration of a vasopressin receptor agonist. An inflarnmatory condition, may be _10 selected trom the group consisting of: sep~is, septicemia, pneumonia, septic shock, systernic inflammatory response syndrome (SIRS). Acute Respiratory Distress Syndronie (ARDS), acute lung injury, aspiration pneumonitis, infection, pancreatitis, bacteremia, peritonitis, abdominal abscess, inflammation due to trauma, inflammation due to surgery, chronic inflammatory disease, ischemia. ischemia-reperfusion injury of an orQan or tissue, tissue damage due to disease, tissue damage due to chemotherapy or radiotherapy, and reactions to ingested.
inhaled, infused, injected, or delivered substances. glomerulonephritis, bowel infection, oppoi-tunistic infections, and for subjects undergoing major surgery or dialysis, subjects who are immunocompromised, subjects on immunosuppressive agents, subjects with HIV/AIDS, subjects with suspected endocarditis, subjects with fever, subjects with fever of unknown origin, subjects with cystic fibrosis. subjects with diabetes mellitus, subjects with chronic renal failure, subjects with acute renal failure, oliguria. subjects with acute renal dysfunction, glomerulo-nephritis.
interstitial-nephritis. acute tubulai- necrosis (ATN). subjects with bronchiectasis, subjects with chronic obstructive Iung disease, chronic bronchitis, emphysema, or asthma, subjeets with febrile neutropenia, subjects with meningitis, subjects with septic arthi-itis, subjects with urinary tract infection, subjects with necrotizing fasciitis, subjects with other cuspected Group A streptococcus infection, subjects who have had a splenectomy, subjects with recurrent or suspected entei-ococcus infection, other medieal and surgical conditions associated with increased risk of infection, Gram positive sepsis, Gram negative sepsis, culture negative sepsis, fungal sepsis, meningococcemia, post-pump syndronie, cardiac stun syndrome, myocardial infarction, sti-oke, congestive heart failure, hepatitis, epiglottitis. E. coli 0157:H7, malaria, gas gangrene, toxic shock syndrome, pre-eclampsia, eclampsia. HELLP syndrome, mycobacterial tuberculosis, Pneumocystis carinii pneumonia, pneunionia, Leishmaniasis, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura, Dengue hemorrhagic fever, pelvic inflammatory disease, Legionella, Lyme disease, Influenza A, Epstein-Barr virus, encephalitis, inflammatory diseases and autoimmunity including Rheumatoid arthritis. osteoarthritis, progressive systernic sclerosis, systemic lupus erythematosus, inf7ammatory bowel disease, idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, systemic vasculitis, Wegener's gT-anulomatosis, transplants including heart, liver, lung kidney bone mai-row, graft-versus-host disease, transplant rejection, sickle cell anemia, nephrotic syndrome, toxicity of agents such as OKT3, cytokine therapy, and cirrhosis.
Assessing subject outcome, prognosis, or response of a subject to vasopressin i-eceptor agonist administration may he accomplished by various methods. For Example, an "APACHE
II" score is defined as Acute Physiology And Chronic Health Evaluation and herein was calculated on a daily 10 basis from raw clinical and laboratory variables. Vincent etul. (VincentJL.
Ferreira F. Moreno R.
2000 Crit Care Clin. 16:353-366) sunimarize APACHE score as follows "Fii-st developed in 1981 by Knaus et al., the APACHE score has become the most commonly used survival prediction model in ICUs worldwide. The APACHE II score, a revised and simplified version of the original prototype, uses a point score based on ini?ial values of 12 i-outine physiologic measures, age, and previous health status to provide a general measure of severity of disease.
The values recorded are the worst values taken during the subject's first 24 hours in the ICU. The score is applied to one of 34 admission diagnoses to estimate a disease-specific probability of mortality (APACHE II
predicted risk of death). The maximum possible APACHE II score is 71, and high scores have been well correlated with mortality. The APACHE II score has been widely used to stratify and compare various Qroups of critically ill subjects, including subjects with sepsis, by severity of illness on entry into clinical trials".

A"Brussels score" score is a method for evaluating oi-gan dysfunction as compared to a baseline.
If the Brussels score is 0 (i.e. rnoderate, severe, or extreme), then organ failure was recorded -[s present on that particular day (see TABLE 2A below). In the following description, to correct for deaths during the observation period, days alive and free of organ failure (DAF) were calculated as previously described. For example, acute lung injury was calculated as follows. Acute lung injury is defined as present when a subject meets all of these four criteria. 1) Need for mechanical ventilation, 2) Bilateral pulmonary infiltrates on chest X---ay consistent with acute Iung injury. 3) PaO2/FiO, ratio is less than 300mmHg, 4) No clinical evidence of congestive heart failure or if a pulmonary artery catheter is in place for clinical purposes, a pulmonary capillary wedge presst-re less than 18 mm Hg (1). The severity of acute lung injury is assessed by measuring days alive and free of acute lung injury over a 28-day observation period. Acute Iung injury is --ecorded as present on each day that the person has mode--ate, severe or extreme dysfunction as defined in the Brussels score. Days alive and free of acute lung injury is calculated as the number of days after onset of acute lung injw-y that a subject is alive and free of acute Iung injury over a defined observation period (28 days). Thus, a(ow~-r score for- days alive and free of acute Iung injury indicates more severe acute lung injury. The reason that days alive and free of acute lung injury is p--eferable to simply p--esence or absence of acute lung injury, is that acute lung injury has a high acute mortality and early death (within 28 days) precludes calculation of the presence or absence of acute lung injLu-y in dead subjects. The cardiovascular, renal, neurologic, hepatic and coagulation dysfunction were similarly defined as present on each day that the person had moderate, severe or extreme dysfunction a~ defined by the Brussels score. Days alive and f--ee of ste--oids are days that a person is alive and is not being t--eated with exogenous corticosteroids (e.g.
hydrocoi-tisone, prednisone. methylprednisolone). Days alive and free of pressors are days that a pei-son is alive and not being treated with int--avenous vasopressors (e.g.
dopamine, norepinephrine, epinephrine or phenylephrine). Days alive and free of an International Normalized Ratio (INR) > 1.5 are days that a person is alive and does not have an INR >
1.5.

TABLE 2A Brussels Organ Dysfunction Scoring System ORGANS Free of Organ Dysfunction Clinically Significant Organ Dysfunction Normal Mild Moderate Severe Extreme DAF ORGAN l 0 DYSFUNCTION
SCORE
Cardiovascular >90 <90 <_90 <90 plus _90 plus Systolic BP Responsive Unresponsive to pH <_7.3 pH_7.2 (mmHg) to fluid fluid Pulmonary >400 400-301 300-201 200-101 <100 P,o,/Flo, (mmHg) Acute lung injury ARDS Severe ARDS
Renal < 1.5 1.5-1.9 2.0-3.4 3.5-4.9 >_5.0 Creatinine (mQ/DI) Hepatic <1.2 1.2-1.9 2.0-5.9 6.0-11.9 > 12 Bilirubin (mg/dL) Hematologic >120 120-81 80-5 I 50-21 <20 Platelets (x IW/mm') Neurolo'-ic 15 14-13 12-10 9-6 <5 (Glascow Score) Round Table Conference on Clinical Trials for the Treatment of Sepsis Brussels, March 12-14, 1994.

2. General Methods One aspect of the invention may involve the identification of subjects or the selection of subjects that ai-e either at --isk of developing and inflammatory condition or the identification of subjectS
who already have an inflammatory condition. For example, subjects who have tmdergone major surgery or scheduled for oi- contemplating major surgery may he considered as being at risk of developing an inflammatory condition. Furthermore, subjects may be determined as having an inflammatory condition using diagnostic methods and clinical evaluations known in the medical arts. An inflammatory condition, may be selected from the group consisting of:
sepsis, septicemia, pneumonia, septic shock, systemic inflammatory response syndrome (SIRS), Acute Respirator/
Distress Syndrorne (ARDS), acute lung inji.-y, aspiration pneumonitis, infection, pancreatitis, bactei-emia, peritonitis, abdominal abscess, inflammation due to trauma, inflammation due to surgery, chronic inflammatory disease, ischemia, ischemia-reperfusion injury of an organ or tissue, tissue damage due to disease, tissue damage due to chemotherapy or radiotherapy, and i-eactions to IS ingested, inhaled, infused, injected, or delivered substances, glomerulonephritis, bowel infection, opportunistic infections, and for subjects undergoing major sLu-gery or dialysis, subjects who are itnmunocompromised, subjects on immunosuppressive agents, subjects with HIV/AIDS, subjects with suspected endocarditis. subjects with tever, subjects with fever of unknown origin, subjects with cystic fibrosis, subjects with diabetes mellitus, subjects with chronic renal failure, subjects with acute renal failure. oliguria, subjects with acute renal dysfunction, Qlomerulonephritis, interstitial-nephritis, acute tubular necrosis (ATN), subjects with bronchiectasis, subjects with chronic obstructive luna disease, chronic bronchitis, emphysema, or asthma, subjects with febrile neutropenia, subjects with meningitis. subjects with septic arthritis, subjects with ui-inary tract infection, subjects with necrotizing fasciitis, subjects with other suspected Group A streptococcus infection, subjects who have had a splenecl.omy, subjects with i-ecurrent or suspected enterococcus infection, other medical and surgical conditions associated with increased risk of infection. Gram positive sepsis, Gram negative sepsis, culture negative sepsis, fungal sepsis, meningococcemia, post-pump syndi-ome, cardiac stun syndrome, myocardial infarction, stroke, congestive heart failure, hepatitis, epiglottitis, E. coli 0157:1-17, malaria, gas gangrene, toxic shock syndrome, pre-eclampsia. eclampsia, HELLP syndrome, mycobacterial tuberculosis, Pneumocystis car-inii pneumonia, pneumonia, Leishmaniasis, hernolytic uremic syndrome/thrombotic thrombocytopenic purpura, Dengue hemorrhagic fever, pelvic inflammatory disease, Legionella, Lyme disease, Influenza A, Epstein-Barr virus, encephalitis, inflammatory diseases and autoimmunity including rheumatoid arthritis, osteoarthritis, progressive systemic sclet-osis, systemic lupus erythernatosus, inflammatory bowei disease, idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis. systemic vasculitis, Wegener's granulomatosis, transplants including heart, liver, lung kidney bone marrow, graft-versus-host disease, transplant rejection, sickle cell anemia, nephrotic syndi-ome, toxicity of agents such as OKT3, cytokine therapy, and cirrhosis.
Once a subject is identified as being at risk for developing or having an inflammator-y conditiori or is to be administered vasopressin receptor agonist, then Qenetic sequence information may be obtained frorn the subject. Or alternatively genetic sequence information may already have been obtained from the subject. For example, a subject may have already provided a biological sample ?O for other purposes or may have even had their genetic sequence determined in whole or in part and stored for future use. Genetic sequence information may be obtained in numerous diffei-ent ways and may involve the collection of a biological sample that contains crenetic material, particularly, genetic material containing the sequence or sequences of interest. Many methods are known in the art for collectina biological samples and extracting Qenetic material from those samples. Genetic ?5 material can be extracted fr-om blood, tissue, hair and other biological material. There are many methods known to isolate DNA and RNA froni biological material. Typically. DNA
may be isolated from a biological sample when first the sample is lysed and then the DNA is separated fr-om the lysate according to any one of a variety of multi-step protocols, which can take varying lengths of tinie. DNA isolation methods may involve the use of phenol (Sambrook, J. et ul., 30 "Molecular Cloning", Vol. 2, pp. 9.14-9.23. Cold Spring Harbor Laboratory Press (1989) and Ausubel, Frederick M. et ul.. "Current Protocols in Molecular Biology", Vol.
l, pp. 2.2.1-2.4.5, John Wiley & Sons, Inc. (1994)). Typically, a biological sample is lysed in a detergent solution and the protein component of the lysate is d.igested with proteinase for 12-18 hours. Next, the lysate is extracted with phenol to remove most of the cellular components, and the remaining aqueous phase is processed further to isolate DNA. In another method, described in Van Ness et al. (U.S. Pat. # 5,130,423), non-corrosive phenol derivatives are used for the isolation of nucleic acids. The resulting preparation is a mix of RNA and DNA.

Other methods for DNA isolation utilize non-corrosive chaotropic agents. These methods, which are based on the use of guanidine salts, urea and sodium iodide, involve lysis of a biological sample in a chaotropic aqueous solution and subsequent pi-ecipitation of the crude DNA fraction with a lower alcohol. The final purification of the precipitated, crude DNA
fraction can be achieved by any one of several methods, including column chromatography (Analects, (1994) 'Vol 22, No. 4, Pharmacia Biotech), or exposure of the crude DNA to a polyanion-containing protein as desci-ibed in Koller (U.S. Pat. # 5,128,247).

Yet another method of DNA isolation, which is described by Botwell, D. D. L.
(Anal. Biocherri.
(1987) 162:463-465) involves lysing cells in 6M guanidine hydrochloride, pi-ecipitating DNA from the lysate at acid pH by adding 2.5 volumes of ethanol, and washing the DNA
with ethanol.

Numerous other methods are known in the art to isolate both RNA and DNA, such as the one described by CHOMCZYNSKI (U.S. Pat. # 5,945,515), whereby genetic material can be extracted efficiently in as little as twenty minutes. EVANS and HUGH (U.S. Pat. #
5,989,431 ) describe ?(l methods for isolating DNA using a hollow membrane filter.

Once a subject's genetic material has been obtained from the subject it may then be further be amplified by Reverse Ti-anscription Polymerase Chain Reaction (RT-PCR), Polymerase Chain Reaction (PCR), Transcription Mediated Amplification (TMA), Ligase chain reaction (LCR), Nucleic Acid Sequence Based Amplification (NASBA) or othei- methods known in the art, and then further analyzed to detect or determine the presence or absence of one oi-more polymoi-phisms or mutations in the sequence of interest, provided that the genetic material obtained contains the sequence of interest. Particularly, a person may be interested in determining the presence or absence of a mutation in a vasopressin pathway associated gene sequence, as 3O described in TABLES I A-D. The sequence of interest may also inctude other mutations, or may also contain some of the sequence surrounding the mutation of interest.

Detection or determination of a nucleotide rdentity, or the presence of one or more single nucleotide polymorphism(s) (SNP typing), niay be accomplished by any one of a number methods or assays known in the art. Many DNA typing methodologies are useful for use in the detection of SNPs. The majority of SNP ~enotypin~ reactions or assays can he assigned to one of four broad roups (sequence-specific hybridization, primer extension, oligonucleotide ligation and invasive cleavage). Furthermore, there are numerous methods for analyzing/detecting the products of each type of reaction (for example, fluorescence, Iuminescence, mass measurement, electrophoresis, etc.). Furthermore, reactions can occur in solution or on a solid support such as a glass slide, a chip. a bead, etc.

In general, sequence-specific hybridization involves a hybridization probe, which is capable of IO distinguishing between two DNA targets differing at one nucleotide position by hybridization.
Usually pi-obes are designed with the polymorphic base in a central position in the probe sequence.
whereby under optimized assay conditions only the perfectly matched probe target hybrids are stable and hybrids with a one base mismatch are unstable. A strategy which couples detection and sequence discrimination is the use of a"molecular beacon", whereby the hybridization probe I S (molecular beacon) has 3' and 5' reporter and qucncher molecules and 3' and 5' sequences which are complementary such that absent an adequate binding ta1-get for the intervenina sequence the probe will form a haii-pin loop. The hairpiri loop keeps the reportei- and quencher in close proximity resulting in quenching of the fluorophor (reporter) which i-educes fluorescence emissions. However, when the molecular beacon hybridizes to the target the fluorophor and the O quencher are sufficiently separated to allow fluorescence to be emitted from the fluorophor.
Similarly, primer extension reactions (i.e. niini sequencing, nucleotide-specific extensions, or simple PCR amplification) are useful in sequence discrimination reactions. For example, in mini scquencing a primer anneals to its tarffet DNA immediately upstream of the SNP
and is extended 25 with a sin-le nucleotide complementary to the polymorphic site. Where the nucleotide is not complementary, no extension occurs.

Oligonucleotide ligation assays require two sequence-specific probes and one common ligation probe per SNP. The common ligation prob-, hybridizes adjacent to a sequence-specific probe and 3O when there is a pei-fect match of the appi-opriate sequence-specific probe, the ligase joins both the sequence-specific and the common probes. Where there is not a perfect match the ligase is Lmable to join the sequence-specific and common probes. Pi-obes used in hybridization can include double-stranded DNA, single-stranded DNA and RNA olieonucleotides, and peptide nucleic acids.
Hybridization methods for the identification of single nucleotide polymorphisms or other mutations involving a few nucleotides are described in the U.S. Pat.
6,270,961; 6.025,136; and 6,872.530. Suitable hybridization probes for use in accordance with the invention incfude oligonucleotides and PNAs from about 10 ro about 400 nucleotides, alternatively from about 20 to about 200 nucleotides, or from about 30 to about 100 nucleotides in length.

Alternatively, an invasive cleavage method requires an oligonucleotide called an Invaderr" probe and sequence-specific probes to anneal to the target DNA with an overlap of one nucleotide.
When the sequence-specific probe is complementary to the polymorphic base, overlaps of the 3' end of the invader oligonucleotide foi-m a structure that is recognized and cleaved by a Flap endonuclease releasing the 5' arm of the allele specific probe.

5' exonuclease activity or TaqManT"^ assay (Applied Biosystems) is based on the 5' nuclease activity of Taq polymerase that displaces and cleaves the oligonucleotide probes hybridized to the target DNA generating a fluorescent sianal. It is necessary to have two probes that differ at the polymorphic site wherein one probe is complementary to the 'normal' sequence and the other to the mutation of interest. These probes have different fluorescent dyes attached to the 5' end and a quencher attached to the 3' end when the probes ai-e intact the quencher intei-acts with the fluorophor by fluorescence resonance energy transfer (FRET) to quench the fluorescence of the probe. Dui-ing the PCR annealing step the hybridization probes hybridize to target DNA. In the extension step the 5' fluorescent dye is cleaved by the 5' nuclease activity of Taq polymerase, leading to an increase in tluorescence of the i-eporter dye. Mismatched probes are displaced without fragmentation. The presence of a mutation in a sample is determined by measuring the signal intensity of the two different dyes.

'S The Illumina Golden Gate"" Assay uses a combined oligonucleotide ligation assay/ allele-specific hybridization approach (SHEN R et (rl Mutat Res 2005573: 70-82). The first series of steps involve the hybridization of three oligonucleotides to a set of specific target SNPs;
two of these are tluorescently-Iabelled allele-specific oligonucleotides (ASOs) and the third a locus-specific oligonucleotide (LSO) binding 1-20 bp downstream of the ASOs. A second series of steps involve the use of a stringent polymerase with high 3' specificity that extends only oligonucleotides specifically matching an allele at a target SNP. The polymerase extends until it reaches the LSID.
Locus-specificity is ensured by requiring the hybridization of both the ASO
and LSO in order that extension can proceed. After PCR amplification with univel-sal primers, these allele-specific oligonucleotide extension products are hybridized to an a -ay which has multiple discretely tagged addresses (in this case 1536 addresses) which match an address embedded in each LSO.
Fluorescent signals produced by each hybridization product are detected by a bead array reader from which genotypes at each SNP locus rriay be ascertained.

It will be appreciated that nume--ous other rnethods for sequence discrimination and detection are known in the art and some of which are described in further detail below. It will also be appreciated that reactions such as arrayed primer extension mini sequencing, tag microarrays and sequence-specific extension could be performed on a microarray. One such array based genotyping platform is the microsphere based taQ-it high throughput genotyping array (BORTOLIN S. et al. Clinical Chemistry (.2004) 50(1 1): 2028-36). This method amplifies genomic DNA by PCR followed by sequence-specific primer extension with universally tagged genotyping pi-imers. The products are then sorted on a Tag-It array and detected using the Luminex xMAP system.

Mutation detection methods may include but are not limited to the following:
Restriction Fragment Length Polymorphisrn (RFLP) strategy - An RFLP Qel-based analysis can be used to indicate the presence or absence of a specific mutation at polymorphic sites within a gene.
Briefly, a short segment of DNA (typically sevei-al hundred base pairs) is amplified by PCR.
Where possible, a specific restriction endonuclease is chosen that cuts the short DNA segment 10 when one polymoi-phism is present but does not cut the short DNA segment when the polymorphism is not present. or vice versa. After incubation of the PCR
amplified DNA with Ihis i-estriction endonuclease, the reaction products ai-e then separated using gel electrophoresis. Thus, when the gel is examined the appearance of two lower molecular weight bands (lower molecular weight molecules travel farther down the gJ during electrophoresis) indicates that the DNA
-15 sarnple had a polymorphism was present that perniitted cleavage by the specific restriction endonuclease. In conti-ast, if only one higher molecular weight band is observed (at the molecular weight of the PCR product) then the initial DNA sample had the polymorphism that could not be cleaved by the chosen restriction endonuclease. Finally, if both the higher molecular weight band and the two lowe-- molecular weight bands are visible then the DNA sample contained both 30 polymorphisms, and therefore the DNA sample, and by extension the subject providing the DNA
sample, was heterozygous for this polymorphism;

For example the Maxam-Gilbert technique foi- sequencing (MAXAM AM. and GILBERT
W.
Proc. Natl. Acad. Sci. USA (1977) 74(4):560-564) involves the specific chemical cleavage of terminally labelled DNA. In this technique four samples of the same labeled DNA are each subjected to a different chemical reaction to effect preferential cleavage of the DNA molecule at one or two nucleotides of a specific base identity. The conditions are adjusted to obtain only partial cleavage. DNA fragments are thus generated in each sample whose lengths are dependent upon the position within the DNA base sequcnce of the nucleotide(s) which are subject to such cleavage. After partial cleavage is performed, each sample contains DNA
fragments of different lengths, each of which ends with the same one or two of the four nucleotides.
In particular, in one sample each fragment ends with a C, in anothet- sample each fragment ends with a C or a T, in a third sample each ends with a G, and in a fourth sample each ends with an A or a G. When the 11) products of these four reactions are resolved by size, by electrophoresis on a polyacrylamide gel, the DNA sequence can be read from the pattern of radioactive bands. This technique permits the sequencing of at least 100 bases from the point of labeling. Another method is the dideoxy method of sequencing was published by SANGER et al. (Proc. Natl. Acad. Sci. USA
(1977) 74(12):5463-5467). The Sanger method relies on enzymatic activity of a DNA polymerase to synthesize I 5 sequence-dependent fragments of various lengths. The lengths of the fragments are determinecl by the --andom incorporation of dideoxynucleetide base-specific terminators.
These fragments can then be separated in a gel as in the Maxam-Gilbei-t procedure, visualized, and the sequence determined. Numerous improvements have been made to refine the above methods and to automate the sequencing p--ocedures. Si-nilarly, RNA sequencing methods are also known. For exaniple, --everse transcriptase with dideox\ mucleotides have been used to sequence encephalomyocarditis virus RNA (ZIMMERN D. and KAESBERG P. Proc. Natl. Acad.
Sci. USA
(1978) 75(9):4257-4261). MILLS DR. and KRAMER FR. (Proc. Natl. Acad. Sci. USA
(1979) 76(5):2232-2235) describe the use of Q(3 replicase and the nucleotide analog inosine for sequencing RNA in a chain-terni ination niechanism. Direct chemical methods for sequencing ?5 RNA are also known (PEATTIE DA. Proc. Natl. Acad. Sci. USA (1979) 76(4):1760-1764). Other methods include those of Donis-Keller et cii. (1977. NucI. Acids Res. 4:2527-2538), SIMONCSITS A. c t ul. (Nature (1977) 269(5631):833-836), AXELROD VD. et ul.
(NucI. Acids Res.(1978 ) 5(10):3549-3563), and KRAMER FR. and MILLS DR. (Proc. Natl. Acad.
Sci. USA.
(1978) 75(1 1):5334-_5338). Nucleic acid sequences can also be read by stimulating the natural 10 tluoresce of a cleaved nucleotide with a laser while the single nucleotide is contained in a fluorescence enhancing niatrix (U.S. Pat. # 5,674,743); In a niini sequencing reaction, a primer that anneals to target DNA adjacent to a SNP is extended by DNA polymerase with a single nucleotide that is complementary to the polymorphic site. This method is based on the high accuracy of nucleotide incorporation by DNA polymerases. There are different technologies for analyzing the primer extension products. For example, the use of labeled or unlabeted nucleotides, ddNTP
combined with dNTP or only ddNTP in thc mini sequencing reaction depends on the method chosen for detecting the products;

Pi-obes uscd in hybridization can include double-stranded DNA, single-stranded DNA and RNA
oligonucleotides, and peptide nucleic acids. Hybridization methods for the identification of single nucleotide polymorphisms or other mutatians involving a few nucleotides are described in the U.S.
Pat. 6,270,961; 6,025,136; and 6,872,530. Suitable hybridization probes for use in accordance with the invention include oligonucleotides and PNAs from about 10 to about 400 nucleotides, 1t) alternatively from about 20 to about 200 nucleotides, or from about 30 to about 100 nucleotides in length.

A template-dii-ected dye-terminator incorporation with fluorescent polarization-detection (TDI-FP) method is described by FREEMAN BD. et crl. (J Mol Diagnostics (2002) 4(4):209-215) for large scale SCreenlna;

Oligonucleotide ligation assay (OLA) is based on ligation of probe and detector oligonucleotides annealed to a polymerase chain reaction amplicon strand with detection by an enzyme immunoassay (VILLAHERMOSA ML. J Hum Vii-ol (2001) 4(5):238-48; ROMPPANEN EL.
?O Scand J Clin Lab Invest (2001) 61(2):123-9; IANNONE MA. et ul. Cytometry (2000) 39(2):131-40);

Ligation-Rolling CiT-cle Amplification (L-RCA) has also been successfully used for genotyping single nucleotide polymoi-phisms as described in QI X. et al. Nucleic Acids Res (2001) 29(22):E116;

5' nuclease assay has also been successfully used for genotyping single nucleotide polymo--phisms (AYDIN A. c t al. Biotechniques (2001) (4):920-2, 924, 926-8.);

_10 Polymerase proofreading niethods are used to determine SNPs identities, as described in WO
0181631:

Detection of sinffle hase pair DNA mutatioris by enzyme-amplified electronic transduction is described in PATOLSKY F et cil. Nat Biotech. (2001) 19(3):253-257:

Gene chip technologies are also known for single nucleotide polyniorphism discrimination whereby numerous polymorphisms may be tested for simultaneously on a single array (EP
1120646 and GILLES PN. et al. Nat. Biotechnology (1999) 17(4):365-70);
i Matrix assisted laser desorption ionization time of flight (MALDI-TOF) mass spectroscopy is also useful in the genotyping single nucleotide polymorphisms through the analysis of microsequencing products (HAFF LA. and SMIRNOV IP. Nucleic Acids Res, (1997) 25(18):3749-50;
HAFF LA.
and SMIRNOV IP. Genome Res. (1997) 7:378-388; SUN X. et al. Nucleic Acids Res.
(2000) _28 e68; BRAUN A. et al. Clin. Chem. (1997) 43:1 151-1 158; LITTLE DP. et ul. Eur.
J. Clin. Chern.
Clin. Biochem. (1997) 35:545-548; FEI Z. et al. Nucleic Acids Res. (2000) 26:2827-2828; and BLONDAL T. et al. Nucleic Acids Res. (2003) 31(24):e155).

Sequence-specific PCR nlethods have also been successfully used for genotyping single nucleotide polymorphisms (HAWKINS JR. et al. Hum Mutat (2002) 19(5):543-553).
Alternatively, a Single-Stranded Conformational Polymorphism (SSCP) assay or a Cleavase Fragment Length Polymorphism (CFLP) assay may be used to detect mutations as described herein.

Altei-natively, if a subject's sequence data is already known, then obtaining may involve retrieval 210 of the subjects nucleic acid sequence data (For example from a database), followed by determining or detecting the identity of a nucleic acid or genotype at a polymorphic site by reading the subject's nucleic acid sequence at the one or more polymorphic sites.

Once the identity of a polymorphism(s) is determined or detected an indication may be obtained as to subject response to vasopressin receptor agonist administration based on the genotype (the nucleotide at the position) of the polymorphism of interest. In the present invention, polyrnorphisms in vasopressin pathway associated gene sequences, are used to predict a subjecl's response to vasopressin receptor agonist treatment. Methods for predicting a subject's response to vasopressin receptor agonist treatment may be useful in making decisions regarding the administration of vasopressin i-eceptor agonist.

Methods of ti-eatment of an inflammatory condition in a subject having an improved response genotype in a vasopressin pathway associated gene are described herein. An improved response may include an iniprovement subsequent to administration of said therapeutic agent, whereby the subject has an increased likelihood of survival, reduced likelihood of organ damage or organ dysfunction (Brussels score), an improved APACHE II score, days alive and free of pressors, inotropes. and reduced systemic dysfunction (cardiovascular, respiratory, ventilation, central nervous system, coagulation I INR> 1.5], renal and/or hepatic).
As described above genetic sequence information or genotype information may be obtained from a subject wherein the sequence information contains one or more polymorphic sites in a vasopressin pathway associated gene sequence. Also, as previously described the sequence identity of one or more polymorphisms in a vasopressin pathway associated Qene sequence of one or more subjects IU may then be detected or determined. Furthermore, subject response to administration of vasopressin receptor agonist may be assessed as described above. Foi- example, the APACHE II
scoring systeni or the Brussels score may he used to assess a subject's response to treatment by comparing subject scores before and after treatment. Once subject response has been assessed, subject response may be correlated with the sequence identity of one or more polymorphism(s).
The correlation of subject response may fua-ther include statistical analysis of subject outcome scores and polymorphisni(s) foi- a number of subjects.

Methods of treatment of an inflammatory condition in a subject having one or more of the risk genotypes in AVP, AVPRI A LNPEP or LRAP (or a SNP in linkage disequilibrium thereto) -10 associated with improved response to a therapeutic agent are described hei-ein. An improved response may include an impi-ovement subsequent to administi-ation of said therapeutic agent, whereby the subject has an increased likelihood of survival, reduced likelihood of organ damage or organ dysfunetion (Brussels score), an improved APACHE II score, days alive and free of pressors, inotropes. and reduced systeniic dysfunction (cardiovascular, respiratory, ventilation, central nervous system. coagulation [INR> 1.5], renal and/or hepatic).

As described above genetic sequence info--rnation or genotype information may be obtained from a subject wherein the sequence information contains one or more single nueleotide polymorphie sites in AVP. AVPRIA LNPEP or LRAP sequences. Also, as previously described the sequence identity of one or more single nucleotide polymorphisms in the AVP, AVPR I A
or LNPEP
sequences of one or more subjects may then be detected or determined.
Furthermore, subject outcome or prognosis may be assessed as &-scribed above, for example the APACHE II scoring system or the Brussels score may be used to assess subject outcome or prognosis by comparing subject scores before and after treatment. Once subject outcome or prognosis has been assessed, subject outcome or prognosis may be correlated with the sequence identity of one or more sin.~le 11 nucleotide polymorphism(s). The correlation of subject outcome or prognosis may further include statistical analysis of subject outcome scores and polymorphism(s) for a number of subjects.

3. Analytical Methods Patient Cohort Selection a. Intensive Care Unit (ICU) Cohort Inclusion Criteria All subjects admitted to the ICU of St. Paul's Hospital (SPH) were screened for study inclusion.
I(l SPH ICU is a mixed medical-surgical ICU in a tertiary care, university-affiliated teaching hospital.
Subjects were included in the study if they met at least two out of four SIRS
criteria: 1) fever (> 38 C) or llypothermia (<36 C), 2) tachycardia (>90 beats/minute), 3) tachypnea (>20 breaths/minute), PaCO2 < 32 nim H(Y, or need for mechanical ventilation, and 4) leukocytosis (total leukocyte count > 12,000 mm) or leukopenia (< 4,000 mm'). Subjects were included in the analysis if they met the diagnostic ci-iteria for septic shock (sepsis at-d ca--diovascular dysfunction (as defined by B--ussels scoring system) and one other organ dysfunction) on admission to the ICU.
Subjects were excluded if blood could not be obtained for genotype analysis.
Baseline characteristics (age, gender, adniission APACHE II score (KNAUS WA. et al.
Crit. Care Med.
(1985) 13:818-829), togethei- with medical vs. surgical diagnosis KNAUS WA. et al. Chest (1991) -10 100:1619-1636.) were reco--ded on admission to the ICU. The full coho--t meeting these criteria includcd 1072 Caucasian subjects and 153 Asian subjects.

The Institutional Review Board at Providerice Health Care and the University of British Columbia approved this study.

?5 b. Biological Plausibility (BP) Cohort Inclusion Criteria An independent cohort of Caucasian subjects (N = 102) scheduled for first time elective coronary artery bypass grafting that required cardiopulmonary bypass is referred to as the "Biological Plausibility" (BP) cohort. Significant SNP-biomarker associations identified in this cohort may 30 provide insight into biological processes underlying SNP-phenotype associations observed in the ICU coho--t or subsets of the ICU cohort.

For the BP cohort, individuals were included in the analysis if they were met diagnostic criteria for systemic intlammatory response syndrome (SIRS). Subjects were excluded from the study if tkey had undergone 1) urgent or emergency cardiopulmonary bypass surgery or 2) valve or repeat cardiac surgery. Subjects with urgent or einergency cardiopulmonary bypass surgery were excluded because they may have had an inflammatory response due to other triggers (i.e. shock).
Subjects with valve surgery or repeat surgery were excluded because they could have had different pre-operative pathophysiology or longer total surgical and cardiopulmonary bypass time than subjects having elective cardiopufmonary bypass surgery.

The Institutional Review Board at Providence Health Care and the University of British Columbia approved this study.

Clinical Phenotype The primary outcome variable evaluated in this study was 28-day mortality.
Various organ dysfunctions were considered as secondary outcome variables. Baseline demographics recorded were age, gcnder, admission APACHE II s;:ore (KNAUS WA. et al. Crit Care Med (1985) 13:318-829), and medical or surgical diagnosis on admission to the ICU (based on the APACHE III
dia2nostic codes) (KNAUS WA. et a1. Chest (1991) 100:1619-1636) (TABLE 2B).
TABLE 2B. Baseline characte--istics key.
Baseline Key AGE Given In Years GENDER Percentage of Male Subjects APACHE II APACHE II score % SURGICAL The cIc of Subjects with a SURGICAL ICU admitting diagnosis SEP.ADMIT Sepsis upon admission SEP.ANY Sepsis anytime during admission SS.ADMIT Septic shock upon admission SS.ANY Septic shock anytime during admission 2 O After meeting the inclusion criteria, data were recorded for each 24-hour period (8 am to 8 ani) for 28-days after ICU admission or until hospital discharge to evaluate organ dysfunction, the interAsity of SIRS (Systemic tnflammatory Response Syndrome) and sepsis. Raw clinical and laboratory variables were recorded using the worst or most abnormal variable for each 24-hour period with the exception of Glasgow Coma Score, for which the best possible score for each 24-hour period was recorded. Missing data on the date of admission was assigned a normal value and missing data after day one was substituted by carrying forward the value from the previous day. When data collection for each patient was complere, all patient identifiers were removed from all records and the patient file was assigned a unique random number linked with the blood samples. The compteted raw data file was used to calculate descriptive and severity of illness scores using standard definitions as described below.

Organ dysfunction was first evaluated at baseline and then daily using the Brussels score (SIBBALD WJ. and VINCENT JL. Chest ', 1995) 107(2):522-7) (see TABLE 2A in General Methods Section). If the Brussels score was moderate, severe, or extreme dysfunction then organ dysfunction was recorded as present on that day. To correct for deaths during the observation period, we calculated the days alive and free of organ dysfunction (RUSSELL
JA. ct al. Crit Care Med (2000) 28(10):3405-11 and BERNARD GR. etal. Chest (1997) I 12(1):164-72) (TABLE
IO 2C). Foi- example, the severity of cardiovascular dysfunction was assessed by nieasuring days alive and free of cardiovascular dysfunction over a 28-day observation period.
Days alive and free of cardiovascular dysfunction was calculated as the number of days after inclusion that a patient was alive and free of cardiovascular dysfuriction over 28-days. Thus, a lower score for days alive and free of cardiovascular dysfunction indicates more cardiovascular dysfunction. The reason that days alive and free of cardiovascular dysfunction is preferable to simply presence or absence of cardiovascular dysfunction is that severe sepsis has a high acute mortality so that early death (within 28-days) precludes calculation of the presence or absence of cardiovascular dysfunction in dead subjects. Organ dysfunction has been evaluated in this way in observational studies (Russell JA. c t al. Ci-it Care Med (2000) 28( l0):3405-1 1) and in randomized controlled trials of new therapy in sepsis. acute t-espiratory distress syndrome (BERNARD GR. et al. N
Engl J Med (1997) 336( l3):912-8) and in critical care (HEBERT PC. ct al. N Engl J Med (1999) 340(6):409-17).

To further evaluate cardiovascular, respiratory, and renal function we also recorded, during each 24-hour period, vasopressor support, mechanical ventilation, and renal support, respectively.
Vasopressor use was defined as dopamine :> 5 g/kg/min or any dose of norepinephrine, epinephrine. vasopressin, oi- phenylephrine. Mechanical ventilation was defined as need for intubation and positive airway pressure (i.e. T- piece and mask ventilation were not considered ventilation). Renal support was defined as hemodialysis, pei-itoneal dialysis, or any continuous renal support mode (e.g. continuous veno-venous hemodialysis).

As a cumulative measure of the severity of SIRS, the presence of two, three or foru- of the SIRS
criteria was scored each day over the 28-day observation period SIRS was considered present when subjects met at least two of four SIRS criteria. The SIRS criteria were I) fever (>38 C) or hypothermia (<36 "C), 2) tachycardia (>90 beats/min in the absence of beta-blockers, 3) tachypnea (>20 breaths/min) or need fo-- mechanical ventilation, and 4) leukocytosis (total leukocyte count >
12,000/ L or <4,000/ L).

TABLE 2C. Primary and secondary outcome variables for the ICU cohort and subsets Survival and Days alive and free (DAF) of organ dysfunction Key SURVIVAL 28-Day Survival ALLDAF Days alive and free of acute Lung Irijur PRESS.DAF Days alive and free of any vasopre,sors PRESS2.DAF Days alive and free of more than 2ug/min of vasopre~~sors PRESS5.DAF Days alive and free of more than 5ug/min of vasopre~~sors PRESS15.DAF Days alive and free of more than 15ug/min of vasopre~~sors INO.DAF Days alive and free of inotro es SIRS2.DAF Days alive and free of 2 of 4 SIRS criteria SIRS3.DAF Days alive and free of 3 of 4 SIRS criteria SIRS4.I)AF Days alive and free of 4 of 4 SIRS criteria STER.DAF Days alive and free of steroids CVS.DAF Days alive and free of cardiovascular dysfunction RESP.DAF Days alive and free of respiratory dysfunction PF300.DAF Days alive and free of Pa02/Fi02 less than 300rnHg VENT.DAF Days alive and free of mechanical ventilators CNS.DAF Days alive and free of neurological dysfunction COAG.DAF Days alive and free of coagulation dysfunction INR.DAF Days alive and free of international normalized ratio > 1.5 ACRF.DAF Days alive and free of acute renal failure ANYREN.DAF Days alive and free of any type of renal dysfunction RENSUP.DAF Days alive and free of renal sup ort ACHEP.DAF Days alive and free of acute hepatic dysfunction ANYHEP.DAF Days alive and free of any type of hepatic dysfunction AFFD.DAF Days alive and free of acute Failure FFD.DAF Days alive and free of acute or chronic failure Baseline characteristics for the Biological Plausibility cohoi-t included age in years, r/c males %smokers, (~'cdiabetes, ~/c hypertension, ejection fraction, bypass time, clamp time and aprotinin.
Outcome variables measured in the Biological Plausibility cohort included Granulocyte colony stimulating factor (GCSF), Interleukin 10 (IL10), Interieukin receptor la (U--Ira), Interleukin 6 (IL6), Interleukin 8(IL8) and Monocyte Chemoattractant Protein I(MCPI ). A key for the variables evaluated in the Biological Plausibility cohort is provided in TABLE
2D.

IO TABLE 2D. Biological plausibility key.
Biolo ig cal Plausibilit Ke H.TENSE Hypertensive (( hypertension) EJEC.FRAC Ejection Fraction BYPASS Bypass Time (hours) CLAMP Clamp Time (hours) APROTININ Aprotinin Use GCSF Granulocyte Colony Stimulating Factor (c,,/mL) ILIO Interleukin 10 ( Q/mL) ILlra Interleukin rece tor la (g/mL) IL6 Interleukin 6 (pg/mL) IL8 Interleukin 8 (pg/mL) MCP Monocyte Chemoattractant Protein (pg/mL) DEL'I'A for protein X preoperatively and 3 hours X.diff postoperatively X.0 protein X levels preoperatively X.3 rotein X levels 3 hours postoperatively Selection of SNPs for Genotyping Publicly available genotype data was queried from the International HapMap Project (www.hapmap.org) and Perlegen Sciences. Inc. (www.perleQ~en.com) to select a set of tag SNF's (tSNPs) in the LNPEP, AVP and AVPR 1 A. regions each having a minor allele frequency (MAF) oreater than 0.05. These tSNPs were chosen using several statistical methods, including pairwise Iinkage disequilibrium (LD) measures (DEVLIN B. and RISCH N. Genomics (1995) 29:31 1-322), haplotype (STEPHENS M. et ul. Ani J Hutn Genet. (2001) 68:978-989; and EXCOFFIER L. and SLATKIN M. Mol. Biol. Evol. (1995) 120):921-927) and haplotype block (HAWLEY
ME. and KIDD KK. J. Heredity. (1995) 86:409-41 l) patterns, as well as phylogenetic (cladistic) distance metrics (HAWLEY ME. and KIDD KK. (1995)). When these methods did not yield a parsimonious conclusion, as was the case for AVP, SNPs closest in physical dist.ance to the given gene of interest were selected. Each polymorphism was genotyped in the ICU
Cohort and the Biological Plausibility Cohort.

Sample Analysis Sample Preparation Discarded whole blood samples, stored at 4 C, were collected from the hospital laboratory. DNA
was extracted from buffy coat using the QlAamp DNA Midi kit (Qiagen, Mississauga. ON, Canada). After extraction, the DNA samples were transfei-red to 1.5 mL
cryotubes, bar coded and ci-oss-referenced with a unique patient number and stored at -80 C.

ABI Genotyping Single nucleotide polymorphisms in AVP, LNPEP and AVPRIA were genotyped using the 5' nuclease. TaqmanT'll (Applied Biosystems; Foster City, CA) polymerase chain reaction (PCR) method. TABLE 2E provides a complete list of the 10 SNPs genotyped for this study.
TABLE 2E: List of tSNPs genotyped in ICU and Biological Plausibility Cohorts Gene tSNPs LNPEP rs 10051637 rs38041 rs27711 rs 18059 A VP rs1410713 rs857240 rs857242 AVPRIA rs3803107 rs 10877970 i-s I495027 Illumina Genotyping Single nucleotide polymorphisms in AVP, LNPEP and AVPRIA were genotyped using the Illumina Golden Gate""' assay from 250 ng of DNA extracted Frorn buffy coat. A
list of these SNPs can be found labeled as cohort `I' in TABLE 1 B found in the General Methods section.
Sequencing of LNPEP region Sequencing of a 157.1 kb region including the LNPEP and LRAP Qenes was undertaken using DNA extracted from six CEPH (i.e., Centre d'Etudes du Polymorphisme Hunlain) individuals obtained through the Coriell Institute for Ntedical Research using the Applied Biosystems 3730 platform. Ascertained polymorphisms were investigated for NCBI rs Id annotation using the UCSC -enome browser (htt :II cnome.iic~c.~du). If a polymorphism was found to not have ari rs Id assigned, it was given a numeric id prefixed by `sirius' (i.e. siriusx).

Linkage Disequilibrium Analysis Included in this patent are SNPs found to b,- associated with 28-day survival or response to vasopressin as well as SNPs determined to be in LD with the former. LD SNPs were ascertained using either Haploview (BARRETT JC. et ul. Bioinformatics (2005) 21(2):263-5 (I~tt~~://tiv~1,w.broad.mit.eduln~p~lhaplovittiv,')) or the LD function in the Genetics Package in R (R
Core Development Group, 2005 - R Development Core Team (ww\\.R-projec.t.org).
A R' threshold of 0.5 was required in order that a SNP be considered in LD with those claimed herein.
All LD SNPs are shown in table I B.

The AVP, AVPRIA, LNPEP and LRAP genes are central to the action of vasopressin given that )5 vasopressin induces vasoconstriction by signaling through the AVPR 1 A
receptor and that vasopressin activity is inhibited when cleaved by LNPEP. Similar protein homology between LNPEP and LRAP suggest that these two ~~enes arose throu-h an ancient gene duplication event (DANCHIN E et cil., hnrnunol Rev (2004) 198:216-332). This homology and the observation of an extended linkage disequilibrium (LD) block throughout the LRAP and LNPEP
recyion (HapMap 10 Phase II data; www.hapmap.org) supports the inclusion of LRAP in the vasopressin pathway.

Furthermore, variability in response to infused (i.e., administered) vasopressin most likely occurs as a result of polymorphisms in the AVP. AVPRIA, LNPEP and LRAP genes because the proteins that these genes encode are central to the actiotls of native and infused vasopressin (AVP).

Statistical Analysis A description of the statistical analysis used is pl-ovided for each example in the following sections.

EXAMPLES

EXAMPLE 1: RESPONSE TO VASOPRESSIN IN SEPTIC SHOCK
METHODS
Cohort Selection To investigate whether genotype predicts response to vasopressin, a subset of Caucasian subjects with septic shock and treated with vasopressin (N = 103) were compared to a conti-ol group of Caucasian subjects with septic shock who had not been administered vasopressin (N = 103).
Vasopressin-treated and control subjects w,--re matched based on age, gender, admission APAC'HE
II score, niedical versus surgical diagnosis and days alive and free of 3 of 4 systematic inflammatory response syndrome (SIRS) criteria. The baseline characteristics of these groups are presented in Table 3.1.

TABLE 3.1 `'5 Baseline characteristics of cases (Caucasian ICU septic shock subjects treated with vasopressin) and controls (Caucasian ICU subjects with septic shock, matched (see text for details) and not treated with vasopressin). For age and APACHE II score, data is given as 25"' percentile I median ~
75111 ercentile. For all other variables, data is Qiven as % (N /N total). N, number of subjects.
Cases ;ALI. Control (Vasopressin-treated) Conihined Test (N=103) (N'=103) (N=?06) Statistic 1GE 44 56 7 1 . 5 47 60' 68.5 -la.'_5 58.5 70 F=0.14d.t.=1204 P=0.713 GENDER 69lf (71/103) 78 l<(80/1Q3) 7314, 0 it/106) X^?=? f)t d.t.=l P=0.t56 ?,PACHE 11 24 29 33 25 30 I 37 21.25 29 34 F=0.38 d.f.=1.'_04 P=0.5 37 `.7SI;RGICAL 44`.i, (45/103) -1-114 (45/103) 441% ( 90/206) X^2=0 d.1:=1 P=1 Data Analysis All data analysis was carried out using statistical packages available in R (R
Core Development Group, 2005 - R Development Core Team (www.R-project.ore). R: A language and envit-onnient for statistical computing. Vienna, Austria. 2005). Chi-square and Kruskal-Wallis (KW) test statistics were used in conjunction with Cox proportional hazards (CPH) regression to identify significant SNP-phenotype associations, as well as to identify significantly different baseline characteristics (age, gender, admitting APACHE 11 score, and medical vs.
surgical admitting S diagnosis) requiring post-hoc, multivariate adjustment. The control population was selected by matching. utiing the MatchIt package in R, by age, gender. APACHE II score, medical vs. surgical diagnosis, and days alive and free of 3 of 4 SIRS criteria. There were no differences in baseline characteristics between vasopressin-treated cases and controls.

iO Using 28-day survival as the outcome variable and a chi-squared test of significance, SNP-phenotype compai-isons were undertaken within and between treatment groups. We considered a by-genotype effect to be significant when two ci-iteria were fulfilled. First, we expected an increase in 28-day survival foi- vasopressin-treated subjects compared to controls. Second, we i-equii-ed a p-value < 0.1 for this difference in 28-day survival. When both criteria were met, we 15 considered the allele or genotype predictin;, increased 28-day survival with vasopressin treatment to be an "improved response genotype" (IR:G). Only IRG polymorphisms were evaluated for oi-gan dysfunction results and were compared between vasopressin-treated subjects and matched controls using a Kruskal-Wallis test.

20 Results 1.1 Leucyl/Cystinyl Aminopeptidase (LNPEP) 1.1.1 Adverse Response to Vasopressin 'Treatment of subjects who have the CC
Genotype of LNPEP rs18059 and Improved Response to Vasopressin Treatment of subjects 25 who have the TT Genotype of LNPEP rs18059 It was unknown whether SNPs within the L.NPEP gene and those regions immediately upstream and downstrcam would be associated with the response to vasopressin. It was found that LNPEP
rs18059 can be used to predict response (28-day survival) to vasopressin in subjects with septic 110 shock. Of 103 vasopressin-treated and 103 niatched-control subjects with septic shock, 73 and 81 were respectively genotyped for LNPEP rs78059. Baseline characteristics for subjects with genotypes are shown in Table 3.2 and Table 3.3.

TABLE 3.2 Baseiine characteristics of a group of vasopressin-treated Caucasian septic-shock subjects by genotype of leucyl/cystinyl aminopeptidase (LNPEP) rs18059. For age and APACHE
II score, data is given as 25th percentile I median 175'f' percentile. For all other variables, data is given as /%
(N /N total). N, number of subjects.
VASOPRESSIN CC CT TT Comhined Test (N=27) (N=33) (N=13) (N=73) Statistic ~GE 14 60 69.5 -l8 6d 72 39 57 66 47 60 68 F=0.7 d.f.=?,70 P=G.5 GENDER 67'70 (18/27) 85'4 (28/33) 77f/c (10/13) 77(70 (56/73) X^2=2.75 d.f.=2 P=[).253 APACHE 11 ?5 32 40 23 30 37 ?6 29 3d 25 30 37 F=0.39 d.f.=?,70 P=0.678 " SURGICaL 48'%(1 3/27) 39111( (13/33) 3114 (-l/1 3) 4111,(30/73) X2=1.17 d.l:=2 P=J.558 TABLE 3.3 Baseline characteristics of a vasopressin untreated matched control group of Caucasian ICU septic shock subjects by genotype of Ieucyl/cystinyl aminopeptidase (LNPEP) rs 18059.
For age and APACHE II score, data is given as 25`h percentile I median 175`h percentile.
For all other variables, 1t) data is given as % (N /N total). N. number of sub'ects.
CONTROL CC CT 'iT Combined Test (N'=1i3) (N=-13) (N=20) (N=81) Statistic :AGE 39.25 46.5 102.75 441 5? 66.5 48.75 67 171 ld I 56 71.5 F=2_58 d.1.=2,78 P=0.0824 GENDER 831 ~, ( 15/I S) 67'1, (29/43) 5011, (10120) 67% (54/81) Chi =4.76 d.f.=2 P=0.0925 AP ACHE ll 23.35 36.5 32.5 26.5 31 37 25 129 ! 34 ?-} 29 134 F=2.24 d.f.=2,78 P=0.1 13 '%St'RGICAL. 2 21 7 ( 4/1S) 33111 (1-t/43) 50'/(]0/?0) 751/~ (28/81 ) Chi=3.4 d.f.=2 P=0.IS3 Table 3.4 and Table 3.5 show 28-day survival and organ dysfunction data by LNPEP rs 18059 genotype for vasopressin-treated and control subjects respectively. Table 3.6 shows the differences in survival and measures of organ dysfunction between by LNPEP
rs18059 genotype 15 between vasopressin-treated and control subjects.
In 2eneral, Table 3.6 shows that vasopressin-treated subjects with LNPEP I-s18059 CC had lower survival and more organ dysfunction than controls as evidenced by negative values for the LNF'EP
rs18059 CC subjects in the DELTA column. In contrast, vasopressin-treated subjects with the LNPEP rs 18059 TT genotype had increased survival and improved ol-gan function (shown by 20 (Yreater DAF) compared to controls as demonstl-ated by the generally positive values in DELTA, column. There was a small increase in survival of subjects with the LNPEP
rs18059 CT Qenotype in vasopressin-treated subjects (36 c) compared to controls (28 %).

'FABLE 3.4 A response association of leucyl/cystinyl aminopeptidase (LNPEP) rs18059 in a group of Caucasian ICU septic shock subjects treated with vasopressin. For 28-day survival, data is given as ~1~ (N survived / N total). N, number of subjects. For all variables besides 28-day survival, clata is given as 25'' ercentile -nedian 175`' el-centile.
VASOPRESSIN-TREATED CC CT TT Combincd Test (N=37) (N=33) (N=13) (N=73) Statistic SL'RVIV:AL, 441<(12/27) 361%(12/33) 38'7,- ( 5/13) 40(7( (29/73) Chis( uarc=0.J2 d.f.=2 P=0.812 DAYS ALIVE 7,5119128 ? I3 28 2 g 28 3 113 28 F=0_71 d.f.=2.70 P=0.496 ALI.DAF ? 8 16 I 3 19 I d 12 1161 17 F=0.2; d.f.=3,70 P=0.71)8 PRESS.DAF 015119 O 3 18 ()10122 0 3 19 F=0.21 d.1': 2,70 7=0.812 PRESS2.DAF 0 5 20.5 0131 18 0 0 22 0 3 20 F=0.16 d.f.=2,70 7=0.855 PRESS5.DAF 0 ' I I! 20.5 0131 19 010123 0 3 21 F=0.12 d.f.=2,70 P=O.SFI7 PRESSI5.DAF 1112123 O 6 22 0 0 25 017123 F=0.51 d.f.=2,70 P=0.6 INO.DAF 6 12128 2 12 26 2 8" 2 IZ 26 F=1.2a d.f.=2,70 P=0.296 SIRS2.DAF 0 0 3.5 0 02 ()1011 0 0 2 F=0.12 d.f.=2.70 P=0.8R3 SIRS3.DAF I5 4 15.5 0 1 9 0 2 14 14 I I F=0.41 d.f.=2,70 P=0b67 SIRS4.DAF 5.5 Id 121.5 2 8 23 ? 5 20 2 10 23 F=0.51 d.f.=2,70 P=0.6 STER.DAF ()13117.5 I 6 ? 0 I 12 7 I f 19 F=0.19 d.f: 2,70 P=0.824 CVS.DAF 012114.5 0 0! 13 0 0 21 0 1 14 F=0.38 d.f.=2,70 P=0.68,4 RESP.DAF 0 Z 17 0' 0 5 (1 0 8 ()1()18 F=0.56 d.f.=2,70 P=0.573 PF300.DAF 0 0 ? U ( l 0 0 Q O 0 0 I F=3.61 d.f.=2,70 P=0.0321 VENT.D,4F 0 0 7 010 5 0 0~ 8 0O S F=0.35 d.l:=2,70 P=0.7G7 CNS.DAF 6.5 14 ~ 27 2 6 24 ? 7 1 24 2 1 I 25 F=1.?9 d.t:=2,70 P=0.281 C'O AG.DAF 2 1 I 26.5 1~ 5 I_16 1 726 I 8 26 F=0.53 d.f.=2,70 P=0.588 INR.DA6 5.5 15126.5 1 8 1 27 I 5 37 ? 8 27 F=0.29 d.f.=2.70 P=0.746 ,ACRF.DAF 2.5 827 0 2 13 0 I'- 26 015 119 F=?.32 d.f.=2,70 P=0.106 1NYREN.DAF 2.5 18124 0 2 1 1 3 0 2 26 0 5 I S F=1.8 d.f.=_',70 P=0.173 RENSIP.DAF 1 16 27.5 ? 5 ? 3 1 1?8 l I 5 127 F=0.23 d.f.=3.70 P=0.796 ACHEP.DAF 1.5 I I24.5 2 19124 2 3 i28 2 927 F=0.1 d.f.=-',70 P=0.906 ,4NYHEI'.DAF 1.5 I I 24.5 7' 9 24 ? 328 2 927 F=0.07 d.f. 2,70 P=0.937 TABLE 3.5 A response association of leucyl/cystinyl aminopeptidase (LNPEP) I-s18059 in a matched control group of Caucasian ICU septic shock subjects not treated with vasopressin. For 28-day survival, data is given as ~/( (N survived / N total). N. number of subjects.. For all variables besides 28-day survival, data is Qiven as 25 i ercentile I median 175"` el-centile.
CONTROL CC' CT TT Combined Test (N=18) (N=43) ('.V=20) (N=81 ) Statistic ;;q SCRVIVAI_ 671< (12/18) _181k (12l43) I51~ ( 3/20) (27/81) Chis uzire=12.59 d.(.=? P=0.00184 DAYS ALIVE 14.25 128 28 2 628 2.5 ~ 5 I 7.25 iH 2 F=7.2T d.l =?,7t3 P=0.00130 AL(.DAF 3.25 12.5 21.75 I? 9 1 3.5 7 1 5 t4 F=3.0d d.f: ?.78 P=0.0537 PRESS.DAF 9.?5 21.5 36 O 7 17.5 0 0 4.25 0~4 22 F=7.98 d.f.=2.78 P<0.00I
PRESS2.DAF 95 24.5 26 O 1 3 t7.5 0 0 1?5 0-t ~? F=8.05 d.l.=?,7S P<0.001 PRESS5.DAF 1 0 25.5 27 0 4 19.5 0 0.5 5 0 4?3 F=7.69d.f: 2.787<0.001 PRESS 15.DAF 14'5 26.5 28 0 5 22 Q' i 6.25 O 526 F=7.52 d.f.=2.78 P=0.00103 INO.DAF I4.25 26.5 28 2 5 20.5 0.75 37.25 1- 6?8 F=5.5d d.f.=2.78 P=0.00561 SIRS?.DAF () 0.5 10.75 0 (l 1.5 O 0O 0' 0 I F=2.28 d.f: 2.78 P=0.109 SIRS3.DAF 245 116.5 o I? 6 0.75 I 2 0? I 7 F=2.81 d.f.=2,78 P=0.0664 SIRS-l.D~\F 9.2 5 16 26.75 1' S 1 19.5 1.75 3.5 6.25 2! 622 F=6.37 d.f.=?,78 P=0.00273 S"I'ER.DAF 7.75 I 17 27.5 114 1 1 13.5 7 I 521 F=1.78 d.1'.=2,78 P=0.175 CVS.DAF 4.75 21.5 24.75 0215.5 00 -l 02119 F=6.7 d.f.=2.78 P=0.00206 RESP.DAF I.25 8.5 1 19.75 0 I' 7.5 0 0.5 3.25 O I IO F=3.45 d.f.=2,78 P=0.0365 PF3O(1.DAF 0 0 ? O 0 I O O I Q 0 I F=0.53 d.f.=2,78 P=0.598 VENT.DAF U S.5 ' 19.75 0 0 7 01011.5 0 0 10 F=3.53 d.f.=2.78 P=0.03-12 CNS.DAF 1 I 25.5 127 0.5 41-3 O.75 -t 7 1 725 F=8.55 d.f.=?,78 P<0,001 COAG_DAF 14.25 78 38 1 ' i ? 1 0.75 5 7 . 25 1' 6 25 F=9 d.f.=2,78 P<0.001 INR.DAF 14 24.5 ?S O 3 16.5 0 3 5.5 014122 F=8.74 d.f.=2,78P<0.00I
ACRF.DAF 9.25 22.5 17 014110. 5 0 0.5 -t 04 20 F=8.63 d.f.=2,78 P<0.001 ANYREN.DAF 9.25 22.5 27 012110.5 0' 0 4 0 3 20 F=9.64 d.f.=2,78 P<0.001 REhSUP.DAF 5.5 23128 I_' 9.5 I 2.5 7.25 I 4 1~ F=5.85 d.f. 2.78 P=0.00431 ACHEP.DAF 14.25 28 28 1 d 20 I 5 7.25 I 6 28 F=6.46 d.f.=2.78 P=0.00254 ANYHEP.DAF 14.25 28 28 I 14 20 I 5 7.25 I 6 28 F=6.73 d.1.=2.78 P=0.00201 TABLE 3.6 Difference in response association of leucyl/cystinyl aminopeptidase (LNPEP) rs18059 between cases (vasopressin-treated group) (Treat) and controls (vasopressin untreated matched control) (Cont) of Caucasian ICU subjects diagnosed with septic shock. For all variables besides 28-day survival, data is presented as medians. For 28-day survival, data is presented as r/c(N survived / N
total). N, number of subjects.
rs 18059 CC rs 18059 CT rs 18059 TT
N=27) (N=18) (h=53) (h=43) (N=13) (N='o) Treat Cont DELTA Trcat Cont DELTA Treat Cont DELTA
Sl'RV'IVAL 4,41-c(I2) 67''c(12) -23`%c 36"~ (12) 28`b(I2) 8 % 3n`1,(5) 151%c(3) 23"c ALI.D.AI; 8 12.5 -4.5 3 2 I 4 ?.5 0.5 PRESS.D.AF 5 24.5 -19.5 3 3 0 0 0 U
PRESS2.DAF 5 24.5 -19.5 0 0 Q 0 PRESS5.DAF 11 25.5 -14.5 3 4 -1 0 0.5 -0.5 PRESSIS.DAF I? 16.5 -14.5 6 5 1 0 2 -2 INO.DAF I? 26.5 -14.5 1'_ 5 7 8 3 5 SIRS2.DAF 0 (1.5 -0.5 0 0 0 0 0 0 SIRS3.DAF -l 4.5 -0.5 4 2 2 2 I 1 SIRSa.DAF 14 I6 -2 8 5 3 5 1.5 1.5 STER.D.>\F 3 17 -14 6 4 2 2 3.5 -l.S
CVS.DAF 2 11.5 -19.5 0 '_ -_' 0 0 0 RESP.D,~\F 2 8.5 -6.5 0 I -I 0 0.5 -0.5 PF30O.D;\F 0 p 0 0 0 0 0 0 0 VENT.DAF 0 8.5 -8.5 0 f) O 0 fl (1 CtiS.DAF 14 25.5 -11.5 6 4 2 7 4 3 COAG.DAF II ?H -17 5 3 2 7 5 2 IN'R.DAI: 15 31.5 -9.5 8 3 5 5 3 2 ACRF.D:AF 8 _12.5 -14.5 2 4 -2 2 0.5 1.5 WYREI~'.DAF 8 22.5 -14.5 2 2 p 2 0 2 RENSUP.DAF 6 ?3 -17 5 3 3 2.5 0.5 WHEP.DMF I1 I8 -17 9 4 5 3 5 -2 A~YHEP.DAF 11 28 -17 9 4 5 3 5 -2 A IoLnstic regression approach was used to test for a statistically significant interaction between IO 'jenotype and vasopressin use as predicted by 28-day survival TABLE 3.7 shows that there is a statisticaily significant interaction between LNPEP rs18059 Qenotype, vasopressin treatment and survival (P = 0.0391 ). confirming that treatrnent with vasopressin decreases 28-day survival in LNPEP rs18059 CC subjects. In contl-ast, 28-day survival for vasopressin-trcated subjects with the LNPEP rs 18059 TT genotype is improved compared with controls. Following adjustment for aae, admission APACHE It score, gender, medical, surgical diagnosis and 3 of 4 systematic inflammatory response syndrome (SIRS) criteria, there was still a statistically significant interaction of the LNPEP rs 18059 genotype, treatment with vasopressin and survival (P = 0.0555) TABLE 3.7 Interaction between vasopressin use vs. no vasopressin use (controls) and CC
or CT genotype vs.
TT Qenotv e of leucyl/cystinyl aminopeptidase (LNPEP) rs18059 on 28-da survival.
Estimate Std. EtTOr z value Pr(> z) Vaso ressin vs. controls +*enotv e interaction - ?.1809 1.057 -2.063 0.039O8 Vaso ressin vs. contmis + venotv.e interaction -.4d usted -2.2301 1.165 -1.914 0.05559 1.1.2 Adverse Response to Vasopressin 7'reatment of Subjects Who Have the AA
Genotype I 0 of LNPEP rs27711 and Improved Response to Vasopressin Treatment of Subjects Who Have the GG Genotype of LNPEP rs27711 It was unknown whether SNPs within the LNPEP gene and those regions immediately upstrearn and downstream are associated with the response to vasopressin. It was found that LNPEP
I> rs2771 I can be used to predict response to vasopressin in subjects with septic shock using 28-day survival and measures of organ dysfunctiorl as outcome val-iables. Of 103 vasopressin-treated and 103 matched-control subjects with septic stiock. 70 and 81 wel-e respectively crenotyped for LNPEP rs2771 1. Baseline characteristics for subjects with genotypes are shown in Tablc 3.8 and Table 3.9. LNPEP rs2771 I is in linkage di,~equilibrium with, for example, LNPEP rs18059 and LNPEP rs 1005 1637, which were also genotyped in this cohort.
TABLE 3.8 Baseline characteristics of vasopressin-treared Caucasian septic-shock subjects by LNPEP rs2771 I
genotype. For age and APACHE II score, data is given as 25'' percentile I
median 175 i percentile.
15 For al1 other variables, data is given as rlc (N /N total). N, number of subjects.
VASOPRESSIN A,\ AG GG Conibined Tcst ('V=21) (N=28) (N=21) (N=70) Statistic AGE 4; 5S 71 50.?5 63.5 ' 7? 39 60 68 47 60 68.5 F=0.32d.f.=2,67 P=0.728 GENDER 71(15/2 i) 75~h (21/28) 81'~,(17/21) 76'9~ (53/70) X^2=0.53 d.1'.=2 P=0.767 APACHE II 25133141 23.75 29.5 36.35 26 29136 25 30 37 F=0.68 d.f.=2,67 P=0.512 qr SURGIC:IL -l3", ( 9/21 ) 461'c (13/28) 2917. ( 6/21) 40% (28/70) X^2=1.7 d.1.=2 P=0.428 TABLE 3.9 Baseline characteristics of a group of Caucasian septic-shock contl-ol subjects by LNPEP rs2771 1 genotype. For age and APACHE tt score, clata is given as 25`" percentile I
median ( 75"' percentile.
For all other variables, data is Qiven as Ic (N /N total). N, number of subjects.
CONTROL AA AG GG Combined Test (N=10) (N=45) (N=26) (N=81) Statistic AGE 39.25 45.5 58.5 43 52 67 -(9 66 74 44 56 71.5 F=3.59 d.1.=178 P=0.0321 GENDER 80'.% ( 8/10) 67% 00/45) 62'7,(16/26) 67'7., (54/81 ) X^2=1.11 d.f.=2 P=0.575 APACHE 11 23.25 26 32.5 26 30 34 27 30.5 38 24 129134 F=1.26 d.f.=2,78 P=0.29 '7SI:RGICAL 20`7,( 2/10) 361I1 (16/45) 38% (10/26) 35'7<(28/81) X^2=1.13 d.f.=2 P=0.568 Tables 3.10, 3.11 and 3.12 contain 28-day Survival and organ dysfunction data for septic-shock subjects genotyped for LNPEP rs27711. In general, vasopressin-treated subjects with the LNPEP
rs2771 1 AA genotype had a dramatically decreased survival (43 %) compared to controls (60 as demonstrated by the negative values in the LNPEP rs2771 1 AA DELTA column in Table 3. 12.
In general, vasopressin-treated subjects with the LNPEP rs2771 I AA genotype also had increased organ dysfunction as denionstrated by fewer DAF of organ dysfunction conlpared with controls,.
In contrast, vasopressin -treated subjects with the LNPEP rs2771 I GG genotype had an increased survival (33 r/c) compal-ed to controls (19 ~/~) as denionstrated by the positive values in the LNPEP
rs2771 I GG DELTA column in Table 3.12 TABLE 3.10 A response association of Ieucyl/cystinyl arninopeptidase (LNPEP) rs2771 I in a group of Caucasian ICU septic shock subjects who were treated with vasopressin. For all variables besides 28-day sw-vival, data is given as 25`l' percentile I median 175"' percentile.
For 28-day survival, data is given as ~Ic (N survived / N total). N, number of subjects.
VASOPRESSIN AA AG GG Combined Test (N=21 ) (N=28) (N=21) (N'=70) Statistic SURVIVAL 43(ri ( 9) (10) 3?'.7c ( 7) 37`,~' (26) Chi;cuare=0.45 d.f.=2 P=0.799 DAYS ALIVE 7112 28 3 17.5' 28 ?' 8 28 3112.5 28 F=0.49 d.f.=2,67 P=0.615 ALLDAF ? 6 12 3 9 21 12 12 I 5.5 17 F=1.65 d.t.=167 P=0.201 PRESS.DAF 0 I 19 04 16.25 00 121 0 I 18 F=0.03 d.f.=2,67 P=0.97 PRESS2.DAF 0 I 20 014 16.25 0 0 21 0 I 18 F=0.04 d.f.=3.67 P=0.96 PRESS5.DA1~ 0 1 120 0 7.5 18 0 0 21 0 1.5 19.75 F=0.09 d.t.=2,67 P=0.91 PRESS 15.DAF I 7 23 0 11.5 21.25 0 2 21 015 22 F=O.a d.f.=167 P=0.672 INO.DAF 7 1 I 2 28 2 I 26 ? 5" 2 12 ~ 26 F=0.99d.f.=2.67P=0.375 SIRS?.DAF 010 3 0 I' 0O I 0 02.75 F=0.24 d.f.=2,67 P=0.787 SIRS3.DAF I47 I 7 I 1?.5 O " 8 I 1 11 F=1.13 d.f.=2.67 P=0.33 SIRS4.11AF 5 IO' 19 2 IS 24 2 5 20 2! 10 21.5 F=0.5 d.f.=2.67 P=0.61 S'I-ER.DAF 0 2 12 I 10124.25 1 3 10 I4 11 .25 F=0_98 d.f'.=2,67 P=0.382 CVS.DAF 0 I 1 4 0' 0.5 13 0 0 14 0 0 13.75 F=O.I d.t'.=2,67 P=0.903 RESP.DAF q i 1 4 0 0 1 5 O q 8 O 0 5 F=0.21 d.f.=2,67 P=0.812 PF00.DAF o 0 -' Q 0 1.25 00 0 0 0 I F=3 d.f.=2,67 P=0.0565 VENT.DAF O O I 3 0 0 2.75 0 0 8 0 04.5 F=0.01 d.f.=2,67 P=0.991 CNS.DAF 6 I l 27 2 1 3 24 ? 7 1 24 ? I l 24 F=0.67 d.f.=2,67 P=0.5I3 ('O.-YG.DAF ? ; i 25 I 13.5 27?5 I 626 I 8 26 F=0.18 d.f.=2,67 P=0.84 INR.DAF 4 1 I 26 1.75 11.5 27 I 5 26 2 8 26.75 F=0.29 d.f.=2,67 P=0.747 ACRF.DAF ? 6?4 0 2 18.25 04 14 0 5 19 F=0.5 d.t:=2,67 P=0.607 AN'YREN.DAF ? 16124 012116.5 04 14 0 5 17.5 F=0.-17 d.t:=2,67 P=0.629 RENSUP.DAF I 3 27 2 7.5 ' 23.5 2 5 33 I 5.5 24.5 F=0.5 d.f.=2,67 P=0.607 ACHEP.DAF I 7 24 3 11 2~.75 ~ ~ f 28 2 92-1.75 F=0.78 d.f.=2.67 P=0.462 .aNYHEP.DAF 1 I 17 124 1 3114124.75 2 14 128 1 2 19 124.75 F=0.77 d.f.=2,67 P=0.466 TABLE 3.11 A response association of leucyl/cystinyl aminopeptidase (LNPEP) rs2771 I in a matched control group of Caucasian ICU septic shock subjects who were not treated with vasopressin. For all variables besides 28-day survival, data is g~iven as 25't' percentile I median 175t'' percentile. For 28-da survival, data is given as '7( (N survive(I / N total). N. number of subjects.
CONTROL AA AG GG Conihined Test (N=10) (N=45) (N=26) (N=81) Statistic SURVIVAL 60(Z( 6) 36'7o (16) 191/1 ( 5) 3317,: (27) Chisc uare=5.63 d.f.=2 P=0.06 DAYS ALIVE 14.?5 28 ?8 2 8128 3 5.5 8.75 3 8 28 F=5.09 d.f.=2,78 P=0.O0839 ALLDAF 7 9.5 19.25 I? 18 I 5 8 I 5 15 F=2.04d.f.=2,78 P=0.1 36 PRESS.DAF 10.75 23 26.75 0 4?3 0 1.5 5.75 0 4 22 F=4.35 d.t:=2,78 P=0.0161 PRESS2.DAF 1 1.5 23 ?6.75 0 4 3 0 1.5 5.75 q 4 22 F=4.41 d.f.=2,78 P=0.0154 PRESS5.DAF 13125 127 0 4123 0 1.5 6.5 O 4 23 F=4.67 d.f.=-',78 P=0.0122 PRESSI5.DAF 14.2 52 6.5 2 8 I 625 0 2.5 7 I 16120 F=5.II d.f.=2.78 P=0.00833 INO.DAF 14.?5 28 28 2 6 25 113.5 8 2 61?8 F=3.76 d.f.=?,78 P=0.0276 SIRS?.DAF 0 I 4 0 0 2 O' O I O 0 I F=1.59 d.1'.=2,78 P=0.21 I
SIRS?.DAF 2 3.5 6.5 D 2 9 (1.25 I? 0 2 7 F=1.19 d.f.=2.78 P=0.308 SIRS4.DAF 9.25 1 10.5 23 I 72' 2 =t 7 2 17 2F=3.72 d.f.=2.78 P=0.0286 STER.DAF 8.5 17 26.25 I a?-l I4.5 17.75 I 15121 F=1.37 d.f.=2,78 P=0.26 C'VS.DAF 7.5 121.5 123.75 02 IR (l 04 0 3 19 F=4.48 d.1.=2,78 P=0.0141 RISP.D.-1F 4.75 I 1 20.75 01 1 9 U 1 3.75 ()11 1 10 F=3.5 d.1'.=2.78 P=0.035 PF3OU.DAF 0 1 S 2 0 0 1 O 0 I O 0 I F=2.04 d.1'.=2,78 P=0.137 VENT.DAF 4 i 10' ?0 0 0 9 O 0 2.75 0O 10 F-3.16 d.1'.=2,78 P=0.048 CNS.DAF 1 1 124 . 5 26 1 7 25 0 - l i 8.5 I 7 25 F=4.78 d.f.=2,78 P=0.01 I
COAG.DAF 1?5 1?8 28 1 424 I 5 8 I 1-15 F=6.32 d.f.=2,78 P=0.00287 I\R.DAF 1 4 ?65 ; 38 1 j 4 ?' f) 3 6.5 0 5 122 1=751 d.f. 2.78 P=0.00104 ACRF.D:\F 11120 27.75 1 15 20 0.5 14.75 0 14 20 F=8.6 d.f.=?,78 P<0.00I
ANYRE'N.D,AF I I ?O 27.75 0 3 20 70 4.75 014120 F=8.38 d.f.=2,78 P<o.(lOI
RENSUP.D\F 1 I 21.5 ?8 1 3 18 1 3 8 I 4 18 F=3.5I d.f.=2,78 P=0.0346 ACHEP.DAF 14.25 28 28 1 622 I.25 15 7.75 I 6 28 F=3.65 d.f.=2,78 P=0.0304 A.NYHEP.DAF 14.35 28 1 28 I 5 i 22 1.35 ' 5~ 7.75 I 6 28 F=3.64 d.f.=2,78 P=0.0309 TABLE 3.12 Difference in response association of leucyl/cystinyl aminopeptidase (LNPEP) rs2771 I between cases (vasopressin-treated group) (Treat) arld controls (vasopressin witreated matched control) (Cont) of Caucasian ICU subjects diagnosed with septic shock. For all variables besides 28-day survival, data is presented as medians. For 28-day survival, data is presented as lc(N survived / N
total). N, number of subjects.
AA AA AG AG GG GG
(:N=?I) T (N=10) (N=28) (N=45) (N=21) (N=26) Treat Cont I)ELTA Treat Cont DELTA Treat Cont DEL1'A
SURVIVAL -l3('/r ( 9) 60 ic ( 6) -187c 361; (10) 36(,7, (16) 0% i3(7,,( 7) 191i ( 5) 14 lc DAYS ALIVE 12 2 8 -16 17.5 8 9.5 8 5.5 2.5 ALLDAF 6 9.5 -3.5 9 2 7 2 5 -3 PRESS.DAF I 23 -22 4 4 0 0 1.5 -1.5 PRESS3.DAF I 23 -22 4 4 0 O 1.5 -1.5 PRESS5.DAF 2 15 -23 7.5 4 ~S 0 1.5 -l.5 PRESSI5.DAF 7 26.5 -t9S 11.5 6 5.5 1 15 INO.DAF 12 28 -16 14 6 8 5 3.5 1.5 SIRS2.DAF 0 I -1 I 0 1 0 0 0 SIRS3.DAF 4 3.5 0.5 7 2 5 2 1 l SIRS4.D.AF 10 10.5 -0.5 15 7 8 5 4 1 STER.DAF 2 17 -15 lo 4 6 3 4.5 -1.5 CVS.DAF I 21.5 -205 0.5 2 -1.5 0 O O
RESP.DAF I l1 -111 0 I -1 O 1 -1 PF300.DAF 0 1.5 -1.5 O 0 O 0 0 0 VENT.D.AF 0 10 -lo 0 O 0 0 0 0 CNS.DAF Il 24.5 -13.5 13 7 6 7 4 3 COAG.DAF 8 28 -211 13.5 4 9.5 6 5 1 INR.DAF II 1-6.5 -15.5 11.5 -! 7.5 5 3 2 ACRF.DAF 6 20 -14 2 5 -3 4 0.5 3.5 AhYREN.DAF 6 20 -14 2 3 -1 d 0 4 RGNSCP.DAF 3 ~ 1.5 -18.5 7.5 3 4.5 5 3 2 ACHEP.DAF 7 1-8 -21 14 6 8 4 5 -1 AtiYHEP.DAF 7 28 -21 1-t 5 y 4 5 -1 1.1.3 Adverse Response to Vasopressin Treatment of subjects who have the GG
Genotype of LNPEP rs10051637 It was unknown whether SNPs within the LNPEP -ene and those regions immediately upstrealn and downstream are associated with the response to vasopressin. It was found that LNPEP
rs10051637 can be used to predict response to vasopressin in subjects with septic shock using 28-day survi%al and measures of organ dysfunction as outcome variables. Of 103 vasopressin-treated and 103 matched-control subjects with septic shock, 72 and 81 were respectively genotyped for LNPEP rs 10051637. Baseline characteristics for subjects with genotypes are shown in Table 3.13 It) and Table 3.14. LNPEP rs10051637 is in linkage disequilibrium with, for example LNPEP
rs18059 and LNPEP G9419812A, which were also genotyped in this cohort.

TABLE 3.13 Baseline characteristics of a group of vasopressin-treated Caucasian septic shock subjects leucyl/cystinyl aminopeptidase (LNPEP) rs 1005 1637 genotype. For age and APACHE II score, data is Qiven as 25 i percentile I median J 75" percentile. For all other variables, data is Qiven as %
(N /N total). N, nunnber of subjects.
VASOPRFSSIN AA AG GG Conihined Test (N=19) (N=29) (N=24) (N=72) Statistic AGE 38 60 68 54 65 72 -13.75 55 I 68.75 47 160 68.5 F=0.89 d.f.=2,69 P=0.417 GENDER 79'/( (15/19) 7917 (23/29) 711I( 17/24) 76`7~ (55/72) X^2=0.62 d.f.=2 P=0.735 AP?.CHE 11 25.5 2K 35 23 30 37. 25 32.5 40.25 25 I 30 37 F=0.49 d.f.=2.69 P=0.616 SI;RGICAL 261%- ( 5/19) -18'?'<(14/29) 387 ( 9/24) W,, (28/72) X^2=3.36 d.f.=?
P=0.308 TABLE 3.14 ?O Baseline characteristics of a matched-control group of Callcasian septic-shock subjects by Ieucyl/cystinyl aminopeptidase (LNPEP) L-sl0051637 genotype. For age and APACHE II score.

data is given as 25th percentile I median 175t'' percentile. For all other variables, data is given as ~I~
(N /N total). N, number of subjects.
CONTROL AA AG GG Combined Test (N=25) (N=46) (N=10) (N=81) Statistic AGE 49167174 43.25152 66.5 39.25 45.5 58.5 44 56 71.5 F=3.91 0.1:=2,78 0=0.024 GENDER 60(Ir ( 15/25) 67% (31/46) I'10(I^ ( 8/10) 67`7c (54/81) X^2=1.3l d.f.=2 P=0.519 APACHE 11 27 29 38 26 30 34 23.25 26 32.5 24 29 34 F=1.04 d.f: 2.78 0=0:359 17SURGICAL 401l(10/25) T351,f(16/46) ?0% ( 2/10) 357~ (28/81) X^2=1.27 d.f.=2 P=0.531 Tables 3.15, 3.16 and Tables 3.17 contain 28-day survival and organ dysfunction data for septic-shock subjects genotyped for LNI'EP rs10051637. Vasopressin-treated subjects with the LNPEP rs 10051637 GG genotype had a dramatically decreased survival (46 le) compared to controls (60 '/() as demonstrated by the negative values in the LNPEP
rs10051637 GG DELTA
column in Table 3.17. Vasopressin-treatecl subjects with the LNPEP rs10051637 GG genotype were also observed to have more organ dysfunction as demonstrated by fewer DAF
of organ l0 dysfutiction. In contrast, vasopressin-treated subjects with the LNPEP rs 10051637 AG and AA
~enotypes had increased survival (26 c/r) compared to controls (20 rr).

TABLE 3.15 A response association of leucyl/cystinyl aminopeptidase (LNPEP) rs10051637 and use of vasopressin in a group of vasopressin-treated Caucasian ICU septic-shock subjects. For all variables besides 28-day survival, data is given as 25'' percentile I tnedian I 75`t' percentile. For 28-dav survival, data is iziven as ~l( (N survive(i / N total). N. number of subjects.
VASOPRESSIN AA :1G GG Combined Test (N=19) (N=29) (N=?-l) (N=7?) Statistic 3g(>( SURVIVAL 26`'~ ( 5719) (11/29) 4617(1 I/34) 38() (27/73) Chis<uare=l.73 d.f.=?
P=0.42-2 DAYS ALIVE 2 6 25.5 3'20 28 7115.5 28 3' 12S 28 F=1.0H d.f.=2.69 P=0.345 ALLDAF I? 6 2 10 2d 1.75 6.5 13 I 5.5 17 F=2.68 d.f.=2,69 P=0.0754 PRESS.DAF 0 0 1 7 . 5 0 1 5 17 O ' 6.5 19.5 0 11 18 F=0.43 d.f.=2,69 0=0.651 PRESS2.DAF () 0 19 Q 5 17 016.5 31 I I 18 F=0.44 d.i: 2,69 P=0.646 PRESS5.DAF 0 0 19.5 018118 018121.25 011.5 20 F=0.48 l.f.=2.69 P=0.619 PRES515.DAF O' 1 20.5 O 1 12 I 21 0.75 12 73.25 O I 5 22.25 F=1.02 d.f.=2,69 P=0.364 INO.DAF 1.5 3 17.5 2 I 15 20 6.5 112 28 3; 13 26 F=2.31 d.f. ?,fi9 P=0.I07 SIRS2.DAF 01011 0 1? 0 0 3.'5 0 0 12 F=0.51 d.f.=2.69 P=0.605 SIRS i.DAF 011 ( i 1 ! 7 1 1 I ! 3.5 f1.5 0.75 3.5 1 1 F=1.54 d.1'.=2,69 P=0.221 SIRS-i.DAF 1.5 14 I 18 2 16 24 -15 10.5 20 ? I 10 22.25 F=1 d.f.=169 P=0.372 STER.DAF I 1216 1 9 16 O 2.5 :0.25 113.5 16 F=0.8 d.f.=2.69 P=0.455 CVS.DAF O ' 0 9 0 1 I 13 0 11.5 16.25 0 0 14 F=0.58 d.f.=2,69 P=0.56 RESP.DAF 0 ' 0 1 f) 1 0 ' 5 0 I l I 7.5 O 0 5.25 F=0.93 d.f, 2.69 P=0.401 PF:OO.DAF 0 O O O O 1 0 0 2 0O I F=5.18 l.f.=2,69 P=0.0079 VEN'r.DAF 0` 0 0 q 1 0 5 0 0 1 7.5 q 0 5.25 F=0.36 d.f.=2.69 P=0.697 CNS.DAF 2 5 19 ? 13 ?a 6~ 11.5 27.25 3 11 24.25 F=1.35 l.f.=2,69 P=0.265 COAG.DAF I 5116.5 I 12 26 1.75'9 25.75 I 7.5 26 F=0.41 l.f. ?,69P=0.666 I:VR.DAF 1' 5 I23.5 '_ 13127 3.5 13 27 1.75 R 27 F=0.81 d.1'.=2,69 P=0.4-48 ACRF.DAF D 3 I 12 0 2 16 1.75 6'-7 04.5 19 F=I.'-1 d.f.=2.69 P=0.303 ANYREN.DAF 011112 02 13 1.75 624.75 04.5 16.5 F=1.16 d.1:=2,69 P=0.318 RENSL;P.DAF 214116.5 2 620 0.75 4.5 28 I 4.5 23.5 F=0.I d.f.=2,69 P=0.908 ACHEP.DAF ? 3? 1 3 15 27. I 8.5 124.25 2 9 25.5 0=1.19 d.1:=2,69 P=0.309 ANYHEP.DAF 2 3? 1 z 15 27 I 8.5 34.25 3 9 25.5 F=1.25 d.f.=2,69 P=0.293 TABLE 3.16 A response association of teucyl/cystinyl aminopeptidase (LNPEP) rs10051637 and use of vasopressin in a matched controt group of Caucasian ICU septic shock subjects who were not treated with vasopressin. For all variables besides 28-day survival, data is given as 25`h percentile median 175'' percentile. For 28-day survival, data is given as k (N survived / N total). N, number of subjects. _ CONTROL AA G GG Combined Test (N=?5) A (N=46) (N=10) (N=8I) Statistic 1017 SL;RV[VAL 5/25) 3511, (16/46) 60`7( ( 6/10) (?7181) Chis uare=5.24d.f.=2 P=0.0727 DAYS ALIVE 3 5 I S 2 8 28 1d.25 '.8 28 3 8 28 F=5.18 d.f.=2.78 P=6.0077 1L1.DAF 115 8 1 2.5 17.?5 7 9.5 ~ 19.?5 1 5115 F=2.04 d.f.=2,78 P=0.137 PRESS.DAF O 1 2 6 03.5 21.25 10.75 :.3 26.75 O ' 4 22 F=4.27 d.f.=2,78 P=0.0174 PRESS-I.DAF O ~ 2 6 Q 7.5 21.25 11.5 '' ;26.75 0 1 22 F==1.32 d.t.=2,78 P=0.0166 PRESS5.DAF 0 3 ! 7 0. 25 ~ 1 22 . 5 1 3 I 25 27 0 4?3 F=4.52 d.f.=3,78 P=0.0138 PRESSI5.DAF 0 117 I 5.5 125 14.25 36.5' 28 1 626 F=4.1) d.1'.=2,78 P=0.0099 INO.DAF 1 3 8 2 6'24.5 14.25 128 28 ? 6'28 F=3.9d.t: 2,78P=0.0243 SIRS2.DAF O ' O 1 0 1011.75 O I 4 O 0' I F=1.57 d.t:=2,78 P=0.214 SIRS 3.DAF 1 12 0' 9 213.5 16.5 ? 7 F=0.94 d.f.=2,78 P=0.395 SIRS4.DAF ? 4 7 1.35 16.5''2 9.25 10.5 23 2 17 22 F=3.59d.f.=2,78 P=0.0322 STER.DAF 1 15 1 8 I 4 21.75 8.5 117120.25 I 121 1 F=1.37 d.f: 3.78 P=0.261 CVS.DAF O t) ~ 4 O' 2 18 7.5 121.5 23.75 013119 F=4.27 tl.f.=2.78 P=0.0174 RESP.DAF O 1 4 11 ~ 1 I 9 1.75 1 1 ' 2 0 . 7 5 0 I 10 0=3.46 d.i.=2,78 P=0.0 3 PF 30Q.DAF 0 ' 0 1 0 0 10.75 O 1 . 5 2 0 ' p I F=2.26 d.C=178 P=O.I I I
VENT.DAF 6 i 3 O 1 O 9 4 10 ?O 0 0 10 F=3.1 d.f.=1,78 P=0.0506 C'NS.DAF 0 37 1~ 7 25 t 1 24.5 26 I 725 17=4.96 d.l.=2.78 P=0.00942 COAG.D.AF 1 15 8 1! 4 124 14.25 2 3 28 I ~ 6 125 F=6.03 d.f: ?,78 P=0.00367 INR.D.,\F 0 3 7 1 21.75 I 1 26.5 28 0 5" F=7.54 d.L=2-78 P=0.00101 A('RF.D.AF -l 1 520 I I 2O 27.75 0 4 20 F=9.11 d.f.=2.78 P<0.001 :A'NYREN.DAF 0 0 1 O 3.5 119.5 11 20 ~:7.75 0~ a 120 F=8.82 d.f.=2.78 P<0.001 RENSL P.DAF 1 1 ? 8 1 l3.5 1 7 . 5 1 I 2 1 . 5 1 28 1 1 a I8 F=5.62 d.f.=2,78 P=0.0313 ,~CHEP.DAF I 5 ~ 8 I 5.5 1 2 2 1415 ?8 28 I 6 38 F=3.54 d.f.=178 P=0.03,9 AYYHEP.DAF 1' 5 18 I IS 22 14.35 'N 28 I 628 F=3.55 d.f.=2.78 P=0.0334 TABLE 3.17 I O Difference in response association of leucyl/cystinyl aminopeptidase (LNPEP) rs 10051637 and use of vasopressin between cases (vasopressin-treated group) and controls (vasopressin untreated matched contl-ol) of Caucasian ICU subjects diat;nosed with septic shock.
rs 10051637 GG rs 10051637 AG rs 100516 37 A A
('N=24) (N=10) ('v'=?9) (N=46) (N=19) (N=25) Treat Cont DELTA Treat Cont DELTA Treat Cont ll};LTA
SCRVIV.AL 4617c 111) 6076 ( 6) -1d% 3817,I I 1 t ?5`1c (16) 1 'Yc 26'7r ( 5) 2011 ( 5) 6`7c DAYS ALIV[: 15.5 28 -12.5 20 8 12 6 5 ;ALI.DAF 6.5 9.5 -3 10 2.5 7.5 ? 5 -3 PRESS.DAF 6.5 23 -16.5 5 3.5 1.5 0 ' -2 PRESS?.DAF 6.5 23 -16.5 5 3.5 1.5 0 2 -2 PRESS5.DAF 8 25 -17 8 -F 4 0 2 -2 PRESSIS.DAF l~ '6S -14.5 12 5.5 6.5 I 3 -2 INO.DAF 12 28 -16 15 6 9 4 3 1 SIRS2.DAF 0 I -1 I 0 1 0 SIRS3.DAF ?.5 3.5 0 7 2 5 I I 0 SIRS4.DAF 10.5 10.5 0 16 6.5 9.5 4 4 0 STER.DAF 2_5 17 -14.4i 9 4 5 2 5 -3 CVS.DAF I.5 21.5 -20 1 2 -1 0 0 0 RESP.DAF 1 II -10 0 1 1 0 1 -1 PF300.DAF 0 1.5 -1.5 0 0 Q 0 0 (1 VENT.DAF 0 10 -1ll 0 0 0 0 0 0 CNS.DAF 11.5 24.5 -13 13 7 6 5 3 2 COAG.DAF 9 28 -19 12 4 8 5 5 0 INR.DAF 13 26.5 -13.5 13 4 9 5 3 2 ACRF.DAF 6 20 -14 2 5 -3 3 O 3 ANYREti~.DAF 6 'O -14 2 3.5 -1.5 3 0 3 RF,NSCP.DAF 4.5 21.5 -17 6 3.5 2.5 4 3 1 1CHEP.DAF 8.5 38 -19.5 15 5.5 9.5 3 5 -2 1NYHEP.DAF 8.5 28 -19.5 15 4.5 10.5 -2 1.2 Arginine Vasopressin (AVP) 1.2.1 Improved Response to Vasopressin Treatment of subjects who have the AA
or AC
Genotype of AVP rs1410713 It is unknown whether SNPs within the A'VP gene and those regions immediately upstream and downstream are associated with the response to vasopressin. AVP rs1410713 can be used to pl-edict re5ponse to vasopressin in subjects with septic shock using 28-day survival and measul-es of organ dysfunction as outcome variables. Of 103 vasopressin-tl-eated and 103 matched-contl-ol subjects with septic shock, 72 and 81 were respectively genotyped for AVP
rs1410713. Baseline IO characteristics for subjects with genotypes are shown in Table 3.18 and Table 3.19.
TABLE 3.18 Baseline characteristics of a group of vasopressin-treated Caucasian septic-shock subjects by arainine vasopressin (AVP) rs 14107 (3 -enotype. For age and APACHE II score, data is given as 25')' percentile I median 175`I' percentile. For all other variables, data is aiven as 9e (N /N total). N
= number ot subjects.
VASOPRESSIN AA AC CC Conibined Tcst (N=8) (\=3Q) (N=34) (N=72) Statistic AGE 50' 66.5 69 39.25 157.5 67.:5 54 f 3.5 71 47 60 68 .5, F=1.23 d.f: 2.69 0=0.300 GENDER 75'=(, ( 6/8) 63"(19/30) 88') (30/.34) 761% (55/72) X^2=5.49 d.f: ?
P=0.0643 APvCHE II 26 28.5 34.75 20 126 30.75 28 32 -10,75 25 130137 0=5.-1 d.L=2.69 0=0.00664 `.4 SI:RGICAL 3817, ( 3/8) 43(?r (1 3 V30) -11'/r (14/34) 42"7o (30172) X^2=0.09 d.f.=? P=0.954 TABLE 3.19 Baseline characteristics of a group of Caucasian septic-shock control subjects by arginine ?[) vasopl-essin (AVP) rs1=I10713 genotype. For age and APACHE II score, data is given as 25`)' percentile I median 175`' percentile. For all other variables, data is given as '/c (N /N total). N.
number of subjects.
C'ONTRQL AA AC C':' Combined Te.~t I (!N=6) (N=35) (N=40) (N=81) Statistic AGE 46 153 59.25 42152168 45.75 61 71.25 44 56 71.5 F=0.72 d.1'.=2,78 P=0.491 GENDER 67:; (4/6) 7 1 % (25/35) 617, (25/40) 67',(54/81 ) X^2=0.67 d.f.=2 P=0.715 aPACHE II 29.5 31.5 32.75 22 27 34 26.75 30.5 34.75 24 29 34 0=1.11 d.f.=2,78 P=0.334 'r( SURGICAL 177<, ( I/6) 4617 (16/35 ) 25%r ( 10/40) 33? (27/81) X^2=4.41 d.f.=2 P=Q.1 I

Tables 3.20, 3.21 and 3.22 contain 28-daiy survival and organ dysfunction data for septic-shock subjects genotyped for AVP rs1410713. Vasopressin -treated subjects with the AVP
rs1410713 AA genotype had a dramatically increased survival (38 k) compared to contl-ols (0 %) as demonstrated by the positive values in the AVP rs1410713 AA DELTA colunin in Table 3.22.
Furthermore, vasopressin-treated subjects with the AVP rs 1410713 AA genotype wel-e observed to have less organ dysfunction as demonstrated by more DAF of organ dysfunction.
Vasopressir.i-treated subjects with AVP rs1410713 AC genotype were also observed to have increased 28-clay survival (471"/r) compared with that of control subjects (37~I~).

I O
TABLE 3.20 A response association of arginine vasopressin (AVP) rs1410713 in a group of Caucasian ICU
septic shock subjects who were treated with vasopressin. For all variables besides 28-day survival, data is given as 25t1' percentile I median 175i1' percentile. For 28-day survival, data is given as 17C
(N survived / N total). N. number of subjects.
VASOPRESSIN AA AC CC Cotnhined Test (N=ti) (N=30) (N=31) (N=72) Statistic SIiRVIVAL 381/, ( 3/8) 47('f( 14/50) 3"7< (I 1/34) 391Ic (28/72) C'hiscuare=1.38 d.f.=2 P=0.501 DAYS :\LIVE 5.75 11 I 28 9.25 22.5 28 2 9 28 11 14 28 F=1.78 d.t.=2,69 P=0.176 :\LI.D,AF 0.75 ' 5.5 20 2 18.5 18.5 I 3.5 16 1 6 17.25 F=0.18 d.f.=2,69 0=0.834 PRESS.DAF O 2 11.25 0 13.5 18.75 0 0 17 0 2' 18.1- 5 F=1.-l9d.f.=2,69 P=0.232 PRESS2.DAF 0 2 1 2 0 14.5 20?5 0 0 17 0? 18.5 0=1.82 d.f.=2.69 P=0.170 PRESS5.D.aF 0.75 ? 12.75 0 15.5 2? O 0 18.5 02.5 ?0.25 1=1,99d.f.=2,69P=Q.144 PRESS I5.DAF I I 5 1 17.?5 2.25 118.5 1 24.75 0 ~ 1 ~ 21.75 010,5 23.25 F=2.5 d.f.=2.69 P=O.O892 I'.VO.D:1F 4.25 ~ 10 ?8 3 19.5 I28 1.25 9 121.75 ? ~ 12 I26 F=1.57 d.f.=2.69 P=0? 15 SIRS?.DAF 0 j t) I.25 0 1 1 I 3 O 1 0 11 01012.25 F=0.74 d.f.=2,69 P=0.48 SIRS3.D.AF 2.25 4.5 116.5 2 5.5 1 1 0.25 2 7.75 0.75 4 111.25 F=0.8 d.1:=2,69 P=0. 455 SIRS4.DAF 4 922.75 6.5 16 23.75 2 5.5 119.75 2 I 10 23 F=1.04 d.f.=2.69 0=0.359 STER.D.,\F 25.5 28 3 1 9.5 122 0 2~ 15 I 1 16.75 F=2.14 d.f.=2,69 P=O.126 CVS.DAF 0~ 1.5 11.25 0 5.5 14 0O 8 00.5 114 F=1.54d.f.=2,69P=O.2?1 RESP.DAP 0 0 4.25 0 2 i ~,.75 O O 8 0 0 6.5 F=O.SI d.f. 2.(i9 P=0.4d9 PF3OO.DAF 0 0 0.5 0 0 1.75 O 0 Q 0(l 1 F=1.75 d.f.=2 69 P=-0.181 VENT.D,\F 0 03.75 0 5.75 O O i H 0 0 6.5 F=0.31 d.f.=2.69 P=O.7? I
CNS.DAF 5 9.5 28 3.75 19126.25 2 723 2' 11 24.25 F= 1.59 d.f.=2,69 P=0.21 I
COAG.D,-\F 4.2516 21.25 1113.5120 117 ?6 I R?6 F=0.14 d.f.=3.69 P=0.867 INR.DAF 3.75 ~ 7 1 3 5 6.25 1 19.5 1 27.75 0.25 ~ 6.5 ~23.75 ?~ 9 12 F=2.88 d.f.=2.69 0=0.063 \CRF.D.aF O 115 ~ 2.75 O 18.5 ~12.5 1 J5 I23 O ~ 5119.25 F=1.1 d.f: 2.69 P=0.254 ANYREN.D:aF 0 I 1._5 12.75 018.5 117.5 I 15 I 19.75 O ~ 5 1 18?5 f=1.34 d.E=2,69 P=0?69 RENSI;P.D.,\F I ? 10.O 3 1 I 26 I 2 26.75 I 15.5 25.5 F=1.39 d.f.=2,69 P=0.256 .aCHEP.DAF 4.25 10 23.25 3.25 115.5 28 11,3 124.75 3 9.5 27.25 F=I.98 d.f.=2.69 P=0.1-16 ANYHEP_D,\F 4.25' 10 23.25 :.25 I5~28 1: 24.75 2 9.J 27.2 5 F=2.I4 d.f.=2,69P=O.126 TABLE 3.21 A response association of arginine vasopressin (AVP) rs1410713 in a matched control group of Caucasian ICU septic shock subjects who were not treated with vasopressin. For all variables besides 28-day survival, data is given as 25th percentile I median 175`h percentile. For 28-day survival, data is (yiven as ~lo (N survived /:N total). N. number of subjects.
CONTROL AA AC CC Combined Test (N=6) (N=35) (N=40) (N=81) Statistic 17(7r 33clr SURVIVAL 0'7- ( 0/6) (13/35) 357< (14/40) (27/81 ) Chis uare=3.28 d.f.=2 P=0.19a DAYS ALIVE 1.75 4.5 5.75 3.5 10 28 1.75 8.5 28 318 28 F=2.06 d.f.=2.78 P=0.134 ALLDAF I 1 I 13.25 2 ~ 7 116.5 1 14.5 18.5 I 5 15 F=2.06 d.f.=2,78 P=0.135 PRESS.DAF I) 11.5 I-1.5 014 122 0 14.5 124.25 0 1d 22 F=0.95 d.f.=2,78 P=0.393 PRESS'_.D.aF 0 1.5 1.5 014 22 04.5 24.25 0 3 22 F=0.95 d.f.=2,78 P=0392 PRESS5.DAF 0.5 2.5 4.5 0 1 24 0 6 252 5 O 4 23 F=0.75 d.f.=2,78 P=0.475 PRF;SS 15.DAF 0.75 I 3.5 14.75 I 6 2b.5 0 7 26 1 6 26 F=1.13 d.f: 2,78 P=0.328 INO.DAF 1.25 3.5 5.75 3.5 8 28 1 5.5 25.75 216 128 F=1.1 d.f.=2,78 P=0.337 SIRS2.DAF 1 0 ' 0 0 0 2 0 0 I O 0 I F=1.22 d.L=2.78 P=0.301 SIRS3.D.AF 0.25 111.75 O 2 8.5 1 ~ 216.75 012 7 F=0.93 d.f.=2,78 P=0.4 S1RS4.DAF 1 2 3. 7 5 2.5 8'" I 17122.25 2 7 I 22 F=2.7 d.f.=2,78 P=0.0736 STER.DAF 1.75 4.5 5.75 I 1(,128 11.5 112.75 1 5 21 F=1.19 d.f.=2,78 P=0.31 C'VS.DAF O i 112.() o' 18.5 O 3 20 0 3 19 F=0.9 d.f.=?,78 P=0.409 RESP.DAF 0.-1 5 I1 3. 0 ~' 1 1.5 0 ~ I 10 Q l 10 F=0.65 d.f.=2,78 P=0.526 PF?ao.DAF o 10.5 I 1.75 0 o 3 0101() 0 0 ~ I F=2.99 d.f.=2,78 P=0.0559 VENT.DAF a1olo.75 011l10.5 u~ollo o;ojlo F=1.05d.f.=2,78P=0.353 CNS.DAF 0.25 I I 3 724.5 I)3.5 126 I 7 125 F=3.55 d.t.=3.78 P=0.0336 COAG.DAF 112.5 5.5 2.5 8 27.5 I 0.5 124.25 I 6 35 F=1.56 d.f.=2.78 P=0.217 INR.DAF 0 0.5 ~.25 2.5 ` 724.5 0 ~ 6123.5 1 5 22 F=2.59 d.f.=2,78 P=0.0812 ACRF.DAF O 0 3 I 1 I21.5 0 5 121.75 0 d 20 F=2.19 d.f.=2,78 P=O.I 18 A.h"YREN.DAF 00 O 1 4 121.5 0 -t.5 120.25 q' 1' 20 F=3.47 d.f.=2,78 P=0.0359 REVSOP.DAF 1 1 2.5 4.75 2 525.5 I~.5 118.25 1 4 18 F=1.42 d.t:=2.78 P=0.247 ACHEP.DAF 1.5 1.5 5.5 2.5 1626 1 7.5 128 I 6 28 F=12 d.f.=2.78 P=0.307 ANYHEP.DAF 1.5 3.5 5.5 2 626 1 L.5 28 1 i 6 ?8 F=0.99 d.f.=2,78 P=0.377 i TABLE 3.22 Differenec in response association of arginine vasopressin (AVP) rs 1410713 between cases (vasopressin-treated group) (Treat) and controls (vasopressin untreated matched control) (Cont) of Cnucasian ICU subjects diagnosed with septic shock. For all variables besides 28-day survival, data is presented as medians. For 28-day survival, data is presented as %(N
survived / N total). N, numbet- of subjects.
AVP rs 1410713 CC AVPrs141O713AC AVPrs1410713AA
(N=34) (N=40) (N=ZO) (V=35) (N=8) (N=(,) '1'reat- Treat- Treat-Trcat Cont Cont Trcat Cont Cont Trcat Cont Cont SLRVIV:AL 331", ( I I) 35!7, (14) -39c 471i ( 1=1) 37",(13) 10(%c 38'!c ( 3) 01l= (()) 38%, DAYS
ALIVE 9 85 0.5 22.5 10 t2.5 II 4.5 6.5 ALI.DAF 3.5 4.5 -1 8.5 7 1.5 5.5 I 4.5 PRESS.DAF 0 4.5 -4.5 13.5 4 9.5 2 1.5 0.5 PRESS2.DA
F 0 4.5 -4.5 Id.S 4 10.5 2 1.5 0.5 PRESS5.DA
F 0 (i -6 15.5 4 11.5 2 2.5 -0.5 PRESSI5.D
\F 1 7 -6 18.5 6 12.5 5 3.5 1.5 I'VO.DAF 9 6.5 2.5 19.5 8 11.5 10 3.5 6.5 SIRS2.DAF 0 0 0 I 0 I 0 (1 0 SIRS3.DAF 2 2 0 5.5 2 3.5 4.5 1 3.5 SIRS4.DAF 5.5 7 -1.5 16 8 8 9 2 7 STER.DAF 2 4.5 -2.5 9.5 6 3.5 5.5 4.5 l CVS.DAF 0 3 -3 5.5 3 2.5 1.5 1 0.5 RESP.DAF 0 1 -1 2 2 0 0 1 -1 PI30O.DAF 0 U 0 0 0 0 0 0.5 -0.5 VENT.DAF 0 0 U 0 I -1 0 0 0 CNS.DAF 7 8.5 -1.5 19 7 12 9.5 I 8.5 COAG.DAF 6.5 0.5 13.5 8 5.5 6 2.5 3.5 INR.DAF 0.5 6 0.5 19.5 7 12.5 7 0.5 6.5 ACRF.DAF 5 5 0 8.5 4 4.5 1.5 0 l.5 AtiYRE'.V.D
\ F 5 4.5 0.5 8.5 4 3.5 1.5 0 1.5 RENSUP.D
AF 2 3.5 -1.5 II 5 6 2 2.5 -0.5 ACHEP.DA
3 7.5 -4.5 15.5 6 9.5 10 3.5 6.5 ANYHEP.I7 AF 3 7.5 -4.5 IS 6 9 10 3.5 6.5 1.2.2 Adverse Response to Vasopressin Treatment of subjects who have the CT
Genotype of AVP rs857240 and Improved Response to Vasopressin Treatment of subjects who have the CC Genotype of AVP rs857240 It was unknown whether SNPs within the AVP gene and those regions immediately upstream ~I_nd downstream are associated with the respome to vasopressin. It was found that AVP rs857240 can he used to predict response to vasopl-essin in subjects with septic shock using 28-day survival and measures of organ dysfunction as respective primary and secondary outcome variables. Of 103 vasopressin-treated and 103 matched-control subjects with septic shock, 73 and 83 were respectively genotyped for LNPEP rs857240. Baseline characteristics for subjects with genotypes 1O are shown in Table 3.23 and Table 3.24 TABLE 3.23 Baseline characteristics of a group of vasopressin-treated Caucasian septic shock subjects by arginine vasopressin (AVP) rs857240 genotype. For age and APACHE II score, data is given as 25'1' pelrentile I median 1 75'I' percentile. For all other variables, data is given as ~/c (N /N total). N, number of subjects.
VASOPRESSIN CC C'r Comnined Test (N_56) ( N=17 ) ( N=73 ) Statistic AGE 46.75 61.5 68.75 39 56 68 47 60 68.5 F=0.33 d.f.=1.71 P=0.569 GENDER 73`~ (41/56) 88'%, (1 5/17) 77% (56171) X^2=I.65 d.f.=I P=0.199 APACHE II 25' 30.5 36.25 24 28 39 25 30 37 F=0.09 d.f.=I,71 P=0.761 4 SI:RGICAL -tl`>i (23/56) 35"'c ( (J17) 40!70 (29/73) XAI=O_18 d.P.=1 P=0.67 TABLE 3.24 Baseline charactel-istics of Caucasian septic shock control subjects by arginine vasopressin (AV:P) ?t) rs857240 genotype. For age and APACHE II score, data is given as 25"' percentile I median 17; i el-centile. For all other variables, data is aiven as ~~ (N /N total). N, number of subjects.
CONTROL CC CT Combined Tcst ( N-69) ( N=1 4) (N=83) Statistic AGE 44 55 68 36.75 SS 71 44 156171.5 F=0.12 l.f: 1.9 1 P=0.7z 1 GENDER 65?c (45/69) 79% (I 1/ 14) 67`lc, (56/83) X^2=0.95 d.f.=1 P=0.331 APACHE II 25 29 34 27 32 34 24 29 34 F=0.59 d.l =1,81 P=0.446 `'rSURGIC.AL 35'7,;(24/69) 29`? (4U14) 34%:(28183) X^2=0.2 d.f.=1 P=0.554 Tables 3.25, 3.26 and 3.27 contain 28-day survival and organ dysfunction data for septic-shock subjects genotyped for AVP rs857240. Vasopressin -treated subjects with the AVP rs857240 CT
genotype had dramatically decreased survival if vasopressin-treated (29 ~Ie) compared to controls -5 (43 %) as demonstrated by the negative values in the AVP rs857240 CT DELTA
column in Table 3.27. Fiu-thermore, vasopressin-treated subjects with the AVP rs857240 CT
genotype were observed to have more organ dysfunction than AVP rs857240 CT control subjects as demonstrated by more DAF of organ dysfunction. In contrast, vasopressin-treated subjects with the AVP
rs857240 CC genotype had increased survival (41 ~l() conipared to controls (30 ~IO as lO demonstrated by the positive values in the AVP rs857240 CC DELTA column in Table 3.27.
Furthermore, vasopressin-treated subjects AVP rs857240 CC subjects were observed to have less organ dysfunction than AVP rs857240 CC control subjects.

TABLE 3.25 15 A response association of arginine vasopre~sin (AVP) rs857240 in a group of Caucasian ICU
septic shock subjects who were treated with vasopressin. For all variables besides 28-day surv ival, data is given as 25`f' percentile I median 175 i percentile. For 28-day survival, data is given as (N survived / N total). N. number of sub'ects. Note: TT genotype fre uenc = 0.
VASOPRESSIN CC CT Cambined Tcst (N=56) (N= 17) ('.V=73) Statistic SURVIV,AL 4I1'1 (23/56) 219~,( 511 7) 3S5, (28/73) Chiscuare=0.7 d.1.=1 P=0.387 D:~YS AL1VE 5.75 ~ 19.5 28 ' - ' S 28 3 13 28 F=2.96 d.f.=1,71 P=0.0899 AI.I.DAF 2 6 17 1~39 I6 17 F=1.?6 d.f.=1,71 P=0.265 PRESS.D:\F 0 7.5 1 9 O O I 5 0 1 19 F=2.66 d.F.=1,71 P=0.108 PRESS2.DAF 0 8 ~ 20.25 0 0 5 0 1 2l) F=2.1 d.E.=1.71 P=0.151 PRESS5.DAF 0 10.5 21.25 O ~0 7 012121 F=2.54 d.f.=1,71 P=0.1 16 PRESSI5.DAF 0 1 14 2=1 0 1 I I I O ~ 6 23 F=3.0I d.f.=1,71 P=0.087 LN O.D.aF 2 ~13.5~28 I14 1" 'J 12126 F=2.51d.t.=1.71P=0.118 SIRS_'.DAF 01012.25 0 ~ o ~ l 010 12 F=0.t8 d_f. L71 P=0.671 SIRS3.DAF I 1 4 1 1 1 . 5 0 12 7 I 14 j ll F=1.56d.f.=1,71 P=0.216 SIRS4.DAF 3 IS 2225 2 320 2~ 10'" F=1.52d.f.=1,71 P=0.221 STER.DAF 1 S ? 1 0 3 11 14 ' 19 F=0.58 d.1'.=1,71 P=0.443 C'VS.DAF 0 ~ ? . 5 114'5 0 0 3 0 0 14 F=1.97d.f.=1,71 P=O.165 RESP.DAF O O 8 01012 0 0 H F=0.19d.f.=1,71 P=0.661 PF200.DAF 01011.25 00 0 0~ 0 1 17=1.43 d.1.=1,71 P=0.235 VEVT.D:AF 0 U' 8 0 0~? 0 0 8 F=0 d.1:=1,71 P=0.946 CNS.D,1F ; f 1 3 25 2 5 ' 2 1 2 1 I 24 F=2.4 d.f.=1.71 P=0.1?6 COAG.D.W 1 . 7 5 9.5 26 I ~ 3 18 f 826 F=1.56 d.f.=1.71 P=O.? 16 INR.DAF 21 1 4 27 1 I d ?0 ? S 27 F=1.95 d.f.=1,71 P=0.167 ACRF.DAF O j 6 ~ 19.25 O i; ~ 5 19 F=0.62 d.f.=1.71 P=0.435 ANYRE.N.D,aF 1 9 0 ~ ~ 5 0 5~ 18 F=0.98 d.f.=1.71 P=0.325 RI?NSUP.DAF 1.75 ~ 7.5 ~ 27.25 1 1 2 1 5 1 5 J 2 F=2.7-1 d.f: 1.71 P=0.102 ,4CHEP.D:aF 2 11 1.5 127.25 2 13 116 2 19 125 F=1.41 d.1.=1,71 P=0'39 ANYHEP.DAF 1 2 ~11.5~27.25 113115 2 19125 ~ F=1.7d.f.=1,71P=0.197 TABLE 3.26 A response association of arginine vasopressin (AVP) r5857240 a matched control group of Caucasian ICU septic shock subjects who were not treated with vasopressin. For all variables besides 28-day survival, data is given as 25" percentile I median 75t1' percentile. For 28-day survival, data is given as ~I( (N survived / N total). N, number of subjects.
Note: TT genotype fre uencv = 0.
CONTROI_ CC CT Conibined Test (N=69) (:N=14) (N=83) Statistic SURVIVAL ~0'7r(21/69) 43% ( 6/14) 3311(27/83) Chisquare=0.82 l.1'.=1 P=0.3Fb DAYS.-YLIVE 3 17 1?8 2 I 16.5 8 3 18 28 F=0.16 d.f.=1,s1 P=0.694 ALLDAF 115111 1.25 2~1.75 I 5 14.5 F=Od.(.=l,til P=0.995 PRESS.DAF O 3 19 0 12.5 1?3.75 0} 23 F=0.49 d.f.=1,81 P=0.487 PRESS?.DAF 0' 3 19 O t2.5 23.75 0 4 1_2 F=0.45 d.f.=1.S1 P=0.503 PRESS5.DAF 04 21 0 I2.5 2 4.5 0 1 23 F=0.13 d.f.=1.81 P=0516 PRESSI5.DAF I 5 26 15' 25.75 0.5 5 26 F=0.05 l.1'.=1,81 P=0.817 INO.DAF I 5 25 2 13 38 2 6 28 F=O. i d.f.=1,81 P=0.53 SIRS2.DAF 0 0 I O 0~ 1.75 0 f) I F=0.1 I d.f.=1,81 P=0.744 S1RS7.D:'~F 01 2 6 0.?5 ? 16 O 2 6.5 F=0.41 tl.1'.=1.81 P=0.524 SIRS4.DAF 2 6 117 1.25 13 24.75 2 16 F=0.16d.f.=1,81 0=0.694 STER.DAF I 5 ~ 1 9 I ' 3 i 19.25 1 1 5 ~'-t) F=o.l9 d.f.=1.81 P=0.666 CVS.DAF 0 ~ 2 1 8 ! i ; ' 2 p ~ 2 ~ t8.5 F=0.64d.f.=1,8I P=0.425 RESP.DAF o I 1 ~ 9 0 3 1 18.25 n ~ 1 9.5 F=O.S7 l.f.=1.81 P=0_354 PF300.D.aF o o ? o 0 1 0O I F=0.06 d.f.=1.81 P=0.81 VENT_DAF O 0 9 0 3 18.25 0 0 9.5 F=1.63 d.1'.=1.81 P=0.205 CNS.DAF I 6 ? - } 1.35 1 5 25.75 1' 7' 75 F=0.47 d.f.=1,81 P=0.497 C01G.DAF I' 6 24 1.25 7.5 28 1 I6 24.5 F=0.34d.f. 1,81 P=0.563 INR.D.AF 1 f 1 4 0 ~ 15.5 24.25 04 121.5 F=0.0 ') d.L=1.81 P=0.855 -ACRF.DAF 04 15 1_15 ~ 9 2ti.75 (114120 F=I.6 d.f.=I.81 P=0.21 ANY'REN'.DAF 0 3 1 5 I ' c ) 24.7'S O 3 19 F=l. 3 9 tl.f.=I,81 P=O.'_4 2 REN'SL'P.D:\F I } 15 I.25 5.5 126.25 I a 17 F=0.52d.f.=1,H1 P=0.475 \CHEP.DAF I 6 22 1.25 1 16.5 28 I 6' 26 F=0.65 tl.f:=1.81 P=0.424 ANYHEP.DAF I 5 1" I.25I 16.5 128 1 16126 F=1.01 d.f=1.81 P=0.319 TABLE 3.27 Difference in response association of arginine vasopressin (AVP) rs857240 between cases (vasopl-essin-treated (troup) (Tl-eat) and control5 (vasopressin untreated matched control) (Cont) of Caucasian ICU subjects diagnosed with septic shock. For all variables besides 28-day survival, data is presented as medians. For 28-day survival, data is presented as r/c(N
survived / N total). N, number of subjects. Note: TT genotype fre uency = 0.
rs857240 CT rs857240 CC
(N=17) N=1-!) (v=56) (ti=69) 1'reat- Treat-Treat Cont Cont Ti-cat Cont Cont SL'RVIV,YL ?9`7.( 5/17) 43"r ( 6/14) -l4 l0 4 1`( (23/56) 30"r (21/69) 11%
DAYS ALIVE 5 165 -11.5 19.5 7 12.5 aLt.D AF 3 1 6 5 1 PRESS.DAF 0 12.5 -12.5 7.5 3 4.5 PRESS3.D.AF 0 12.5 -12.5 S 3 5 PRESS5.DAF 0 12.5 -12.5 10.5 4 6.5 PRESSI5.DAF I 15 -14 14 5 9 ItiO.DAF 4 13 .9 13.5 5 8.5 SIRS2.D.aF O 0 U 0 O 0 SIRS3.DAF 2 ' 0 4 2 2 SIRS4.DAF 3 14 -11 15 6 9 STER.DAF 3 2 1 5 5 0 CVS.DAF 0 8 -8 2.5 2 0.5 RESP.DAF 0 3 -3 0 1 -l PF300.DAF 0 0 0 0 0 0 VENT.DAF 0 3 -3 0 0 0 CNS.DAF 5 15 -10 13 6 7 COAG.DAF 3 7.5 -4.5 9.5 6 3.5 INR.DAF 4 15.5 -11.5 la 1 10 AC'RF.DAF 3 9 -6 6 1 2 ANYREN.DAF 3 9 -6 6 3 3 REN'SCP.DAF 2 5.5 -3.5 7.5 -1 3.5 ACHEP.DAF 3 16.5 -13.5 11.5 6 5.5 AN'YHEP.DAF 3 16.5 -13.5 11.5 5 6.5 1.2.3 Adverse Response to Vasopressin Treatment of subjects who have the AC
Genotype of AVP rs857242 and Improved Response to Vasopressin Treatment of subjects who have the CC Genotype of AVP rs857242 It was unknown whether SNPs within the AVP Qene and those regions immediately upstream and downstream are associated with the response to vasopressin. It was found that AVP rs857242 can be used to predict response to vasopressin in subjects with septic shock using 28-day survival and measures of organ dysfunction as I-espectivi-, primary and secondary outcome variables. Of 103 1 0 vasopressin-treated and 103 matched-control subjects with septic shock, 75 and 81 were 1-espectively genotyped for AVP rs857242. Baseline characteristics for subjects with genotypes, are shown in Table 3.28 and Table 3.29.

TABLE 3.28 Baseline characteristics of a group of vasopressin-treated Caucasian ICU
septic shock subjects by oenotype of arginine vasopressin (AVP) rs 857242. For age and APACHE II score, data is given as 25"' percentile I median 175`' percentile. For all other variables, data is given as %(N /N total).
N, number of subjects.
VASOPRESSIN AC CC Combincd Tcst (N=16 ) (N=59) ( N=75 ) Statistic AGf 39.75 601 68.75 465 ( I 69.5 47 60 68.5 0=0.09 0.0=1,73 P=0.763 GENDER 91`; (15/16) 73`7,(.1 3159) 77/, (58/75) X^2=3.1 33 d.f.=l P=0.D77 APACHE 11 24.75 28 39.5 25 30 35 25 30 37 0=0 d.f.=1.73 P=0.96 54 SF~RGICAL 38'7, ( 6/16) 41C%(24/59) -)0'7. (30/75) X^2=0.05df.=I P=0.~18 ?I) TABLE 3.29 Baseline characteristics of a vasopressin untl-eated matched control group of Caucasian ICU septic shock subjects by genotype of arginine vasopressin (AVP) rs 857242 . For age and APACHE II
score, data is given as 25'' percentile I median J 75'" percentile. For all other variables, data is viven as %(N /N total). N, number of subjects.

CONTROL AA AC CC Combined Test (N=1) (N= 13) (!V`=67) (N=8I) Statistic AGE 72 73 72 .39148 65 43.5 55 70 44 56 71.5 F=0.98 d.1:=2,78 P=0.38 GENDER 01,/( 0/I ) 69`10 ( 9/13) 697, (46/67) 6817 (55/81) X^2=_'.I4 d.f.=?
P=0.342 APACHE 11 19 I 19 19 23 30 3~ 25.5 29 34 Za 29 34 F=1.03 d.1: 2,78 P=0.361 `~ SURGICAL 0", ( 0/1) 32S"7< ( 5/13) 3417, (23/67) 3547c (28/81) X^2=0.62 d.f.=2 P=0.734 Tables 3.30, 3.31 and 3.32 contain 28-day survival and organ dysfunction data for septic-shock subjects genotyped for AVP rs857242. Vasopressin -treated subjects with the AVP rs857242 AC
genotype had a dramatically deereased survival (38 %) compared to controls (54 ~Ic) as demonstrated by the negative values in the AVP rs857242 AC DELTA column in Table 3.32.
Furthermore, vasopressin-tl-eated subjects with the AVP rs857242 AC genotype were observe(i to have more organ dysfilnetion as demonstrated by more DAF of organ dysfunction.
In contrast, vasopressin-treated subjects with the AVP rs857242 CC genotype were observed to have increased survival (41 (/(-) compared with controls (309c). As well, vasopressin-treated subjects with AVP
IO rs857242 CC genotype were observed to have increased 28-day survival (47%) compared with that of control subjects (37~/c) as demonstrated by the positive values in the AVP
rs857242 CC DELTA
column in Table 3.32. Furthermore, vasopressin-treated subjects with the AVP
rs857242 CC
(irenotype were observed to have less organ dysfunction as demonstrated by more DAF of organ dysi'unction TABLE 3.30 A response association of arginine vasopressin (AVP) rs857242 in a group of Caucasian ICU
septic shock subjects who we--e treated with vasopressin. For all variables besides 28-day survival, data is given as 25''' pe--centile I median I 75"' percentile. For 28-day survival, data is given as %
(N stu-vived / N total). N. number of subjects. Note: AA genotype fre uency =
0.
VASOPRESSIN AC CC Conibined Test (N=16) (N=59) (N=75) Statistic SLRVIVAL 385~(6116) 4 1% f24/59) 401,11"(30/75) Chiscuare=0.05d.f.=1 P=0.818 DAYS ALIVE 1.75 ~ 7,5128 5 19 J?,S i I5 I 38 F=096 d.f.=1.73 P=0.332 ALI.DAF 1 ~ 6.5 ~ 17.25 ? 16 ~ 18.5 1 161 17.5 F=0.4 d.f.=1.73 P=0.528 PRESS.D.AF o ~ o; 18.75 0 ~ 7119 013111) F-1.65 d.f.=1,73 P=0.204 PRESS2.DAF 00 18.75 0 7 1205 0 3 20.5 F=1.22 d.f.=1,73 P=0.273 PRESS5.DAF 0 0 19.5 0 I(1 21..S O ~1 21 F=1.55d.f.=1.73P=0.217 PRESSI5.D;\ F 0 IS 21 0 14 24 0 7 23.5 F=1.81 d.1'.=1,73 P=0.18?
ItiO.DAF 1 6 24.5 Z 13 27.5 2112126.5 F=0.96 d.t:=1,73 P=0.331 SIRS2.DAF O' 0.5 3 0!0 ? 01012.5 F=0.06 d.f.=1,73 P=0.802 SIRS3.DAF Q 2.5 19.75 I-1 12 I!4 111.5 F=O.19 d.f.=1.7? P=0.66 SIRS4.DAF 2 6_5 11- 3.25 2.5 114 22.5 3 10 23 F=0.23 d.f=1,73 Pd0.635 STER.DAF O 3.5 117.25 I 5 19.5 I 14119.5 F=0.08 d.f.=1,73 P=0.776 CVS.DAF ()1()18 0 3 14.5 011 Id F=1.21 d.f.=1,73 P=0.276 RESP.DAF 010.5 1 11 O (') I 7 O O 18 F=0.04 d.f.=1,73 P=0.835 PF300.DAF 01010.25 O O l I O O J I F=0.I9 d.L=1,73 P=0.667 VEN'T.DAF 0~0 19.25 01017 0~0~8 F=0.23d.f.=1.73P=0.632 CNS.DAF 2 6.5 24 3 13 25 2 t 1 25 F=0.89 d.f.=1,73 P=0.349 COAG.DAF 0.75 3.5 120.75 1.519 126.5 1 18 I 26 F=0.7 d.f.=1,73 P=0.407 INR.DAF 1.75 5.5 24.25 2 113 127 2110127 F=0.61 0.1.=1,73 0=0.-138 .\CRF.DAF 0 3.5 16.25 0.5 6 22 015 22 F=0.4 0.1.=1.73 P=0.529 ANYREN'.DAF 0 3.5 12.25 0.5 6!9 0 5 19 F=0.72d.f.=1,7' , P=0.399 RE'VSUP.DAF I 2 12.25 2 6 2H I 6 27 F=2.25 d.f.=1,73 P=0.138 AC11EP.DAF 1.75 3.5 18.25 2 IO 27.5 2 19 26 F=0.57 d.1:=1,73 0=0.453 ANYHEP.DAF 1.75 13.5118.25 21101 17.5 2 9 26 F=0.48d.f.=1,73P=0.493 TABLE 3.31 A response association of arginine vasopressin (AVP) rs857242 in Caucasian septic-shock control subjects. For all variables besides 28-day survival, data is given as 25t"
percentile I median I 75`n percentile. For 28-day survival, data is given as % (N survived / N total). N, number of subjects.
Note: AA -enoty e frequency = 0.
CONTROI- AC' CC C'onthined Tcst (N=13) (N=67) (N=80) Statistic SI:RVIV:\L 54", ( 7/13) Z0`7o (70/67) 34111, (27/80) Chis uarc=2.8 d.f.= I
P=0.09d DAYS YLIVE 1' 28 I 78 2.5 7 ~ 23 3 8 28 F=1.67 d.1'.=1,78 P=0.199 aLI.DAF I -l22 I~ 5 [25 I 5 15.75 F=0.35 d.f.=1,78 P=0.554 PRESS.DAF I 17 125 0 L3 8.5 014123 F=1.9 d.f.=1.78 P=0.172 PRESS?.DAF ? 17 126 0 3 1 18.3 O I a 123 F=2.1 d.f.=1,78 P=0.152 PRESSS.DAF 4 120 26 ) ~-i ?0.3 014 123.5 F=2.21 d.f.=1,78 P=0.141 PRESS 15.DAF 4 24 ,8 0.5 5 25 0.75 5.5 26 F=1.67 d.t.=1,78 P=0.201 INO.DAF -l ~ 20 28 I 5 28 1.75 16 28 F=1.15 d.1.=1,78 P=0.287 SIRS?.DAF 0 2' 1 3 O O I o 0 I 1=4.68 d.f.=1.78 P=0.0335 SIRS3.DAF 214 0 I I 5 0' 6.25 F=4.99 d.1'.=1,78 P=0.0284 S1RS4.DA1-4 227 2 ~ 5 16 216.5 22 F=3.23 0.1. 1,78 P=0.0761 STER.DAF I 6 26 I 5 17 1 52I.75 F=0.09d.f.=1,78P=0.769 CVS.DAF 0 11 123 21 02.5 i 19 F=1.58 d.f.=1,78 P=0.212 RESP.DAF O ) 19 O 11) 011 9.25 F=0.I3 d.f.=1,78 P=0.722 PF?00.DAF () O O O 1 ( l I S 0 0 1 F=0.79 6.f.=1,78 P=0.376 VENT.DAF O ~4 1 19 O I 0 9 01019.25 F=0.75 d.f.=1,78 P=0.39 CNS.DAF 4 õ ~2H 1 ~ 5 I 24 1 I 7 I-'5 F=3.3 d.f.=1.78 P=0.0732 C:OAG.DAF 3! 12 128 I 6! 3-l 1 16 25.5 F=1.7 d.1:=1,78 P=0.107 INR.DAF -f! 11 26 04 I8 0.7514.5 73.5 F=1.91 d.f.=1,78P=0.171 ACRF.DAF 1 7 128 04 17.5 O 420.75 F=3.05 d.l:=1,78 P=0.0844 ANYRE'N.DAI` 1 7' 27 0 17S 0 3.5 20 F=1.2 d.f.=1.78 P=0.278 REtiSI;P.DAF l 9'-8 1 ~-l' 14.5 1 14110.5 F=0.49 d.f:=1,78 P=0.488 ACHEP.DAF 4 22 ,8 I 6 2 1 . 5 I ~ 6' 2 8 F-2 9 d.f.=1,78 P=0.0926 ANYIIEP.DAF 4' ?-? I?8 I 5 21.5 16 I 28 F=3.27 d.t:=1.78 P=0.0745 TABLE 3.32 Dif'ference in I-esponse association of arginine vasopressin (AVP) rs857242 between cases lO (vasopressin-treated group) (Treat) and coritrols (vasopressin untreated matched control) (Cont) of Caucasian ICU subjects diagnosed with septic shock. For all variables besides 28-day survival, data is presented as medians. For 28-day survival, data is presented as r1c(N
survived / N total). N, number of sub'ects. Note: AA genotype fre uency = 0.
rs857242 AC rs857242 CC
(N=16) (N=13) (N=59) (N=67) Treat Cont DEL'I'A Treat Cont llEL'1'A
SIRVIVAL ZK% 1 6/16) 5417 ( 7/13) -(6`Io 4 1"0 (24/59) 30`-Ir (20/671 114c DAYS ALIVE 7.5 28 -20.5 19 7 12 ALI.DAF 6.5 4 2.5 6 5 1 PRESS.DAF 0 17 -17 7 3 4 PRESS2.DAF 0 17 -17 7 3 4 PRESS5.DAF 0 '_O -20 10 4 6 PRESSI5.DAF 1.5 24 -22.5 14 5 9 1NO.DAF 6 20 -14 13 5 8 SIRS2.DAF 0.5 2 -1.5 0 0 0 SIRS3.DAF 3.5 4 -1.5 4 1 3 SIRS4.DAF 6.5 32 -15.5 14 5 9 STER.DAF 3.5 6 -2.5 5 5 0 CVS.DAF 0 II -11 3 2 1 RESP.DAF 0.5 4 -3.5 0 1 -l PF30O.DAF 0 0 0 0 0 l1 VENT.DAP 0 -t -4 0 0 0 CvS.DAF 6.5 2_' -15.5 I? 5 8 COAG.DAF 3.5 12 -8.5 9 6 3 INR.DAF 5.5 14 -8.5 13 -1 9 ACRF.DAF 1.5 7 -3.5 6 4 2 AhYREh.D.AF ~.5 -3.5 6 3 3 REtiSIP.DAF y -7 6 4 2 ACHEP.DAF 3.5 22 -18.5 10 6 4 ANYHEP.D.AF 3.5 -18.5 10 1.3 Arginine Vasopressin Receptor ]la (AVPRIA) 1.3.1 Adverse Response to Vasopressin Treatment of subjects who have the TT
Genotype of AVPRIA rs1495027 and Improved Respionse to Vasopressin Treatment of subjects who have 5 the CC Genotype of AVPRIA rs1495027' It was unknown whether SNPs within the AVPRIA oene and those regions immediately upstream and downstream are associated with the response to vasopressin. It was found that AVPR 1 A
rs1495027 can be used to predict response to vasopressin in subjects with septic shock using 28-IO day survival and measures of ol-Ean dysfunction as respective primary and secondary outcome variables. Of 103 vasopressin-treated and 1.03 matched-control subjects with septic shock, 72 and 79 were respectively genotyped for AVPR I A rs 1495027. Baseline characteristics for subjects with genotypes are shown in Table 3.33 and Table 3.34.

TABLE 3.33 Baseline characteristics of a group of vasopressin-treated Caucasian ICU
septic shock subjects by Orenotype of arginine vasopressin receptor Ia (AVPRIA) rs1495Q27. For aee and APACHE II
score, data is given as 25`I' percentile median 175`' percentile. For all other variables, data is ~iven as ~I( (N /N total). N. number of subjects.
VASOPRESSIN CC CT TT Conihincd Test (N=14) (N=45) (N=13) (N=7?) Statistic AGE 57 67 72 4255 66 39 65 ' 71 -17 60 68 F=2.6 d.t.=2,69 0=0.0816 GESiDFR 79`Ir (11114) 8017( (36/66) 62% ( S/13) 76% (55/72) XA2=1.05 d.f. 2 P=0377 APACHE 11 23.75 30 33.75 25 31137 25 30 40 25 30 37 F=0.12 d.f.=2,69 P=0.889 rSI;RGICAL 50!% ( 7/14) 40`7: (18/66) 3 t'(,( 4(t3) d0<1, (29/71) XA2=I.04 d.t.=2 P=0.594 TABLE 3.34 Baseline characte--istics of a vasopressin untreated matched control group of Caucasian ICU septic shock subjects by genotype of arginine vasopressin receptor I a(AVPR I A) rs 1495027. For age and APACHE II score, data is given as 25''' percentile I median 175'' percentile. For all other variables, data is (Yiven as cIc (N /N total). N, number of subjects.
CONTROL CC CT "IT Conibined Test (;ti=29) (N=37) (N==13) (N=79) Statistic AGE 44 57 68 43 52 167 49 64 72 44 56171.5 F=0.68 d.f.=2,76 P=0.51 GENDER 521,~ (15/391 76'f (28/37) 771.~(10/13) 67`1, (53/79) X^2=4.91 P=0.086 APACHE Il 27 31 33 25 29 34 29 34 37 24 29 34 F=1.06 d.f.=2,76 P=0.351 '7< SLRGI('AL 24"'~ ( 7/29) 32"7, (12/37) 54(~ ( 7/13) 33(1< (26/79) X^2=3.6 d,f: 2 P=0.166 Tables 3.35, 3.36 and 3.37 contain 28-day survival and organ dysfunction data for septic-shock subjects genotyped for AVPRIA rs14950'<'7. Vasopressin-treated subjects with the AVPRIA
I o 1-s 1495027 TT had a dramatically decreased survival (23 ~Ic) compared to controls (46 k) as demonstrated by the negative values in the AVPRIA rsl495027 TT DELTA column in Table 3.37.
Furthermore, vasopressin-treated subjects with the AVPRIA rs1495027 TT
genotype were obsel-ved to have more organ dysfunction as demonstrated by fewet- DAF of organ dysfunction. In contrast, vasopressin-treated subjects with the AVPRIA rs1495027 CC genotype were shown to I S have increased sut-vival (50%) over AVPR 1 A rsl495027 CC contl-ols (24(lc) as demonstrated by the positive values in the AVPRIA rs1495027 TT DELTA column in Table 3.37. In addition, vasopressin subjects with the AVPRIA rs1495027 CC genotype had less organ dysfunction as evidence(i by more DAF of or-an dysfunction.

20 TABLE 3.35 A response association of AVPR 1 A rs 1495027 in vasopressin-treated Caucasian septic-shock subjects. For all variables besides 28-day survival, data is given as 25`' percentile I median 175"
ercentile. For 28-day survival, data is given as cl( (N survived / N total).
N, number of subjects.
VASOPRESS[N CC CT IT Conibined Test (N=11) (N=45) (N=13) (N=72) Statistic SCRVIVAL 50(,( ( 7/I4) 38!/< (17/45) 23? ( 3/13) 38T(27/73) Chis uarc=2.09 d.f.=2 P=0.352 DAYS ALIVE 3.75 18.5 28 2 10 28 12 20 23 3 12 28 F=0.75 d.1:=2,69 P=0.477 ,\LI.D.4F 2.25 5.5 1 10.75 1 13 17 3 I 6 117 115.5 I 17 F=0.17 d.f.=2.69 P=0.842 PRESS.DAF 0 8.5 1 )1.75 0 J 0 1 9 0 17 114 0 11 118.25 F=0.2 0.1.=2,69 P=0.821 PRESS2.DAF 0~8.5121.75 0~1120 017117 0 11 18.5 F=0.16d.1'.=2.69P=0.855 PRESS5.DAF (l 9 23 0 I 20 0 l I I 8 1.5 120.25 F=0.22 d.f.=2,69 P=0.S01 PRESSI5.DAF 13 16 0 ~ 3 22 4114120 0 5 23 F=0.84d.f.=2,69 P=0.435 INO.DAF ?' 13.5 26 ? 8 28 10 119 " ? 1226.25 F=0.17 d.f.=2.69 P=0.845 SIRS?.D.AF 01014 0 0 3 C I 1 2 0 0 3 F=0.8; d.f.=2.69 P=0.442 SIRS3.DAF 1 . 2 5 ! 3S 1 1 7 0 2 9 4 7 1 0 O 31 1.25 F=2.34 d.1-.=2,69 P=0.104 SIRS4.DAI: 2.5 112 25 1 8 22 8 16' 20 219 122.25 F=1.33 d.f.=2.69 P=0.272 STER.DAF 015 25.0 I 3 f 9 1! 7 15 0.75 3.5 119.25 F=0.01 d.f.=169 P=0.989 CVS.DAF (114 115.75 0 0 13 O 3 13 010114 F=0.21 d.f.=2.69P=0.814 RESP.DAF (1 0 10.75 0 I 0 8 Q 1 5 O 0 8 F=0.04 d.f.=2.69 P=0.956 PF;oO.DAF O o ~ 0a5 1 0 ~ o ~ 2 0 0 1 F=0.04 d.f.=2,69 P--0.962 VENT.DAF 0 0 10.5 0 0 8 0 0 2 O H F=0.32 d.1'.=2,69 P=0.7 CNS_DAF 2.75 12 126.25 2 17 124 9113 120 2 10.5 124.25 F=0.59 d.1.=2,69 P=0.556 COAG.DAF 2 7 27.75 I 17 26 4112120 1 17.5 26 F=0.25 d.f.=2,69 P=0.781 INR.DAF 1116.5 28 117 126 6 13 21 1.75 18126.25 F=0.42 d.f.=2,69 P=0.658 ACRF.DAF O 2 25 0 321 5 9 14 0 5 120.25 F=0.45 d.f.=2,69 0=0.642 A'VYREV.DAF 0 2117.7 0 3 24 5 9 14 015 18.25 F=0.6 d.f.=2,69 0=0.549 RENSU'P.DAF I2.5 126 1 3 28 2110117 114.5 27.25 F=O.I4 d.f: 2,69 P=Q.868 .ACHEP.DAF 2.25 8.5 128 I 3 120 10114122 2 7.5 24 F=1.62d.f: 2,69 0=0?04 ANYHEP.D.aF 2.25 828 113 12O 10 14'22 2 7 24 F=1.7d.f.=2,69P=0.186 'CABLE 3.36 A response association of arginine vasopressin receptor la AVPRIA rs1495027 in Caucasian septic-shock control subjects. . For all val-iables besides 28-day survival, data is given as 25`I' percentile I median 175'' percentile. For 28-day survival, data is given as k (N survived / N total).
N, number of sub'ects.
CONTROL CC CT TT Comhined Test (N=29) (N=37) (N=1?) (N=79) Statistic SURVIVAL 7129) 351-S (1 '07) 46 1; ( 6/13) 33`~r (26/79) Chisc uarc=2.13 d.f.=2 P=0.345 DAYS ALIVE 2 1 6 2 1 3 8 28 4115128 3 8 J 28 F=0.77 d.L=2,76 P=0.467 ALI.DAF 1 ! 3 11 1' S~ I4 2 720 I 5 14S F=0.4' d.f.=2,76 P=0.661 PRESS.DAF 0 13 1 I-l 04 124 I 19119 O ~-t ~" F=0.46 d.f.=2,76 P=0.633 PRESS?_DAF 0 I 3 1 I-F f) ~4 ~24 2 ~ 9 119 p ~ 4 ~22 F=0.48 d.f.=3.76 P=0.62 PRESSS.DAF O I 3 ! I 1 0 14 125 1 9 ~? I 014 123 F=0.7 d.f -2,76 P=0.501 PRESSI5.DAF 03 18 I 626 ? 1 15 126 0.5 526 F=1.04d.f. 2.76P=0.359 ['VO.DAF L 3 20 3 17 128 2 I S ?8 ? 6 28 F=1.15 d.f.=2,76 P=0.322 S[RS~_'.DAF 0' 0 I 0 0 0 1 2 0O 2 ()11)11 F=1.05 d.f.=2,76 P=0.355 SIRS3.DAV 1' 1 5 0 2 8 ? 1410 02 6.5 F=0.94 d.f.=2.76 P=0.394 SIRS4.DAF I 6 1 1 '_ 5?5 4110122 2 6 21.5 F=0.76 d.1:=2.76 P=0.471 STER.DAF 012 10 1! 5 24 2`5 15 I 5 120 F=0.71 d.t:=2.76 P=0.495 CVS.DAF O O ! 1 3 O I 3 1 8 0 4 ' 1 9 0 2 18.5 F=0.45 d.1:=2.76 P=0.637 RESP.DAF 0 1 ' 9 0 2 1 7 0 I 7 O I 9.5 F=0.37 d.f: 3,76 P=0.694 PFOO.DAF 0 0 q O 0 2 0 1 0~ 0 fO 1-5 F=1.42 d.f. 2,76 P=0.248 VENr.DAF o ~ o ~ 9 0 ~ 0 112 0 0 ~ 7 0 10 ~ 9.5 F=0.07 d.f.=2,76 P=0.93 CNS.DAF I 5 ~ 18 [ 7 26 4 1I4 ~_'5 1 17 125 F=0.34 d.f.=2.76 P=0.712 COAG.DAF I 5 ~ I 5 1 6 28 ~ I5 28 I 10124.5 F=0.54 d.l: 2,76 P=0.583 INR.DAF 0 ~ 3 2 1 O I S 121 1110127 0 4 21.5 F=0.36 d.1:=2,76 P=0.701 ACRF.DAF 0 I 3' 9 016123 0 10 ?0 014120 F=0.42 d.1.=2.76 P=0.658 ANYRF. V.DAF 0 2 ' 9 0 5 123 Q' 1O 1 20 014119 F=O.?S d.1:=2.76 P=0.757 RENSUP.DAF I 12 = l I 7 23 ? 5' 16 I 1 17 F=2.45 d.f.=2.76 P=0.0928 ACHEP.DAF I 5 I 19 2 7 28 7 115 178 I 6 76 F=1?l d.['.=2.76 P=0.303 ANYHEP.DAF 15 19 I 6' 28 4 15 78 l 6 26 F=0.94 d.f: 2.76 P=0.397 TABLE 3.37 Difference in response association of arginine vasopressin receptor l a(AVPR I
A) rsi 495027 Il) between cases (vasopressin-treated group) (Treat) and contl-ols (vasopressin Flntreated matched control) (Cont) of Caucasian ICU subjects diagnosed with septic shock. For all variables besides 28-day survival, data is presented as mediarls. For 28-day survival, data is presented as %(N
survived / N total). N, number of subjects.
rs 1495027 TT rs 1495027 CT rs 1495027 CC
(N=13) (5J=13) (N=-IS) (N=37) (ti=1=1) (N='9) I'i-eat Cont DELTA Treat Cont DELTA Trea( Cont DI':L7'A
SURVIVAL 3) 46`~( 6) -23% 3817,(17) 35% (13) 3'.?c 50% (7) 241Ic ( 7) 26%
DAYS AL.1VG 20 15 5 10 8 3 18.5 6 12.5 ALI.DAF 6 7 -1 3 5 -2 5.5 3 2.5 PRESS.DAF 7 9 -2 O 4 -4 8.5 3 5.5 PRESS?.DAF 7 9 -2 1 4 -3 8.5 3 5.5 PRESS5.DAF Il 9 2 t 4 -3 9 3 6 PRESSI5.DAF 14 15 -1 3 6 -3 13 3 10 INO.DAF 19 15 4 8 7 1 13.5 3 10.5 SIRS2.DAF 1 0 1 0 0 0 O O 0 SIRS3.DAF 7 4 3 ? 2 0 3.5 1 2.5 SIRS4.DAF 16 o 6 8 5 3 12 6 6 STER.DAF 7 5 2 3 5 -2 5 2 3 CVS.DAF 3 4 -1 0 3 -3 4 0 4 RESP.DAF I I 0 -2 0 I -1 PF300.DAF 0 0 0 0 O 0 0 0 0 VENT.D.MF 0 0 0 0 0 0 0 0 0 CVS.DAF 1~3 14 -1 7 7 0 12 5 7 COAG.DAF 12 15 -3 7 6 1 7 5 2 INR.DAF 13 10 3 7 5 2 16.5 3 13.5 ACRF.DAF 9 IO -1 3 6 -3 ? 3 --ANYRE'V.DAF ~t IO -l 3 5 -2 2 2 0 RENSUP.DAF 10 5 5 3 7 --l 1.5 2 0.5 ACHl:P.DAF I-l 15 -1 3 7 -4 8.5 5 3.5 a'VYHEP.DAF 14 15 -l. 3 (; -3 K 5 3 A logistic regression approach was used to test for a statistically significant interaction between genotype and vasopressin use as predicted by 28-day survival TABLE 3.38 shows that there Was a statistically significant interaction between AVPR 1 A rs 1495027 genotype, vasopressin treatment and survival, confirniina vasopressin treat-nent decreases 28-day swvival in AVPR I A rs 1495027 TT Lyenotype subjects while vasopressin treatment increases 28-day survival in AVPR I A
rs 1495027 CC subjects compared to controls (P = 0.04662). Following adjustment for age, adnlission APACHE lI score, -ender. medical, surgical diaQnosis and days alive and free of 3 of 4 systematic inflammatory response syndronie (SIRS) criteria, there was still a statistically IF) significant interaction of the AVPRlA rs1495027 genotype and treatment with vasopressin (P =
0.0339).

TABLE 3.38 Interaction between genotype and vasopressin use vs. no vasopressin (Controls) and CC or CT
I S genotype vs. TT genotype of arginine vasopressin receptor I a(AVPR 1 A) rs 1495027 on 28-day survival.
Estirnate Std. Eiror 2 valuc Pr(> i) Vaso pressin \s. controh +Lenotv e interaction 2.195 I.1(131 I 99 0.04662 Vas re~tiin 4s. cnntrols + genotye interaction - Adjusted 2.6035 1.2271 2.122 0.03 387 Example I Summary Genotypinlg of SNPs LNPEP --s 18059, LNPEP rs2771 I. LNPEP rs 10051637, AVP rs 1410713, 20 AVP rs857240, AVP rs857242, and AVPRIA rs1495027 in snbjects with septic shock can predict response to administration of vasopressin as measured by 28-day survival and/or DAF of organ dysfunction. Subjects with genotypes including LNPEP rs18059 CC, LNPEP rs2771 1 AA, LNPEP rs10051637 GG, AVP rs1410713 CC, AVP rs857240 CT, AVP rs857242 AC and AVPR I A rs 1495027 TT should not be administered a vasopressin receptor agonist as this could potentially decrease survival and increase risk of organ dysfunction. In contrast. subjects with LNPEP rs 18059 TT, LNPEP rs27711 GG, LNPEP rs 10051637 AA, AVP rs 1410713 AA
and rs 1410713 AC, AVP rs857240 CC, AVP rs857242 CC and AVPR 1 A i-s 1495027 CC
genotypes should be administered a vasopressin receptor agonist as such ti-eatment has the potential to inci-ease survival and decrease risk of organ dysfunction.

EXAMPLE 2: RISK OF DEATH AND ORGAN DYSFUNCTION
Methods Cohort Selection To investigate whether genotype predicts risk of death and organ dysfunction, selected subsets of the ICU cohort were used for this study. All patients who were treated with vasopressin for septic shock were excluded. The four study groups were: ICU Caucasians with SIRS upon admission (n=874), ICU Caucasians with sepsis upon admission (n=690). ICU Caucasians with septic shock upon admission (n=440) and ICU Asians with SIRS upon admission (n=108).

2(1 Data Analysis All data analysis was carried out using statistical packages available in R (R
Core Development Group, 2005 - R Development Core Teani ( www.R-project.org). R: A language and environment for statistical computing. Vienna, Austria. 2005). Chi-square and Kruskal-Wallis (KW) test statistics were used in conjunetion with Cox proportional hazards (CPH) regression to identify significant SNP-phenotype associations, as well as to identify baseline characteristics (age, gender, admitting APACHE II score, and medical vs. surgical admitting diagnosis) requiring post-hoc, multivariate adjustment. Genetica{ly heterogenous populations were subsetted prior to analysis to avoid confounding from potential population stratification.

Results 2.1 Leucyl/Cystinyl Aminopeptidase (LNPEP) 2.1.1 LNPEP rs18059 2.1.1.1 Systematic Inflammatory Response Syndrome - Caucasians TABLE 4.1 gives the baseline characteristics of 710 Caucasian SIRS subjects who wel-e successfully genotyped (CC vs, CT/TT) a.t LNPEP rs I8059. No significant differences were detected between the two Qenotype groups on admission to the ICU.
TABLE 4.1 Baseline characteristics of a cohort of Ca(lcasian Subjects with systematic inflammatory response syndrome by genotype of leucyl/cystinyl aminopeptidase (LNPEP) rs18059 (CC vs.
CT/TT). For age and APACHE II score, data is Qiven as 25"' percentile / median / 75t' pel-centile. For all other variables. data is iven as ~lf (N survived / N total). N, number of subjects.
CC C'lf / TT Combined Test (V=1;-;) (N=555) (N=710) Statistic AUE 4-1.5 / 58 / 70 45 / 591 71 46 / 59l 71 F=0.96 d.f.=1,708 P=0.327 GENDER 63i'r ( 97/155) 61-1 (336/555) 6(Z. (433/710) X^2=0.21 d.f.=1 P=0.645 APACHI:II 1 5 1 2O1 26 16 / 22 / 27 M121.5 / 27 F=2.52 d.t:=1,708 P=0.1 I 3 sURUICAL 20'7, ( 31/155) 231,'1, (1 30/555) 23';~ (163/710) X^2=0.81 d.f.=l P=0.368 SEP.ADn4I'f 81 `7 (125/155) 7811( (435/555) 7917( (560/710) X^2=0.37 d.f.= t P=0541 SEP.A'VY 831~~ (129/I55) 80`<(442/555) 801>, (571/710) X^2=0.99 d.f.=1 P=0.32 SS.AllnIIT 5_2 !~,(81/155) 51!~r(385h55) 52'c-(366/710) X^2=0.04d.f.=1P=0.842 SS.A'VY 55`4. (85/155) 55`i(306/555) 55(7,(391/710) X^2=0 d.f.=1 P=1).9_18 Figure 1 and TABLE 4.2 summarize important SNP-phenotype associations.
Subjects with LNPEP rs I 8059 CC genotype showed a sir,nificantly greater survival (P =
0.0331) and had significantly mol-e (lays alive (P = 0.0144) and days alive and free of vasopressors (P = 0.0088), days alive and free of vasopressors at doses of more than 2 ug/min(P=0.0101).
5 ug/min (P=0.0037) and 15 ug/min (P=0.0157), inotropes (P = 0.0252), coagulation dysfunction (P =
0.0030), any renal dysfunction (P = 0.0088), renal support (P = 0.0145), acute hepatic dysfunction (P = 0.0335) and any hepatic dysfunction (P = 0.0456). Subjects who carried the LNPEP rs 18059 CC genotype also showed a strong trend for more days alive and free of neurological dysfunction (P = 0.071 ). These findings indicate that these patients who have who carry the LNPEP 1-s 18059 CC genotype at LNPEP rs 18059 CC have less need of inotrope and vasopressor therapy and have a lower I-isk of organ dysfunction (coagulation, rena(, hepatic and neurological).

TABLE 4.2 Days alive and free of organ dysfunction (DAF) by allele of leucyl/cystinyl aminopeptidase (LNPEP) 1-518059 (CC vs. CT/TT) in a cohort of Caucasian subjects with systematic inflammatory 1-esponse syndrome. For all variables besides 28-day survival, data is given as 25`h percentile /
median / 75`l' percentile. For 28-day survival, data is given as cIc (N
survived / N total). N, number _t) of subjects.

CC cT /'iT Combined Test (N-155) (\=555) (V=710) Statistic SURVIVAL 75`9c 0 17/155) 660 (369/555) 687( (486/710) X^2=4.53 d.t:=1 P=0.0331 DA 28/28/28 10/28/29 12I28I28 F=6.02d.f.=1,708P=0.0144 PRESS.D.AF 17.5 /?7 ! 28 7/ 25 l 28 9/ 26 / 28 F=6.9 d.f.=1,708 P=0.0088 PRESS2.DAF 17.5 / 27 / 38 7.5 I26 / 28 101 26 /?8 F=6.64 01=1,708 P=0.0101 PRESS5.DAF I S.5 / 27 / 28 8 /'_6 / 28 10 / 36 / 28 F=8.49 d.f.=1,708 P=0.00369 PRESSI5.DAF 23.5I28/38 9/28/28 12/28/28 F=5.86d.f.=1,708P=0.0 157 INO.D.AF 24 / 28 / 28 9 /'-8 / 28 1 1.3 /?8 / 28 F=5.03 d.f.=1,708 P=0.0252 CNS.DAF 14/27/28 7/26/28 7.25/27/28 F=3 .27 d.f.= 1,708 P=0.071 COAG.DAF 20 /?8 l 28 7/ 28 / 28 8.25 / 28 / 28 F=8.87 d.f.=1,708 P=0.00299 INR.DAF I4/28/28 5/27/28 7/27/28 F=3.51d.f.=1,708P=0.0615 aNYREN.DAF 9l 2A / 38 2 I 22 i 28 3l 25 / 28 F=6.9 d.f.=1.708 P=0.00882 RENSUP.DAF 14/28/28 4/28(28 5/28/28 F=6d.1', 1,708P=0.0145 ACIdEP.DAF 17 !?8 / 28 7/ 28 I 28 8 /?8 / 28 F=4.54 d.t.= I.708 P=0.0335 ANYHEP.DAF 15.5 ( 28 / 28 61 28128 7 128/ 28 F=4.01 d.f.=1,708 P=0.0456 2.1.1.2 Sepsis - Caucasians TABLE 4.3 gives the baseline characteristics (age, gender, APACHE II score, medical vs. surgical diagnosis. septic shock upon admission and septic shock anytime) of 561 Caucasian sepsis subjects who were successfully genotyped (CC vs. CT/TT) at LNPEP rs 18059. No significant differences were detected betweetl the two genotype groups on admission to the ICU.

TABLE 4.3 Baseline characteristics of a cohort of Caucasian Subjects with sepsis by allele of leucyl/cystinyl IO aminopeptidase (LNPEP) rs18059 (CC vs. CT/TT). Forage and APACHE II score, data is given as 25 i percentile / median / 75`h percentile. For all other variables, data is given as '/C (N survived / N tota)). N, nurnber of subjects.
CC CT 1'IT Cunibincd Tcst (N=126) (N=4:15) (N=561) Statistic AGE -16/58/70.8 45/59/71.5 -17/59/72 F=0.=15d.f: 1,559P=0.501 GENDER 65`/, ( 8'/1?6) 629 (270/435) 63'7 (352/561) X^2=0.38 d.f. I P=0.538 :\PACHEII 16/22/27 17/23/28 17J32/28 1~=1.9501=1,559P=0.163 SURGICAL -' I'.<( 26/126) 231"(' (100/435) "7r (126/561 ) X^2=0.31 d.f. 1 P=0.577 SS.?.DM1T (4 /r ( 81/126) 66'7, (285/415) 65';i (366/561 ) X^?=0.07 d.r.=1 P=0.798 SS.ANY 66f ( 83/1261 70!~ (3p31=135) 69'~(386/561) X^2=0.6>d.f.=1 P=0.12 TABLE 4.4 summarizes important SNP-phenotype associations. Subjects with the LNPEP
1 5 rs 18059 CC genotype showed significantly more days alive and fr-ee of vasopressors (P = 0.0377), days alive and free of vasopressors at doses of more than 2 ug/min(P = 0.0424) and 5 ug/min (P =
0.0194) and coagulation dysfunetion (P = 0.0359). Subjects who carried the LNPEP rs 18059 CC
genotype also showed a strong trend for mol-e days alive and t'ree of renal support (P = 0.07).
These findings indicate that Caucasian sepsis subjects who carry the LNPEP rs 18059 CC genotype 20 have less need of vasopressor therapy and have a lower risk of organ dysfunction (coagulation and renal).

TABLE 4.4 Days alive and free of organ dysfunction (DAF) by allele of leucyl/cystinyl aminopeptidase (LNPEP) rs 18059 (CC vs. CT/TT) in a cohort of Caucasian subjects with sepsis.
Data is given as 25'1' ercentile / median / 75i1' percentile. N, number of subjects.
CC CT 1 TT Comhined Test (N=1?6) (N=435) N=561) Statistic PRESS.DAF 15 I 26128 81 25 I 28 10 I ?5 / 28 F=4.34 d.f.=1.559 P=0.0377 PRESS2.DAF 15 / 26 / 28 8.5 /?5 / 28 10 / 25 l 28 F=4.14 d.t:=1.559 P=0.0424 PRESS5.DAF 17.3 / 27 / 28 9l 25 1 28 1 1 1261 28 F=5.5 d.t.=1559 P=0.0194 COAG.D;aF 20/28128 9/28/28 0l28/28 F=6.06 d.f.=1.559 P=0.0142 RENSUP.DAF I 1.3 / 28 / 2!i 5 l 28 / 2 6 1 281 28 F=3.29 d.f.=1,559 P=0.07 2.1.1.3 Septic Shock - Caucasians TABLE 4.5 gives the baseline characteristics (age, gender, APACHE 11 score and medical vs.
surgical diagnosis) of 366 Caucasian septic shock subjects who were successfully genotyped (CC
vs. CT/TT) at LNPEP rs I 8059. No significant differences were detected between the two genotype groups on adnlission to the ICU.
TABLE 4.5 Baseline characteristics of a cohort of Caucasian Subjects with septic shock by allele of leucyl/cystinyl aminopeptidase (LNPEP) rs18059 (CC vs. CT/TT). For age and APACHE II
score, data is given as 25'' percentile / meclian / 75`(' percentile. For all other variables, data is given as Ilo (N srn-vived / N total). N. number of subjects.
'C T / TT 'onihined est V-81) N=285 ) N=366) Statistic AGE 17/59l71 18/63(73 48162/73 F=1.91d.t.=1,3640=0.168 ;ENDER 41~, ( 52181 ) 00`, (1721285) l`", (2241366) X^2=0.39 d.f.=1 P=0.531 APAC'HEII 17/'_4/39 20135130 19/24/30 F=1.819.1:=1,3640=0.180 SURGICAL 211,' ( 171811 2617 ( 74/285) 2517, ( 9113661 X^2=0.84 9.1.=1 P=0.360 TABLE 4.6 summal-izes impol-tant SNP-phenotype associations. Subjects with the LNPEP
t-s 18059 CC genotype showed a strong trend for greater survival (P = 0.0862) and significantly more days alive (P = 0.0353) and days alive and free of vasopressors (P =
0.0404), days alive and free of vasopressors at doses of more than 2 ug/min (P = 0.0372), 5 ug/min (P
= 0.0 132) and 1.5 ug/min (P = 0.0373), coagulation dysfunction (P = 0.0079), any renal dysfunction (P = 0.0394) and renal support (P = 0.0364). LNPEP 1-s 18059 CC individuals also showed a strong trend for more days alive and free of itlotropes (P = 0.0646) and acute renal dysfunction (P
= 0.0593). These findings indicate that Caucasian septic shock subjects who carry the CC
genotype at LNPEP
rs18059 have less need of inotrope and vasopressor thel-apy and at-e have a lower risk of oraan dysfunction (coagulation and renal).

TABLE 4.6 Days alive and free of organ dysfunction (DAF) by allele of leucyl/cystinyl aminopeptidase (LNPEP) rs 18059 (CC vs. CT/TT) in a oahort of Caucasian subjects with septic shock. For all variables besides 28-day survival, data is given as 25`h percentile / median /
75"' percentile. For 28-day survival, data is given as % (N survived / N total). N, number of sub'ects.
CC. C'T / TT Combined Test ('V=81) (N=285) (N=366) Statistic SURVIVAL 69`3( 50/81) 59~7(167/285 ) 614 (223/366) X^2=2.94 d.f. l P=0.0862 1)A 22 /18 l28 8/ 28 / 28 9/ 28 / 28 F=4.46 d.f.=1,364 P=0.0353 PRESS.DAF 1 1/ 24 / 27 4/ 21 /'_6 5.75 / 23 / 26 F=4.23 d.f.=1.464 P=0.0404 PRESS2.DAF I I/ 24 / 27 4 / 22 / 26 5.75 / 23 / 26 F=4.37 d.f.=1,364 P=0.0372 PRESS5.DAF 13 / 25 / 27 5/ 23 / 27 6/ 241 27 0=6.2 d.f.=1.364 P=0.0132 l'RESS15.DAF 17 / 27/ 28 6 /'_6 / 28 tl / 26 / 28 F=4.37 d.f. 1.364 P=0.0373 INO.DAF I8/38/28 6/26/28 7/28/28 0=3.440.1:=1.3640=0.0646 COAG.DAF 17 / 28 / 2K 5 / 24 / 28 6( 25 / 28 F=7.14 d.f.=1.364 P=0.0079 INRI).AF 11- /25/2S 4/22/28 5/24/28 F=2.81d.f.=1.364P=0.0944 ACRF.DAF 1O / 27 / 28 3/ 20 / 28 3/ 22 / 28 F=3.58 4.1.=1,364 P=0.0593 ANYRI:N.1)A
1" 9/26/28 2/IS/28 2.75/1950/28 F=4.27d.f. 1.3640=0.031)4 RENSUP.DAF 10/?8 / 28 3/ 23 / 28 4/ 25 / 28 F=4.41 d.f.=1,364 P=0.0364 2.1.2 LNPEP rs27711 2.1.2.2 Svstematic Inflammatory Response Syndrome - Caucasians TABLE 4.7 summarizes the baseline characteristics (age, gender, APACHE II
score, medical vs.
surgical diagnosis, sepsis upon admission, sepsis anytime, septic shock upon admission and septic shock anytime) of 717 Caucasian systematic inflammatory 1-esponse syndrome subjects who were successfully genotyped (AA vs. GG/AG) at LNPEP rs2771 1. No significant differences were detected between the two genotype groups on admission to the ICU.

TABLE 4.7 Baseline characteristics of a cohort of Caucasian Stlbjects with systematic inflammatory resporlse syndrome by genotype of leucyl/cystinyl alninopeptidase (LNPEP) rs277I 1(GG/AG
vs. AA). For age and APACHE 11 score, data is given as 25`(' percentile / median / 75"' percentile. For all other variables, data is Qiven as Ie (N survived /]v total). N, number of subjeets.
Combine AA GG / AG d Test (N=98) (N=619) `N=717) Statistic 43.5 /
AGE 57/71 45/59/70.5 46/59/71 F=1.1 d.f.=1,715 P=0.294 6Oc,7c ( 62%
GENDER 59/98) 62% (382/619) (441/717) X^2=0.08 d.f.=1 P=0.776 15/201 i6/21.5/
APACHEII 27 16 / 22 / 27 27 F=1.42 d.f.=1,715 P=0.234 19ck( :2Ck SURGICAL 19/98) 23% (141/619) (160/717) X^2=0.56 d.f.=1 P=0.454 79% ( i 9%
SEP.ADMIT 77/98) 79% (487/619) (564/717) X^2=0 d.f.=l P=0.981 SEP.ANY 81 ~c ( K01/', (497/619) 80% XA2=0.01 d.f.= I P=0.94 79/98) (576/717) 52%( 51 ( SS.ADNZIT 51/98) 51 Ic (317/619) (368/717) X^2=0.02 d.f.=1 P=0.879 521`/c ( 559c SS.ANY 51/98) 55 Ic (342/619) (393/717) X^2=0.35 d.f.=1 P=0.553 TABLE 4.8 summarizes important SNP-phenotype associations. Subjects with the LNPEP
rs2771 I AA genotype showed significantly more days alive and free of vasopressors (P = 0.0330), days alive and fi-ee of vasopressors at doses of more than 2 ug/min(P=0.0362), 5 ug/min (P=0.0221 2) and 15 u-/min (P=0.0961). Subjects with the LNPEP rs2771 I AA
genotype also had a strong trend for more days alive and free of steroids (P = 0.0871). These findings indicate that Caucasian subjects who have SIRS and have the AA genotype at LNPEP rs2771 I
have less need for vasopressor therapy and steroid therapy.

1 o TABLE 4.8 Days alive and free of organ dysfunction (DAF) by allete of leucyl/cystinyl aminopeptidase (LNPEP) rs2771 l(GG/AG vs. AA) in a cohort of Caucasian subjects with systematic inflammatory response syndrome. Data is given as 25`h percentile / median /
75`h percentile. N.
number of sub'ects.
AA GG / AG Combined Test (N=98) (N=619) (N=717) Statistic PRESS.DAF 28 9 26 / 28 9/ 26 / 28 F=4.56 d.f'.=1,715 P=0.0330 PRESS2.DAF 28 9/ 26 / 28 10 / 26 / 28 F=4.41 d.f.=1.715 P=0.0362 PRESS5.DAF 28 10 / 26 / 28 10 / 26 / 28 F=5.25 d.f.=1.715 P=0.0222 20.5 / 28 /
PRESSI5.DAF 28 11 / 28 / 28 12 /-'_8 / 28 F=2.78 d.f.=1,715 P=0.0961 6/26.5/
STER.DAF 28 2/ 22 / 28 2 / 23 / 28 F=2.93 d.f.=1.715 P=0.0871 2.1.3 LNPEP rs10051637 2.1.3.1 Systematic Inflammatory Response Syndrome - Caucasians TABLE 4.9 summarizes the baseline characteristics (age, gender, APACHE II
score, medical vs.
?O sucgical diagnosis, sepsis upon admission, sepsis anytime, septic shock upon admission and septic shock anytime) of 710 Caucasian SIRS subjects who were successfully genotyped (AA vs.
AG/GG) at LNPEP rs 1005 1637. No significant baseline differences were detected between the two genotype groups on admission to the IC'U although the AG/GG group is more likely to be diagnosed with sepsis throughout an ICU stay.

TABLE 4.9 Baseline characteristics of a cohort of Caucasian Subjects with systematic inflammatory response syndrome by genotype of leucyl/cystinyl aminopeptidase (LNPEP) rs10051637 (AA
vs. AG/GG).
For age and APACHE II score, data is given as 25`' percentile / median / 75`t' percentile. For all other variables, data is ~iven as ~Ic (N survived / N total). N, number of sub'ects.
Combine AA AG / GG d Test (N=236) (N=474) (N=710) Statistic 45.3/58/ 46/59/
AGE 44 / 61 / 72 70 71 F= 1.06 d.f.=1,708 P=0.304 63 clc 62%
GENDER 60%, (142/236) (297/474) (439/710) X^2=0.41 d.f.=l P=0.52 16/21.5/
APACHEII 17 / 22 / 27 15 I 22 I 27 27 F=0.2 d.f.=1.708 P=0.657 24% 23cio SURGICAL 21 % ( 49/236) ( I I 3/474) (162/710) X^2=0.85 d.f.=1 P=0357 80% 78%
SEP.ADMIT 759c (177/236) (378/474) (555/710) X^2=2.08 d.f.=1 P=O.149 8 2 c'c KO%
SEP.ANY 76% (179/236) (389/474) (568/710) X^2=3.81 d.f.=1 P=0.05 I
5 2 ck 51 clc SS.ADMIT 489c (1 14/236) (247/474) (361/710) X^2=0.91 d.f.=1 P=0.339 56% 55('Ic SS.ANY 51 clc (121/236) (266/474) ( 387/7 (0) X^2=1.=f9 d.f.=1 P=0.222 TABLE 4.10 sunimarizes important SNP-phenotype associations. Subjects with the LNPEP
rs 1005 1637 AG or GG genotype showed significantly more days alive and free of inotropes (P =
0.0357) and 2 of 4 SIRS criteria (P = 0.02 26). These findings indicate that Caucasian subjects who have SIRS who carry either the AG oi- GG genotype at LNPEP rs 10051637 have less need of inotrope therapy and less SIRS.

TABLE 4.10 Days alive and free of organ dysfunction (DAF) by allele of leucyl/cystinyl aminopeptidase (LNPEP) i-s10051637 (AA vs. AG/GG) in a cohort of Caucasian subjects with systematic inflammatory response syndrome. Data is given as 25`'' percentile / median l75`f' percentile. N, number of subjects.
AG
AA GG Combined Test (N=474 (N=236) ) (N=710) Statistic I5/28/ 11.3/28/
INO.DAF 7/ 28 / 28 28 28 F=4.43 d.f.=1.708 P=0.0357 MSIRS2.
DAF 0 /2 / 20 0/6 /'_ 1 0/5 / 21 F=5.22 d.f.=1,708 P=0.0226 CSIRS2.D
AF 0 /3 / 20 0/5 / 20 0/5 I 20 F=3.23 d.f.=1.708 P=0.0726 2.1.4 LNPEP rs38041 2.1.4.1 Svstematic Inflammatory Response Syndrome - Caucasians TABLE 4.11 summarizes the baseline characteristics (age, gender, APACHE II
score, medical vs.
surgical diagnosis, sepsis upon admission, sepsis anytime, septic shock upon admission and septic shock anytime) of 717 Caucasian SIRS subjects who were successfully genotyped (AA vs.
GG/AG) at LNPEP rs38041. No signifieant differences were detected between the two genotype k-Troups on adniission to the ICU.

TABLE 4.11 Baseline characteristics of a cohort of Caucasian Subjects with systematic inflammatory response syndrome by genotype of leucyl/cystinyl aminopeptidase (LNPEP) rs38041 (AA vs.
GG/AG). For age and APACHE II score, data is given as 25"' percentile / median / 75`' percentile. For all other variables, data is given as Ic (N survived / N total). N, number of subjects.
AA GG / AG Combined Test (N=143) (N=574) (N=717) Statistic 45.5 / 56 /
AGE 70.5 45 / 59 / 71 46 / 59 / 71 F= 1.15 d.f.=1,715 P=0.283 _59cIc ( 629c GENDER 85/143) (356/574) 62% (44l/717) X^2=0.32 d.f.=1 P=0.57 APACHEI
I 15/21/27 16/22/27 6/21.5/27 F=0.84d.f.=1,715P=0.361 SURGICA 24% ( 22c1c L 35/143) (128/574) 23%, (163/717) X^2=0.31 d.f.=1 P=0.579 SEP.ADM 8 2% 78%
IT (117/143) (445/574) 78 Ic(5621717) X^2=1.24d.f.=1 P=0.265 83,-/c 794%c SEP.ANY (119/143) (456/574) W% (575/717) X^2=I.03 d.f.=t P=0311 52c'c ( 5 0 %
SS.ADMIT 75/143) (289/574) 51 1,16, (364/717) X112=0.2 d.f.=1 P=0.653 55%,, ( 54~/(, SS.ANY 78/143) (312/574) 54cIc(39O/7l7) X^2=0d.f.=t P=0.967 TABLE 4.12 summarizes important SNP-phenotype associations foi- LNPEP rs3804I
I. Subjects with the LNPEP rs38041 AA genotype showed significantly more days alive and free of vasopressors at doses of more than 5 ug/min (0.0278) and I 5 ug/min (0.0384) and any renal dysfunction (P = 0.0475). Subjects with the LNPEP rs38041 AA genotype also showed a strong trend for more days alive and free of vasopressors (P = 0.067) and days alive and free of 21 O vasopressors at a dose of more than 2 ug/min (0.0751). These findings indicate that Cauc.asian subjects who have SIRS and have the AA genotype at LNPEP rs38041 have less need of vasopressor therapy and are a lower risk of organ dysfunction (renal).

TABLE 4.12 Days alive and free of organ dysfunction (DAF) by allele of leucyl/cystinyl arninopeptidase (LNPEP) rs38041 (GG/AG vs. AA) in a cohort of Caucasian subjects with systematic inflammatory response syndronie. Data is given as 25"' percentile / median /
75"' percentile. N.
number of subjects.
AA GG / AG Combined Test (N=143) (N=574) (N=717) Statistic PRESS.DAF 28 28 9l 26 / 28 F=3.37 d.f.=1.7I5 P=0.067 15/26/ 8.25/26 PRESS2.DAF 28 / 28 10 / 26 / 28 F=3.18 d.f.=1,715 P=0.0751 PRESS5.DAF 28 28 10 / 26 / 28 F=4.86 d.f.=1.715 P=0.0278 PRESSI5.DA 21/28/ 10.3/28 F 28 / 28 12 / 28 / 28 F=4.3 d.f.=1,715 P=0.0384 ANYREN.DA 9/ 28 / 2/ 24 /
F 28 28 3/25/28 F=3.94d.E=1,715P=0.0475 Arginine Vasopressin (AVP) 2.2.1 AVP rs1410713 2.2.1.1 Systematic Inflammatorv Response Syndrome - Caucasians TABLE 4.13 summarizes the baseline chai-acteristics (age, gender, APACHE 11 score, medical vs.
surgical diagnosis, sepsis upon admission, ~epsis anytime, septic shock upon admission and septic shock anytime) of 717 Caucasian SIRS subjects who were successfully genotyped at AVP
rsL410713. No sionificant differences were detected between the genotype groups on admission to the ICU.

TABLE 4.13 Baseline characteristics of a cohoi-t of Caucasian Subjects with systematic inflammatory response syndrome by genotype of Arginine Vasopressin (AVP) rs 1410713 (AA vs. CC/AC).
For age and APACHE II score, data is given as 25`" percentile / median / 75"' percentile.
For all other variables, data is aiven as rk (N survived / N total). N, number of subjects.
AA CC / AC Combined Test (N=49) (N=668) (N=717) Statistic AGE 48/59/74 45/59/70 46/59/71 F=1.01d.f.=1,715P=0.315 GENDER 5 I cIc ( 25149) 629c (416!668) 62cIc (441/717) X^2=2.44 d.f.=1 P=O. l APACHEII 16 / 23 / 28 l6 / 22 / 27 16 / 21.5 / 27 F=0.25 d.f.=1,715 P=0.617 SURGICAL 18cIc (9/49) 23cIc (155;668) 23cIc (164/717) X^2=0.61 d.f.=1 P=0.437 SEP.ADMI
T 82~/c ( 40/49) 78% (523/668) 79 Ic (563(717) X^2=0.3 d.f.=l P=0.583 SEP.ANY 82cIc ( 40/49) 80% (536/668) 80% (576/717) X^2=0_06 d.f.=1 P=0.813 SS.ADMIT 47% ( 23/49) 5190 (343/668) 51% (366/717) X^2=0.36 d.f.=I P=0_55l SS.ANY 49c1c ( 24/49) 55cc (367/668) 55 Ic (391/717) X^2=0.65 d.f.=1 P=0.419 2O Figure 2 and TABLE 4.14 summarize important SNP-phenotype associations for AVP
rs 1410713. Subjects in the AVP rs 1410713 CC/AC genotype group had significantly increased survival (P = 0.0140), significantly more da\rs alive (P = 0.0149) and significantly more days alive and free of neurological dysfunction (P = 0.0482), coagulation dysfunction (P
= 0.0167), INR > 1.5 (P=0.0108), acute renal dysfunction (P = 0.0414), acute hepatic dysfunction (P
= 0.0218) and any hepatic dysfunction (P = 0.0175). The AVP rs 1410713 AA group also showed a strong trend for fewer days alive and free of inotropes (P=0.0709). These findings indicate that Caucasian subjects with SIRS and either the AVP rs 1410713 CC or AC genotype have a lower risk of orQan dysfunction (neurological, coagulation, renal and hepatic).

TABLE 4.14 Days alive and free of organ dysf'unction (DAF) by genotype of Arginine Vasopressin (AVP) i-s1410713 (AA vs. CC/AC) in a cohort of Caucasian subjects with systematic inflammatory i-esponse syndrome. For all variables besicles 28-day survival, data is given as 25'' percentile /
median / 75"' percentile. For 28-day survival, data is given as ~'lc (N
survived / N total). N, nurnber of sub'ects.
AA CC / AC Combined Test (N=49) (N=668) (N=717) Statistic SURVIVAL 53,-1( ( 26/49) 70% (46"1/668) 69,-/c (493/717) X^2=6.03 d.f.=1 P=0.0140 DA 6 1 28 / 28 15 / 28 / 28 12 / 28 / 28 F=5.96 d.f.=1,715 P=0.0149 tN'o.DAF 6/28/28 13.8/28/28 11.3/28/28 F=3.27d.f.=1,715P=0.0709 CNS.1)nF 2/ 22 / 28 8.75 / 27 / 28 7.25 / 27 / 28 F=3.91 d.f.=1.715 P=0.0482 c'oAG.I?AF 3/ 20 / 28 10 / 28 / 28 8.25 / 28 / 28 F=5.75 d.f.=1.715 P=0.0167 INR.DAF 2/ 15/28 7/27/28 7/27/28 F=6.53 d.f.=1.715 P=0.0108 ACR>;.DAF 2/ 16/28 5.75/27/28 5/27/28 F=4. 18 d.f.= 1,715 P=0.0414 ACHEI'.nnF 6 22 / 28 8.75 / 28 / 28 8/ 28 / 28 F=5.28 d.f.=l,715 P=0.0218 :vNrHEI'.DAF 4/ 20 / 28 7/ 28 / 28 7/ 28 / 28 F=5.67 d.f.=1,715 P=0.0175 2.2.1.2. Sepsis - Caucasians TABLE 4.15 summarizes the baseline characteristics (age, gender, APACHE II
score, niedical vs.
surgical diagnosis and shock upon admission and septic shock anytime) of 564 Caucasian sepsis subjects who were successfully genotyped at AVP rs1410713. No significant differences, othei:-than a small gender difference, were detected between the genotype groups on admission to the ICU.
TABLE 4.15 Baseline chai-acteristics of a cohort of Caucasian Subjects with sepsis by genotype of Arginine Vasopressin (AVP) rs1410713 (AA vs. CC/AC). For age and APACHE II score, data is given as 25`1' percentile / median / 75'i' percentile. For all other variables, data is given as ~Ie (N survived / N
total). N, number of subjects.
AA CC / AC Combined Test (N=40) (N=524) (N=564) Statistic AGE 48 / 60.5 / 73.3 46 / 59 / 71 47 / 59 / 72 F= 1.26 d.f.=1,562 P=0.262 GENDER 48clc ( 19/40) 65% (338;524) 63cIc (357/564) X^2=4.63 d.f.=1 P=0.0315 APACHEII 16/23.5/28.3 17/23/28 17/22/28 F=0.13d.E=1.562P=0.71.5 SURGICAL 18% (7/40) 23% (120/524) ?3%c (127/564) X^2=0.62 d.f.= I P=0.431 SS.ADMIT 57% ( 23/401 65% (343i524) 65% (366/564) X^2=1.03 d.f.=l P=0.309 ~ SS.ANY 160% ( 24/40) 69~Ic (362/524) 68% (386/564) X^2=1.42 d.f.=1 P=0.23"
Figure 3 and TABLE 4.16 summarize important SNP-phenotype associations for AVP
rs 1410713. Subjects with either the AVP rs 1410713 CC or AC genotype had significantly ineT-eased survival (P = 0.0325), significantly more days alive (P = 0.0314) and significantly more days alive and free of acute renal dysfunction (P = 0.0388). Subjects with either the AVP
rs 1410713 CC or AC genotype also had a strong trend for more days alive and free of coagulation dysfunction (P = 0.0706), acute hepatic dysfunction (P = 0.0783) and any hepatic dysfunction (P =
0.0627). These findings indicate that Caucasian sepsis subjects who have either the CC or AC
genotype at AVP rs1410713 have a lower risk of organ dysfunction (coagulation, renal and hepatic).
TABLE 4.16 Days alive and fi-ce of organ dysfunction (DAF) by genotype of Arginine Vasopressin (AVP) rs1410713 (AA vs. CC/AC) in a cohort of Caucasian subjects with sepsis. For all variables besides 28-day survival, data is given as 2~" percentile / median / 75"' percentile. For 28-day survival, data is griven as %(N survived / N total). N, number of subjects.
AA CC / AC Combined Test (N=40) (N=524) (N=564) Statistic SURVIVAL 529c ( 21/40) 69% (361/524) 68% (382/564) X^2=4.57 d.f.=l P=0.0325 DA 6.75/28/28 15.75/28/28 15/28/28 F=4.65d.f.=1.562P=0.0314 COAG.DAF 4/ 22 / 28 I I/ 28 / 28 10 / 28 / 28 F=3.28 d.f.= I.562 P=0.0706 1.75 / 13.50 /
INR.DAF 28 8.75 / 27 / 28 8/ 27 / 28 F=7.7 d.f.=1.562 P=0.00571 ACRF.DAF 2 / 15.5 / 28 6/2) 6 / 28 6 / 26 / 28 F=4.29 d.f.=1.562 P=0.0388 ANYREN.D
AF 1.5/15.5/28 4/24/28 3/24.5/28 F=2.7d.f.=1,562P=0.10 1 ACHEP.I)A
F 6.75/23/28 9/28/28 9/28/28 F=3.11 d.f.=1.562P=0.0783 ANYHEP.D
AF 6/ 21 / 28 8/ 28 / 28 8/ 28 / 28 F=3.48 d.f.= I.562 P=0.0627 2.2.1.3 Septic Shock - Caucasians TABLE 4.17 summarizes the baseline characteristics (age, gender, APACHE II
score and med ical ?U vs. sur11ical diagnosis) of 366 Caucasian septic shock subjects who were successfully genotyped at AVP rsl4107l3. No significant differences were detected between the genotype groups on admission to the ICU.

TABLE 4.17 Baseline characteristics of a cohort of Caucasian Subjects with septic shock by genotype of Arginine Vasopi-essin (AVP) rs1410713 (AA vs. CC/AC). For age and APACHE II
score, data is given as 25''' percentile / median / 75'j' percentile. For all other variables, data is given as % (N
survived / N total). N, number of subjects.

AA CC / AC Combined Test (N=23) (N=343) (N=366) Statistic AGE 50/67/75.5 48/62/72 48/62/73 F=1.16d.f.=1,364P=0.283 GENDER 43,-/c ( 10/23) 62 k (214/343) 61 k (224/366) X^2=3.25 d.f.=1 P=0.0716 APACHEII 23.5 / 26 / 31 19.5 / 24 / 30 19 / 24 / 30 F=0.97 d.f.=1,364 P=0.324 SURGICAL 139c (3/23) 25~Ic ( 87/343) 259c ( 90/366) X^2=1.76 d.f.=1 P=(l 184 Figure 4 and TABLE 4.18 summarize important SNP-phenotype associations for AVP
rs 1410713. Subjects with either the AVP rs 1410713 CC or AC genotype had significantly increased survival (P = 0.0269), significaritly more days alive (P = 0.0402) and significantly more days alive and ti-ee of 4 of 4 SIRS criteria (P = 0.0445), acute renal dysfunction (P = 0.0373) and INR>1.5 (P=0.00816). Subjects with either the AVP rs1410713 CC or AC genotype also had a stronQ trend for moi-e days alive and free af vasopressors at doses of more than 2 ug/min(P =
0.0982) and 5 ug/min (P = 0.0982), inotropes (P = 0.0962), coagulation dysfunction (P = 0.0931), any renal dysfunction (P = 0.0744) and any hepatic dysfunction (P = 0.0619).
These findings iO indicate that Caucasian septic shock subjects, who have either the CC or AC
genotype at AVP
rs 1410713 have less need of vasopressor, and inotrope therapy, have less severe SIRS and have a lowei- risk of organ dysfunction (coagulation, renal and hepatic).

TABLE 4.18 Days alive and free of organ dysfunction (DAF) by genotype of Arginine Vasopressin (AVP) rs1410713 (AA vs. CC/AC) in a cohort of Caucasian subjects with septic shock.
For all variables besides 28-day survival, data is given as 25`1' percentile / median / 75"' percentile. For 28-day survival, data is given as ~'Ic (N survived / N total). N. number of subjects.
AA CC / AC Combined Test (N=23) (N=343) (N=366) Statistic SURVIVAL 39% (9/23) 62c10 (2 14/343) 6117c, (223/366) X^2=4.9 d.f.=1 P=0.0269 DA 6/ 15/28 9.5/28/28 9/28/28 F=4.24d.f.=1.364P=0.0402 PRESS.DAF 2/9 / 25 7/ 23 / 26 5.75 / 23 / 26 F=2.96 d.f.=1.364 P=0.086 PRESS2.DAF 2/9 / 25 7 / 23 / 26 5.75 / 23 / 26 F=2.75 d.f.=1.364 P=0.0982 PRESS5.DAF 2 / 10 / 25 7.5 / 24 / 27 6/ 24 / 27 F=2.75 d.f.=1,364 P=0.0982 INO.DAF 6/ 15 / 28 8/ 28 / 28 7/ 28 / 28 F=2.78 d.f.=1.364 P=0.0962 MSIRS4.DAF 3.5 / 1 I/ 26.5 7 / 24 / 27 7 / 23.5 / 27 F=4.06 d.f.= I,364 P=0.0445 CSIRS4.DAF 4.5 / I l/ 26.5 8/ 25 / 27 7/ 24 / 27 F=3.93 d.f.=1.364 P=0.048 1 COAG.DAF 4/ 15 / 28 H/ 26 / 28 6/ 25 / 28 F=2.83 d.f.=1,364 P=0.0931 INR.DAF 0/7 / 26 6/ 23 / 28 5/ 24 / 28 F=7.08 d.f.=1,364 P=0.00816 ACRF.DAF U/ 10 / 27 4/ 22 / 28 3/ 22 / 28 F=4.37 d.f.=l .364 P=0.0373 ANYREN.DA
F 0/ 10/27 3/ 19/28 2.75 / 19.5/28 F=3.2d.f.=1.364P=0.0744 ANYHEP.DA
F 5/ 12 / 26 6/ 28 / 28 5.75 / 26.5 / 28 F=3.51 d.f.=1,364 P=0.0619 2.2.2 AVP rs857240 2.2.2.1 Sepsis - Caucasians TABLE 4.19 gives the baseline characteristics (age, gender, APACHE II score, medical vs.
surgical diagnosis, shock upon admission and septic shock anytime) of 573 Caucasian Subjects with sepsis who were successfully genotyped at AVP rs857240. No significant differences were detected between the genotype groups on admission to the ICU.
'TABLE 4.19 Baseline characteristics of a cohort of Caucasian Subjects with sepsis by genotype of Arginine Vasopressin (AVP) rs857240 (CC vs. CT/TT). For age and APACHE II score, data is given as 25`h percentile / median / 75'f' percentile. For all other variables, data is given as k (N survived / N
total). N, number of sub'ects.
CC CT / TT Combined Test (N=471) (N=102) (N=573) Statistic AGE 46 / 59 / 7 1 43.3 / 55.5 / 71 47 /_59 / 72 F=0.57 d.f.=1,571 P=0.449 GENDER 63 lc (299/471) 651'Ic ( 66/102) 64% (365/573) X^2=O.05 d.t'.=1 P=0.816 APACHEII 17 / 23 /?8 15.3 / 21 / 27 17 / 22 /28 F=2.84 d.f.=1,571 P=0.0926 SURGICAL 22% (103/471) 25~(,, (?6/102) Z3~Ic (129/573) X^2=0.6 3 d.f.=1 P=0.427 SS.ADMIT 64% (303/471) 691I( ( 70/102) 651-7c (373/573) X^2=0.68 d.f.=1 P=0.409 SS.ANY 68elc (32U471 ) 72c/(- ( 73/102) 69rlc (394/573) X^2=0.46 d.f.=1 P=0.5 TABLE 4.20 summarizes important SNP-phenotype associations for AVP rs857240.
Subjects with either the AVP rs857240 TT or CT ge.notype had a trend for increased survival (P = 0.0697), significantly more days alive (P = 0.0398), significantly more days alive and free of inotropes (P =
0.0457). coagulation dysfunction (P = 0.0382). INR> 1.5 (P=0.036), acute renal dysfunction (P =
0.0238). any renal dysfunction (P = 0.0087), renal support (P = 0.0126), acute hepatic dysfunction (P = 0.0292) and any hepatic dysfunction (P = 0.0251). Subjects with either the AVP rs857240 TT
or CT genotype also had a strong trend for more days alive and fi-ee of 4 of 4 SIRS criteria (P =
0.0555). These findings indicate that Caucasian subjects who have sepsis who carry either the ?O AVP rs857240 TT or CT genotype at AVP rs857240 have less need of inotrope therapy, have less severe SIRS, and have a lower i-isk of orgari dysfunction (coagulation, renal and hepatic).
TABLE 4.20 Days alive and free of organ dysfunction (DAF) by genotype of Arginine Vasopressin (AVP) ?5 rs857240 (CC vs. CT/TT) in a coho--t of Caucasian subjects with sepsis. For all variables besides 28-day survival, data is given as 25`' percentile / median / 75" percentile.
For 28-day survival, data is ~4iven as ~~c (N survived / N total). N, number of subjects.
CC CT / TT Combined Test (N=471) (N=102) (N=573) Statistic SURVIVAL 66% (312/471) 75%,, ( 77/102) W/c (389/573) X^2=3.29 d.f.=1 P=0.0697 F=4.24 d.f.=1.571 DA 1I/28/28 28/28/28 I5 /28/28 P=O.O398 F=4.0I d.f.=1.571 INO.DAF i l/ 28 / 28 25 /?8 / 28 12.3 / 28/ Z8 P=0.0457 MSIRS4.DAF 8/ 25 / 28 20.3 /?6 / 28 1 1/?5 / 28 F=3.68 d.f.=L.571 P=0.0555 F=3.15 d.f.= L.57 I
CSIRS4.DAF 9/ 26 / 28 2 I/ 26 / 28 1 1/ 26 / 28 P=0.0764 F=4.32 d.f.=1.571 COAG.DAF 9.5 / 28 / 28 21 / 28 / 28 10 / 28 / 28 P=0.0382 INR.DAF 7/ 27 / 28 17.3 / 27 / 28 8/ 27 / 28 F=0.84 d.f.=1.571 P=0.136 F=5.14 d.f.=1.571 ACRF.DAF 4.5 / 25 / 28 10,3 / 28 / 28 6 I 26 / 28 P=0.0238 ANYREN.DA F=6.94 d.f.=1.57I
F 3 / 22 / 28 10 /28,1 28 3/24.5/28 P=0.00868 RENSUP.DA F=6.26 d.f.=1.571 F 5/28128 15/28/28 6/28/28 P=0.0126 F=4.78 d.f.=1.571 ACHEP.DAF 7.5/28/28 19.3/213/28 9/28/28 P=0.0292 ANYHEP.DA F=5.04 d.f.=1.571 F 6/28/28 18.3/28/28 8/28/28 P=0.0251 2.2.2.2 Septic Shock - C'aucasians TABLE 4.21 summarizes the baseline characteristics (age. gender, APACHE II
score and me(lical vs. surgical diagnosis) of 373 Caucasian septic shock subjects who were successfully genotyped at AVP rs857240. No significant differences were detected between the genotype groups on admission to the ICU.

TABLE 4.21 Baseline characteristics of a cohort of Caucasian Subjects with septic shock by genotype of Arginine Vasopressin (AVP) rs857240 (CC vs. CT/TT). For age and APACHE II
score, data is given as 25'' percentile / median / 75"' percentile. For all other variables, data is given as %(N
survived / N total). N, number of subjects.
CC CT / TT Combined Test (N=303) (N=70) (N=373) Statistic AGE 48 / 61 / 72 46.3 / 59 / 73.8 48 / 62 / 73 F=0 d.f.=1. 371 P=0.96 GENDER 62% (187/303) 61% ( 43!70) 62% (230/373) X^2=0 d.f.=I P=0.964 APACHEII 20.5 / 25 / 30 17.5 / 24 / 28 19 / 24 / 30 F=2.3 d.f.=1.371 P=0.130 SURGICAL 2Yk ( 70/303) 31% ( 22170) 25% ( 92/373) X^22.12 d.f.=1 P=0.145 TABLE 4.22 summarizes important SNP-phenotype associations for AVP rs857240.
Subjects with eithei- the AVP rs857240 TT or CT genotype had a trend for increased survival (P = 0.091 i, significantly more days alive (P = 0.0467). >ignificantly more days alive and free of inotropes (P =
0.0416), acute renal dysfunction (P = 0.0114), any renal dysfunction (P =
0.0052), renal supporl (P
= 0.0266), acute hepatic dysfunction (P = 0.0190) and any hepatic dysfunction (P = 0.01 15).
Subjects with either the AVP rs857240 TT or CT genotype also had a strong trend for fewer days alive and free of vasopressors at doses of more than 5 ug/min(P = 0.0895) and 15 ug/min (P =
0.0747) and days alive and free of 4 of 4 SIRS criteria (P = 0.0771). These findings indicate that Caucasian subjects with septic shock who had either the TT or CT genotype at AVP rs857240 have less need of vasopressor and inotrope therapy, have less SIRS, and have a lower risk of organ dysfunction (renal and hepatic).

TABLE 4.22 Days alive and free of organ dysfunction (DAF) by genotype of Arginine Vasopressin (AVP) rs857240 (CC vs. CT/TT) in a cohort of Caucasian subjects with septic shock.
For all variables besides 28-day survival, data is given as '25`" percentile / median / 75`h percentile. For 28-day survival, data is Eiven as ~Ic (N survived / N total). N, number of subjects.
CC CT / TT Combined Test (N=303) (N=70) (N=373) Statistic 59%
SURVIVAL (179/303) 70% ( 49/70) 61% (228/373) X^2=2.86 d.f.=l P=0.091 DA 8/ 28 / 28 22.5 / 28 / 28 9/ 28 / 28 F=3.98 d.t.=1.371 P=0.04-67 PRESS5.DAF 5/ 23 / 27 16.5 / 25 / 27 6/ 24 / 27 F=2.9 d.f.=1.371 P=0.0895 PRESS15.DAF 6/ 26 / 28 19.8 / 27 / 28 8/ 26 / 28 F=3.2 d.f.=1,37I P=0.0747 INO.DAF 6/ 27 / 28 20.3 / 28 / 28 7/ 28 / 28 F=4.18 d.f.=1,371 P=0.0416 MSIRS4.DAF 6/ 23 / 27 15.3 / 25 / 27 7/ 23.5 / 27 F=3.14 d.f.=1,371 P=0.0771 ACRF.DAF 3/ 20 / 28 10 / 27.5 / 28 3 / 22 / 28 F=6.47 d.f.=1.371 P=0.O114 ANYREN.DAF 1.50 / 18 / 28 9.25 / 27 / 28 2.75 / 19.50 / 28 F=7.91 d.f.= l.37 I
P=0.00517 RENSUP.DAF 3/ 24 / 28 12.5 / 28 / 28 4/ 25 / 28 F=4.95 d.f.=1.371 P=0.0266 ACHEP.DAF 5.5 / 27 / 28 17.3 / 28 / 28 6/ 28 / 28 F=5.55 d.f.=1,371 P=0.0190 ANYHEP.DAF 5/ 24 / 28 16.25 / 28 / 28 5.75 / 26.5 / 28 F=6.45 d.f.=1.371 P=0.01 15 IO
2.2.3 AVP rs857242 2.2.3.1 Systematic Inflammatorii Response Syndrome - Caucasians TABLE 4.23 summarizes the baseline characteristics (age, gender, APACHE II
score, medical vs.
surgical diagnosis. sepsis upon admission, sepsis anytime, septic shock upon admission and septic shock anytime) of 722 Caucasian systematic inflammatory response syndrome subjects who were successfully genotyped at AVP rs857242. Significant differences were detected between the genotype groups on admission to the ICU (APACHE II).

TABLE 4.23 Baseline characteristics of a cohort of Caucasian Subjects with systematic inflammatory response syndrome by genotype of Arginine Vasopressin (AVP) rs857242 (AC/AA vs. CC).
Foi- age and APACHE II score, data is given as 25 ' percentile / median / 75"' percentile.
For all other variables, data is given as ck (N survived / N total). N, number of subjects.
AC / AA CC Combined Test (N=154) (N=568) (N=722) Statistic AGE 43.3 / 56 / 69.8 45 / 59.5 / 71 46 / 59 / 71 F= 1.93 d.f.=1,720 P=0.165 GENDER 64~k ( 98/154) 61 lc (349i568) 6?QIc (447/722) X^2=O.25 d.f.=1 P=0.619 F=4.63 d.f.=l.720 APACHEII 15/20/26 16/22/28 16/21.5/27 P=0.0317 SURGICAL 25%, ( 39/154) 22% (124/568) 23% (163/722) X^2=0.85 d.f.=1 P=0.358 SEP.ADMI
T 73c/c ( 1 12/154) 801:/c (454/568) 78%, (566/722) X^2=3.71 d.f.=l P=0.0541 SEP.ANY 74% (114/154) 82% (4651568) 80 Io (5791722) X^2=4.69 d.f.=1 P=0.0304 SS.ADIlIIT 49% ( 76/154) 51cIc (292/568) 51% (368/722) fX^2=p.21 d.f.=i P=0.05 SS.ANY 53`~0 ( 8?1t541 55 1, (312(5681 551", (394/722) X^2=0.14 d.C=1 P=0.71 Figure 5 and TABLE 4.24 summarize iniportant SNP-phenotype associations for AVP rs85 7242.
Subjects with either the AVP rs857242 AC or AA genotype had significantly increased survival (P
= 0.0108), significantly more days alive (P = 0.0032) and significantly more days alive and free of vasopressors at doses of more than 5 ug/niin (P = 0.0361) and 15 ug/min (P =
0.0026), days alive and fi-ee of inotropes (P = 0.0394), 3 of 4 SIRS criteria (P=0.0 170), 4 of 4 SIRS criteria (P =
0.0043), neurological dysfunction ( P= 0.033), coagulation dysfunction (P <
0.001), acute ren.31 dysfunction (P = 0.0341), any renal dysfunction (P = 0.0127), renal support (P
= 0.0017), acw.e hepatic dysfunction (P = 0.0013) and any hepatic dysfunction (P = 0.0021). The AVP rs8572-L2 AC ol- AA individuals also showed a strong trend for days alive and free of vasopressors (P=0.0752). days alive and fl-ee of vasopressors at a dose of more than 2 uQ/min (P=0.0524), =, of 4 SIRS criteria (P=0.059), INR>1.5 (P=0.0679). These findings indicate that Caucasian subjects with SIRS who had either the AC or AA 2enotype at AVP rs857242 have less need of vasopressor and inotl-ope thel-apy, have less severe SIRS and have a lower risk of organ dysfunction (neurological, coagulation, renal and heparic).
TABLE 4.24 Days alive and fi-ee of organ dysfunction (DAF) by genotype of Arginine Vasopressin (AVP) rs857242 (AC/AA vs. CC) in a cohort of Caucasian subjects with systematic inflammatory response syndrome. For all variables besides 28-day survival, data is given as 25'h percentile /
median / 75'h pel-centile. For 28-day survival, data is given as % (N survived / N total). N, number of subjects.
AC / AA CC Combined Test (N=t54) (N=568) (N=722) Statistic SURVIVAL 77% (119/154) 67% ( 378/568) 69% (497/722) X^2=6.49 d.f.=1 P=0.0108 DA 28/28/28 9.75/28/28 12/28/2 F=8.74d.f.=1.720P=000321 PRESS.DAF 18.3 / 26 / 28 7/ 26 / 28 9/ 26 / 28 F=3.18 d.f.=1.720 P=0 0752 PRESS2.DAF 18.3 I 26 / 28 7/ 26 / 28 10 / 26 / 28 F=3.78 d.f.=1.720 P=0.0524 PRESS5.DAF 20.25 / 27 / 28 7.75 / 26 / 28 10 / 26 / 28 F=4.41 d.f.=1.720 P=0.0361 PRESS15.DAF 25 f 28 I 28 9/ 28 I 28 12 / 28 / 28 F=9.16 d.f.= 1.720 P=0.00256 INO.DAF 25 / 28 / 28 8 J 28 1 28 11.3 I 28 / 28 F=4.26 d.f.=1.720 P=0.0394 MSIRS2.DAF 1 l6 / 22 0/4 / 20.3 0/5 / 21 F=3.58 d.f.=1.720 P=0.059 MSIRS3.DAF 7.25 / 22 / 26 2 / 19 / 26 3/ 19 / 26 F=5.72 d.f.=1.720 P=0.0170 MS1RS4.DAF 19.50 / 27 / 28 7 / 26 / 28 9.25 / 26 / 28 F=8.19 d.f.=1.720 P=0.00434 CSIRS2.DAF 1 15.5 l 22 O /4 / 2C 0/5 / 20 F=3.23 d.f.=1.720 P=O.O726 CSIRS3.DAF 8/ 22 l 26 3/ 19 l 26 4/ 20 / 26 F=5.84 d.f.=1.720 P=O.'.)159 CSIRS4.DAF 21 / 27 / 28 8/ 26 / 28 10 / 26 / 29 F=8.22 d.f.=1,720 P=O.,)0427 CNS.DAF 18.25 / 27 / 28 5.75 / 27 - / 28 7.25 / 27 / 28 F=4.56 d.f.=1.720 P=0.033 COAG.DAF 21.25 / 28 / 28 7 / 28 / 28 8.25 / 28 / 28 F=1 1.6 d.f.=1.720 P<O.()Ol INR.DAF 15/28/28 5/27/28 7 / 27 / 28 F=3.34d.f.=1.720P=0.0679 ACRF.DAF 10/28/28 4/26/28 5/27/28 F=4.51 d.f.=1,720P=0.0341 ANYREN.DAF 9/ 28 / 28 2/ 23 / 28 3 / 25 / 28 F=6.25 d.f.=1.720 P==0.0127 RENSUP.DAF 15/28/28 4/28/28 5/28/28 F=9.92d_f.=1.720 P=0.00171 ACHEP.DAF 21 / 28 / 28 6.75 / 28 / 28 8 / 28 / 28 F=10.4 d.f.=1,720 P=0.001 32 ANYHEP.DAF 18.8 / 28 / 28 6/ 28 I 28 7/ 28 / 28 F=9.52 d.f.=1,720 P=0.002I I
2.2.3.2 Sepsis - Caucasians TABLE 4.25 gives the baseline characteristics (age, gender, APACHE II score, medical vs.
surgical diagnosis, shock upon admission and septic shock anytime) of 567 Caucasian sepsis subjects who were successfuLly genotyped at AVP rs857242. No significant differences were detected between the genotype groups on admission to the ICU.

TABLE 4.25 Baseline characteristics of a cohort of Cau.casian Subjects with sepsis by genotype of Arginine Vasopressin (AVP) rs857242 (AC/AA vs. CC). For age and APACHE II score, data is given as 25'h percentile / niedian / 75"' percentile. For all other variables, data is given as ~Ic (N survived / N
total). N. number of subjects.
AC / AA CC Combined Test (N=112) (N=455) (N=567) Statistic AGE 44 / 56/ 69.3 46 I 60l 71 47 / 59 / 72 F=1.05 d.f.=1.565 P=0.306 GENDER 63% ( 71/I 12) 64 Ic (289/455) 631c (360/567) X^2=0 d.f.=l P=0.98 APACHEII 1 6 / 2 1 / 27 17.5 / 23 l 28 17 J 72 / 28 F=2.8 d.f.=1.565 P=0.0945 SURGICAI. 27% 301112) 21 cgc ( 90/455) 22% (126/567) X^2=1.68 d.f.=1 P=0.I95 SS.ADMIT 68((- ( 76/112) 641-/c (292/455) 65c1c (368/567) X^2=0.53 d.f.=1 P=0.465 SS.ANY 72% ( 81/1 12) 68% ( i031455) 69% (389/567) X^2=0.89 d.f.=I P=0.34-1 Figure 6 and TABLE 4.26 summarize important SNP-phenotype associations for AVP
rs857242.
Subjects with either the AVP rs857242 AC or AA genotype had significantly increased survival (P
= 0.0220). significantly more days alive (P = 0.0059) and significantly days alive and free of vasopressors at a dose of more than 15 ug/min (P = 0.0078), 3 of 4 SIRS
criteria (P=0.0219), 4 of 4 SIRS criteria (P = 0.0058), coagulation dysfunction (P = 0.0012), acute renal dysfunction (P
0.01 16). any renal dysfunction (P = 0.0089), renal support (P = 0.0104), acute hepatic dysfunction ( P= 0.0013) and any hepatic dysfunction (P = 0.0014). Subjects with either the AVP rs857242 AC or AA genotype also had a strong trend for more days alive and free of inotropes (P = 0.0646) INR>1.5 (P=0.0636) and neurological dysfi.inction (P = 0.0803). These findings indicate that Caucasian subjects with sepsis who had either the AVP rs857242 AC or AA
genotype at AVP
rs857242 have less need of vasopressor and inotrope therapy, have less severe SIRS and are have a lower risk of organ dysfunetion (neurological, coagulation, renal and hepatic).

TABLE 4.26 Days alive and free of organ dysfunction (DAF) by genotype of Arginine Vasopressin (AVP) rs857242 (AC/AA vs. CC) in a cohort of Caucasian subjects with sepsis. For all variables besides 28-day survival, data is given as 25" percentile / median / 75'' percentile.
For 28-day survival, data is given as c (N siirvived / N total). N, number of subjects.
AC / AA CC Combined Test (N=112) (N=455) (N=567) Statistic SURVIVAL 77% ( 86/1 12) 65% (298/455) 68% (384/567) X^2=5.24 d.f.=1 P=0.0220 DA 28 / 28 / 28 10 / 28 / 28 15 / 28 / 28 F=7.62 d.f_=1.565 P=0.0!)595 PRESS15.DAF 24.8 / 28 / 28 9.5 / 27 / 28 13 / 27.5 / 28 F=7.13 d.f.=1.565 P-0.00779 INO.DAF 24.8 / 28 / 28 9/ 28 / 28 12.3 / 28 / 28 F=3.43 d.f.=1,565 P=0.0646 MSIRS3.DAF 8/ 19 / 26 2/ 16 ; 25 3/ 17 / 25 F=5.29 d.f.=1.565 P=0.0219 MSIRS4.DAF 19 / 27 / 28 8 / 25 i 28 1 1/ 25 / 28 F=7.66 d.f.=1.565 P=0.00582 CSIRS3.DAF 8 / 2 1 / 26 3 / 1 7 i 25 4/ 19 /25 F=5.32 d.f.=1,565 P=O.O:? 14 CSIRS4.DAF 21 / 27 / 28 8/ 25 i 28 1 1/ 26 / 28 F=6.87 d.f.=1.565 P=0.00902 CNS.DAF 18 I 26 / 28 7/ 26 / 28 8/ 26 / 28 F=3.07 d.f.=1.565 P=0.0803 COAG.DAF 22 / 28 / 28 8.5 / 28 / 28 l0 / 28 / 28 F=10.6 d.f.=1,565 P=0.00123 INR.DAF 15.8 / 27.5 / 28 6/ 26 /'8 8/ 27 / 28 F=3.46 d.f.=1,565 P=0.0636 ACRF.DAF I I/ 28 / 28 4/ 25 / 28 6/ 26 / 28 F=6.42 d.f.=1565 P=0.01 16 ANYREN.DAF 1O / 28 / 28 3/ 22 / 28 3/ 24.5 / 28 F=6.9 d.f.=1565 P=0.00887 RENSUP.DAF 15 / 28 / 28 5 28 / 28 6/ 28 / 28 F=6.61 d.f.=1.565 P=0.0104 ACHEP.DAF 21.8 / 28 / 28 7 28 / 28 9/ 28 / 28 F=10.4 d.f.=1565 P=0.001 31 ANYHEP.DAF 21 / 28 / 28 6/28/28 8/28/28 F=10.2 d.f.=1.565 P=0.00145 ti 2.2.3.3 Septic Shock - Caucasians TABLE 4.27 summarizes the baseline characteristics (age, gender, APACHE II
score and me(lical vs. surgical diagnosis) of 368 Caucasian septic shock subjects who were successfully genotyped at AVP rs857242. No significant differences were detected between the genotype groups on admission to the ICU.
TABLE 4.27 Baseline characteristics of a cohort of Caucasian Subjeets with septic shock by genotype of Arginine Vasopressin (AVP) rs857242 (A(-'/AA vs. CC). For age and APACHE 11 score, data is I5 ~iven as 25"' percentile / median / 75'" percentile. For all other variables, data is given as I/( (N
survived / N total). N, number of subects.
AC / AA CC Combined Test (N=76) (N=292) (N=368) Statistic AGE 44.8/57/71 48/63/"72 48/62/73 17=1.28d.f.=1.366P=0.258 GENDER 59% ( 45/76) 62 Ic ( 181/292) 61~Io (226/368) X^2=0.2 d.f.=1 P=0.658 APACHEII 17 / 24 / 28. 3 20.8 / 25 / 3 19 / 24 / 30 F=2.52 d.f.=1.366 P=0.1 13 SURGICAL 329c ( 24/76) 22% ( 65,292) 24~Ic ( 89/368) XA2=2.86 d.f.=1 P=0.091 Figure 7 and TABLE 4.28 summarize important SNP-phenotype associations for AVP
rs857242.
Subjects with either the AVP rs857242 AC or AA genotype had significantly increased surviva' (P
= 0.0466), sig7nificantly more days alive (P == 0.0129) and significantly more days alive and free of vasopressors at a dose of more than 15 ug/min (P = 0.0032) , 4 of 4 SIRS
criteria (P = 0.0146), neurological dysfunction (P = 0.0365) coagulation dysfunction (P = 0.0027), acute renal dysfunction (P = 0.0103), any renal dysfunction (P = 0.0063), renal support (P
= 0.0165), acute hepatic dysfunction (P = 0.00 13) and any hepatic dysfunction (P < 0.001).
Subjects with either the AVP rs857242 AC or AA genotype also had a strong trend for days alive and free of vasopre;sors at doses of more than 2 ug/min (P = 0.0839) and 5 ug/min (P = 0.054), INR>1.5 (P=0.0549) and inotropes (P = 0.0592). These findings indicate that Caucasian subjects with septic shock whD had either the AC or AA genotype at AVP rs857242 had less need of vasopressor, and inotrope therapy, had more sever SIRS and had a lower risk of organ dysfunction (neurological, coagulation, renal and hepatic).

TABLE 4.28 Days alive and fi-ee of organ dysfunction (DAF) by genotype of Arginine Vasopressin (AVP) rs857242 (AC/AA vs. CC) in a cohort of Caucasian subjects with septic shock.
For all variables besides 28-day survival, data is given as 25"' percentile / median / 75`1' percentile. For 28-day survival, data is given as %(N survived I:v total). N, number of subjects.
AC / AA CC Combined Test (N=76) (N=292) (N=368) Statistic SURVIVAL 71 le ( 54/76) 59% (171/292) 61 ~/c (225/368) X^2=3.96 d.f.=1 P=0.0466 DA 23. 3 l 28 / 28 7/ 28 / 28 9 l 28 / 28 F=6.25 d.t'.=1.366 P=0.0129 PRESS.DAF 13.75 / 24 / 26 4/ 22 / 26 5.75 / 23 / 26 F=2.91 d.f.=1.366 P=0.089 PRESS2.DAF 13.75 / 24 / 26 4 / 22 / 26 5.75 / 23 / 26 F=3 d.f.=1.366 P=0.0839 PRESS5.DAF 15.8 / 25 / 27 5 / 23 / 27 6 I 24 / 27 F=3.74 d.f.=1.366 P=0.054 PRESS15.DAF 21 I 27 I 28 6 I 26 / 28 8/ 26 / 28 F=8.81 d.f.=1.366 P=0.0032 INO.DAF 19.8 / 28 / 28 6/ 28 ! 28 7/ 28 / 28 F=3.58 d.f.=1.366 P=0.0592 0.75 /2.5O /
MSIRS2.DAF 17.75 0121 15 O l2 l 16 F=3.08 d.f.= 1.366 P=0.0803 MSIRS3.DAF 6.75 / 15.50 / 25 1 / l 2 I 23 2/ 13 / 23 F=4.42 d.f.=1,366 P-=0.0362 MSIRS4.DAF 14.25 / 25 / 28 5.75 / 23 / 27 7 / 23.50 / 27 F=6.02 d.f.=1366 P=0.0146 CSIRS3.DAF 6/ 16 / 25 2/ 13.5 / 23.3 3/ i4 / 24 F=3.79 d.f.=1,366 P=0.0525 CSIRS4.DAF 15.8 / 25 / 28 6/ 24 i 27 7 / 24 / 27.3 F=5.72 d.f.=1.366 P=0.0229 CNS.DAF 14.8 / 25.5 / 28 5/ 24l 28 6/ 25 / 28 F=4.41 d.t'.=I,366 P==0.0365 COAG.DAF 15 / 28 / 28 6/ 24 / 28 6/ 25 /28 F=9.15 d.f.=1.366 P==0.00266 INR.DAF 14.8/25.5/28 3/22/28 5/24/28 F=3.71 d.f.=1.366P==0.0549 ACRF.DAF 10 / 27.5 / 28 3 / 20 / 28 3/ 22 l 28 F=6.65 d.f.=I366 P==0.0103 ANYREN.DAF 9.75 / 27 / 28 2 l l8 / 28 2.75 / 19.5 / 28 F=7.55 d.f.=1.366 P=:O.00628 RENSUP.DAF 13.5 / 28 / 28 3/ 24/ 28 4/ 25 / 28 F=5.81 d.f.=1.366 P=:0.0165 ACHEP.DAF 17.5 / 28 / 28 5/ 25.5 / 28 6l 28 / 28 F=10.4 d.f.=i.366 P=0.00134 ANYHEP.DAF 16 / 28 / 28 5/ 23.50 / 28 5.75 / 26.5 / 28 F=l 1.7 d.f.=1.366 P<:0.001 Arginine Vasopressin Receptor la (AVP:RIA) 2.3.1 AVPRIA rs1495027 2.3.1.1 Septic Shock - Caucasians TABLE 4.29 gives the baseline characteristics (age, gender, APACHE II score, and medieal vs.
surgical diagnosis) of the 361 Caucasian septic shock subjects who were successfully genotyped at AV PR I A rs 1495027 (CC vs. CT/TT). No s ~gn ificant differences were detected between the two genotype groups on admission to the ICU.

TABLE 4.29 Baseline characteristics of a cohort of Caucasian Subjects with septic shock by genotype of arginine vasopressin receptor 1 a(AVPRI A) rs 1495027 (CC vs. CT/TT). For age and APACHE II
score, data is given as 25"' percentile / median / 75`h percentile. For all other variables. data is given as %(N survived / N total). N, nurnber of subjects.
CC CT / TT Combined Test (N=129) (N=232) (N=361) Statistic 48.8/61.5/
AGE 47 / 61 / 72 72.3 48 / 62 / 73 F=0.42 d.f.=1,359 P=0.516 649c GENDER 59% ( 76/129) (148/232) 62CIc (224/361) X1'2=0.84 d.f.=1 P=0.36 APACHEII 19/25/31 20/25/29 19/24/30 F=0.01 d.f.= 1,359 P=0.918 SURGICA
L 28/129) 25% ( 59/232) 24% ( 87/361) X^2=0.63 d.f.=l P=0.428 TABLE 4.30 summarizes important SNP -phenotype associations for AVPR 1 A rs 1495027.
Subjects with either the AVPR I Ai-s 1495027 CT or TT genotype had significantly more days alive and free of renal support (P = 0.0325). Subjects with either the AVPR 1 A rs 1495027 CT or TT
cyenotype also had a strong trend for more days alive and free of vasopressors at a dose of 5 uOmin (P = 0.0832) and 2 of 4 SIRS criteria (P = 0.0958). These findings indicate that Caucasian subjects with septic shock with the CT or TT genotype at AVPRIA rs1495027 have less need of vasopressors and have decreased risk of SiRS and organ dysfunetion (renal).
TABLE 4.30 Days alive and free of organ dysfunction (DAF) by genotype of arginine vasopressin receptor I a (AVPRI A) rs1495027 (CC vs. CT/TT) in a cohort of Caucasian subjects with septic shock. Data is Ljiven as 25t" ercentile / median / 75't' ercentile. N. number of subjects.
CC CT / TT Combined Test (N=129) (N=232) (N=361) Statistic PRESS5.DAF 5 / 23 / 26 H/ 24 / 27 6/ 24 / 27 F=3.02 d.f.=1.359 P=0.0832 NISIRS2.DAF 011113 0/2 / 16 0/2 / 16 F=2.99 d.f.=1,359 P=0.0845 RENSUP.DAF 3/ 18/ 28 6/ 28 / 28 4/ 25 / 28 F=4.61 d.f.=1,359 P=0.0325 2.3.2 AVPRIA rs3803107 2.3.2.1 Systematic inflammatory response syndrome - Caucasians TABLE 4.31 gives the baseline cha--acteristics (age, gender, APACHE II score, medical vs.
suraical diagnosis, sepsis upon admission, sepsis anytime, septic shock upon admission and septic shock anytime) of the 729 Caucasian SIRS subjects who were successfully genotyped (CT/TT vs.
CC) at AVPRIA rs3803107. No significant differences were detected between the two (Yenotype oroups on admission to the ICU.

TABLE 4.31 Baseline characteristics of a cohort of Caucasian Subjects with systematic inflammatory response syndrome by genotype of arginine vasopressin receptor I a (AVPRIA) rs3803 107 (CC/CT vs.
TT). Foi- age and APACHE II score, data is given as 25"' percentile / median /
75"' percentile. For all other variables, data is given as % (N survived / N total). N, number of subjects.
CC / CT TT Combined Test (N=706) (N=2:S) (N=729) Statistic AGE 44 / 58 / 71 47.5 / 61 / 69 46 / 59 / 71 F=0.01 d.f.=1,727 P=0.934 GENDER 62 Ic (435/706) 6517c ( 15/23) 6217c (450/729) X^2=0.12 d.f.=1 P=0.726 APACHEII 1 6 / 22 / 27 1 9 / 25 / 27.5 16 / 21.5 / 27 F=2 d.f.=1.727 P=0.157 SURGICAL 23% ( 159/706) 2290 (5/23) 22% (164/729) X^2=O.O1 d.f.=l P=0.93 SEP.ADMIT 78% (549/706) 87% ( 20/23) 78% (569/729) X^2=1.1 d.f.=l P=0.294 SEP.ANY 80% (562/706) 87% ( 20/23) 80% (582/729) X^2=0.75 d.f.=1 P=0.387 SS.ADMIT 50% (354/706) 70e1o ( 16/23) 51~Ic (370/729) X^2=3.36 d.f.=I P=0.0667 SS.ANY 549c (380/706) 70% ( 16/23) 54r/o (396/729) X^2=2.22 d.f.=1 P=0.136 Figure 8 and TABLE 4.32 summarize important SNP-phenotype association results for AVPRI A
i-s3803107. Subjects with either the AVPF:IA rs3803107 CC or CT genotype had a strong trend for increased 28-day survival (P = 0.0709) and siQnificantly more days alive (P =
0.0468) and significantly moi-e days alive and free of vasopressors (P = 0.0270), more days alive and free of vasopressors at doses of 2 ug/min (P = 0.0286) and 5 ug/min (P = 0.0163), cardiovascular dysfunction (P = 0.0304) and respii-atory clysfunction (P = 0.0476). Subjects with either the AVPRI A rs3803107 CC or CT Qenotype also had a strong trend for more days alive and fi-ee of inotropes (P = 0.0966), 4 of 4 SIRS criteria (P = 0.0621), mechanical ventilation (P = 0.0763) and acute hepatic dysfunction (P = 0.087 1). These findings indicate that.
Caucasian subjects with SIRS
who had either the CC or CT Qenotype at AVPR I A rs3803107 have less need of vasopressors thei-apy and have decreased risk of SIRS and organ dysfunction (cardiovascular, respiratory, and hepatic).

TABLE 4.32 Days alive and free of organ dysfunction (DAF) by genotype of arginine vasopressin receptor a (AVPR I A) rs3803107 (CC/CT vs. TT) in a cohort of Caucasian subjects with systematic intlammatoiy response syndrome. For all variables besides 28-day survival, data is given as 25 i percentile / median / 75 ' percentile. For 28-day survival, data is given as %(N survived / N total).
N, number of sub' ects.
CC / CT TT Combined Test (N=706) (N=23) (N=729) Statistic 70~1c 699c SURVIVAL (493/706) 52CIo ( 12/706) (505/706) X^2=3.26 d.f.=1 P=0.0709 DA 15/28/28 4.5/28/28 12/28/28 F=3.97 d.f.=1,727 P=0.0468 ALI.DAF 5/ 24.5 / 28 2/9 / 27.5 4/ 24 / 28 F=3.41 d.f.=1,727 P=0.065I
10.3/26/
PRESS.DAF 28 3/ 22 / 26 9/ 26 / 28 F=4.9I d.f.=1.727 P=0.0270 PRESS2.DAF 1 I/ 26 / 28 3/ 22 / 26 10 / 26 / 28 F=4.81 d.f.=1,727 P=0.0286 11.3/26/
PRESS5.DAF 28 3/ 25 / 26 10 / 26 l 28 F=5.8 d.f.=1,727 P=0.0 163 INO.DAF l4 / 28 / 28 4/ 23 / 28 1 l.3 / 28 / 28 F=2.77 d.f.=1,727 P=0.0966 3.50 / 16 /
MSIRS4.DAF 1 1/ 26 / 28 27.50 9.25 / 26 / 28 F=3.49 d.f.=1.727 P=0.062I
CSIRS4.DAF I 1/ 26 / 28 3.5 / 16 / 28 10 / 26 / 28 F=3.46 d.f.=1.727 P=0.0632 CVS.DAF 6 / 23 / 27 2.5 /8 / 24.5 5/ 23 / 27 F=4.7 d.f.=1,727 P=0.0304 RESP.DAF 1/ 21 / 27 1/6 / 20.5 l/ 20 / 26 F=3.94 d.f.=1.727 P=0.0476 PF300.DAF 0/1 / 11 0/0 /2 0/1 / 10 F=3.1 1 d.f.=1.727 P=0.0783 VENT.DAF 0/ 19 / 26 0/6 / 20.5 0/ 19 / 26 F=3.15 d.f.=1,727 P=0.0763 ACHEP.DAF 8.25 / 28 / 2 4.50 / 10 / '2 8 8/ 28 / 28 F=2.94 d.f.=1,727 P=0.0871 2.3.2.2 Systematic inflammatory response syndrome - Asians TABLE 4.33 summarizes the baseline characteristics (age, gender. APACHE II
score, medical vs.
surgical diagnosis, sepsis upon admission. sepsis anytime, septic shock upon admission and septic shock anytime) of the 108 Asian SIRS subjects who were successfully genotyped (C vs. T) at AVPR I A rs3803107. No significant diffei-ences were detected between the two allelic group~~ on admission to the ICU.

TABLE 4.33 Baseline characteristics of a cohort of Asian Subjects with systematic inflammatory response syndrome by allele of arginine vasopressin receptor la (AVPRIA) rs3803 107 (C
vs. T). For age and APACHE 11 score, data is given as 251" percentile / median / 75`' percentile. For all other variables. data is aiven as % (N survived / N total). N, number of subjects.
C T Combined Test (N=186) (N=30) (N=216) Statistic AGE 51 /68/76 58/71.5/76.8 54.5/69/76 F=0.57d.f.=l.2141'=0.451 GENDER 61 cIc (1 14/ 186) 47% ( 14/30) 59c1o (128/216) X^2=2.29 d.f.= I P=O.

APACHEII 17 / 22.5 / 29 19/25.5/33.5 17/23/30 F=3.12 d.f.=1.214 P=0.0787 SURGICAL 24%c ( 44/186) 139c 4/30) 22% ( 48/216) X^2=1.59 d.f.=1 P=0.207 SEP.ADMIT 77c1o (143/186) 77% (='.3/30) 77cIo (166/216) X^2=0 d.f,=I P=0.98 SEP.ANY 80% (148/186) 80% (=4/30) 80c1c (172/216) X^2=0 d.f.=1 P=0.95"1 SS.ADMIT 55% ( 102/I86) 5 3('c ( 16/30) 55% (1 18/216) X^2=0.02 d.f.=1 P=0.878 SS.ANY 63% ( I 18/186) 60 7c ( 18/30) 63 Ic (136/216) X^2=0.13 d.f.=l P=0.717 Figure 9 and TABLE 4.34 summarize important SNP-phenotype association results for AVPRI A
rs3803107. Subjects with the C allele had a significantly increased 28-day survival (P = 0.0377) and significantly more days alive (P = 0.0206) and significantly more days alive and free of vasopressors (P = 0.0386), more days alive and fi-ee of vasopressors at doses of 2 ug/min (P =
0.02=286), 5 (P = 0.0296) and 15 ug/min (P = 0.0132), inotropes (P = 0.0379), 4 of 4 SIRS criteria (P = 0.0494). cardiovascular dysfunction (P= 0.0365), respiratory dysfunction (P = 0.0214) mechanical ventilation (P = 0.0411), neurological dysfunction (P = 0.0488) and INR>l.5 (P=0.0296). Subje.cts with the AVPR I A i-s3803107 C allele also had a strong trend for more days alive and free of any hepatic dysfunction (P = 0.0894). These findings indicate that, Asian subjects with SIRS who had the C allele at AVPRIA rs3803107 have less need of vasopressors and are at decreased --isk of SIRS and organ dysfunction (cardiovascular, respiratory, neurological and hepatic).
TABLE 4.34 Days alive and free of organ dysfunction (DAF) by allele of arginine vasopressin receptor 1 a (AVPR I A) rs3803107 (C vs. T) in a cohort of Asian subjects with systematic inflammatory response syndrome. For all variables besides 28-day survival, data is given as 25`' percentile /
median / 75" percentile. For 28-day survival, data is given as Ic (N survived / N total). N, number of subjects.
C T Combined Test (N=186) (N=30) (N=216) Statistic 60cIc 57~Ic SGRVIVAL (1 12/186) 403- ( 12/30) ( l24/216) X^2=4.32 d.f.=] P=0.0377 DA 7 /
28 / 28 3.25I10.5128 6/28/28 F=5.44 d.f.= 1.2 14 P=0.0206 PRESS.DAF 4 / 24 / 28 1/ 8/ 26 2/ 21.5 / 28 F=4.33 d.f.=1,214 P=0.0386 2.75/21.50/
PRESS2.DAF 4 l 24.50 / 28 1/ 8/ 26 28 F=4.33 d.f.=1.214 P=0.0386 3.75 / 23.50 I
PRESS5.DAF 5/ 25 / 28 I / 8 I 26.7`i 28 F=4.8 d.f.=1.214 P=0.0296 PRESS15.DA
F 6 / 27 / 28 1/ 8/ 27 4_75 l 26 / 28 F=6.25 d.f.=1.214 P=0.0132 4.75/27.50/
INO.DAF 6/ 28 / 28 2.25 / 9/ 28 28 F=4.36 d.f.=1.214 P=0.0379 MSIRS2.DAF 0/3.5 / 21 0/0/3 0/ 3 I 20 F=9.25 d.f.=1.214 P=0.00265 ,NIS1RS3.DAF I / 1 7 / 27 U/ 1.5 / 21.5 I/ 14.5 / 26 F=7.43 d. f.=1,214 P=0.00693 MSIRS4.DAF 5/ 25 / 28 2 l 7/ 27.8 4/ 25 / 28 F=3.66 d.f.=1.214 P=0.057 CSIRS2.DAF 0 /4/23 0/0/6 0/3l21.3 F=9.13 d.f.=1.214 P=0.00282 CSIRS3.DAF 2/ 17 / 27 0/2/ 19.3 I I 16 I 26 F=8.5 d.f.=1,214 P=0.00394 2.25 / 7.50 /
CSIRS4.DAF 5/ 25 / 28 27.75 4.75 l 25 l 28 F=3.91 d.f.=1.214 P=0.0494 CVS.DAF I / 13.5 / 27 0 l4/ 17 1 / 1 I/ 26 F=4.43 d.f.=1,214 P=0.0365 RESP.DAF 0/ I 5/ 27 O / 1.5 / 23.5 0/ 1O / 27 F=5.37 d.f.=1.214 P=0.0214 VENT.DAF 0l 101 26 010.51 19 0/ 8.5 / 26 F=4.22 d.f.=1.214 P=0.041 I
CNS.DAF 5/ 27 / 28 I/ 7/ 28 3/ 24 / 28 F=3.93 d.t'.=1,214 P=0.0488 INR.DAF 5/27/28 117.5/28 4l25/28 F=4.79d.f.=1.214P=0.0296 ANYHEP.D A
F 4.25 / 27 / 28 1 l 8.5 I 28 2 / 20l 28 F=2.91 d.f.=1,214 P=U.0894 2.3.3 AVPRIA rs10877970 2.3.3.1 Systematic inflammatory response syndrome - Caucasians TABLE 4.35 gives the baseline characteristics (age, gender, APACHE II score, medical vs.
sur-ical diagnosis, sepsis upon admission, s psis anytime, septic shock upon admission and septic shock anytime) of 725 Caucasian SIRS subjects who were successfully genotyped (CC vs.

TT/CT) at AVPRI A rs10877970. No significant differences were detected between the two genotype groups on admission to the ICLC.

TABLE 4.35 Baseline characteristics of a cohort of Caucasian Subjects with systematic inflammatory response syndrome by genotype of a--ginine vasopressin receptor I a(AVPR I A) rs10877970 (CC vs.
TT/CT). For age and APACHE II score, data is given as 25`' percentile / median / 75`h percentile.
For all other variables, data is given as ~lo (N survived / N total). N.
number of subjects.
CC TT / CT Combined Test (N=20) (N=705) (N=725) Statistic AGE 49.5/56/68.5 44/58/71 46/59/71 F=0.1 d.f.=1,723P==0.75 GENDER 7090 ( 14/20) 611/-, (432/705) 62 k (446/725) X^2=0.63 d.f.=1 P=:0.429 APACHEII 22 / 25.5 / 27.3 16 / 22 / 27 16 / 21.5 / 27 F=3.25 d.f.=1,723 P=0.0716 SURGICAL 15 lc (3/20) 22(lc (158/705) 22% (161/725) X^2=0.62 d.f.=1 P=0.432 SEP.ADMIT 80 Ic ( 16/20) 78% (552/705) 78% (568/725) X^2=0.03 d.t.=l P=0.855 SEP.ANY 80%, ( 16/20) 80% (565/705) 80 7e (581/725) X^2=0 d.f.=l P=0.987 SS.ADbIIT 60% ( 12/20) 51 k (357/705) 51% (369/725) X^2=0.68 d.f.=1 P=0.409 SS.ANY 601Ic ( 12/20) 54e1c (383/705) 54(lc, (395/725) X^2=0.25 d.f.=l P=0.615 TABLE 4.36 summarizes important SNP-phenotype associations for AVPRIA i-s10877970.
Subjects with either the TT or CT genotype had significantly more days alive and free of acute lung injury (P = 0.0331 ), respiratory dysfunction (P = 0.0134) and mechanical ventilation (P =0.0276). Subjects with either the AVPRIA i-s10877970 TT or CT
genotype also had a strong trend for more days alive and free of vasopressors (P = 0.0 183), and more days alive and free of vasopressors at doses of 2 ug/min (P = 0.0638) and 5 ug/min (0.0575). These findings indicate that Caucasian subjects with SIRS with the TT or CT genotype at AVPR 1 A rs 10877970 have less need of vasopressors, are at decreased risk of acute lung injui-y and organ dysfunction (respiratory).

?O TABLE 4.36 Days alive and free of organ dysfunction (DAF) by genotype of arginine vasopressin receptor la (AVPR 1 A) rs 10877970 (CC vs. TT/CT) in a cohort of Caucasian subjects with systematic inflanimatory response syndrome. Data is -iven as 25`n percentile / median /
75`" percentile. N.
number of sub'ects.
CC TT / CT Combined Test (N=20) (N=705) (N=725) Statistic ALLDAF 2/9 / 24 5/ 24 / 28 4/ 24 / 28 F=4.56 d.f.=1.723 P=0.0331 PRESS.DAF 6/21/ 25.3 28 9/ 26 / 28 F=3.45 d.f.=1,723 P=0.0638 PRESS2.DA 10 / 26 / 10 / 26 /
F 6/ 21 / 26 28 28 F=3.31 d.f.=1,723 P=0.0692 PRESS5.DA II / 26 / 10 / 26 /
F 6.5 / 23 / 26 28 28 F=3.62 d.f.=1,723 P=0.0575 3.25/ 14/
CVS.DAF 24.25 5/ 23 / 27 5 / 23 / 27 F=2.68 d.f.=1.723 P=0.102 RESP.DAF 0/5.5 / 20 l/ 21 / 27 l/ 20 / 26 F=6.15 d.f.=1.723 P=0.0134 PF300.DAF 0/ 0/ 2.75 0/1 / I 1 0/ I/ 10 F=3.4 d.f.=1,723 P=0.0656 VENT.DAF 0/ 5.5 / 20 0/ 19 / 26 0/ 19 / 26 F=4.87 d.f.=1,723 P=0.0276 AFFD.DAF 0/ 0/ 0 0/ 0/ 4 0/ 0/ 3 F=3.12 d.f.=1.723 P=0.0779 2.3.3.2 Systematic inflammatory response syndrome - Asians TABLE 4.37 gives the baseline characterisxics (age, gender, APACHE II score, medical vs.
surgical diagnosis, sepsis upon admission, ~epsis anytime, septic shock upon admission and septic shock anytime) of the 108 Asian systematic inflammatory response syndrome subjects who were successfully genotyped (C vs. T) at AVPR I A rs 10877970. No significant differences, other than a small difference in APACHE 11 score, were detected between the two allelic groups on admission to the ICU.
TABLE 4.37 Baseline characteristics of a cohort of Asian Subjects with systematic inflammatory response syndrome by allele of arginine vasopressin receptor Ia (AVPRIA) rs10877970 (C
vs. T). For age and APACHE II score, data is given as 25"' percentile / median / 75`' percentile. For all other variables, data is given as r/~ (N survived /:V total). N. number of subjects.
C T Combined Test (N=33) (N=183) (N=216) Statistic AGE 57 / 73 / 77.0 51 / 68 / 77 54.5 / 69 / 76 F=0.52 d.f.=1.214 P=0.471 GENDER 48% ( 16/33) 60% (1 10! 183) 58,-/c ( 126/216) X"2=1.55 d.f.=1 P=0.212 APACHEII 19 / 26 / 34 17 / 23 / 29 17 / 23 / 30 F=4 d.f.=1.214 P=0.0467 SURGICAL 18~/c (6/33) 24% ( 44/183) 23% ( 50/216) X^2=0.54 d.f.=1 P=0.462 SEP.ADIVIIT WIc ( 25/33) 76% (139,1183) 76% (164/216) X^2=0 d.f.=1 P=0.98 SEP.ANY 79% ( 26/33) 79% (144,1183) 79% ( 170/216) X^2=0 d.f.=l P=099 SS.ADMIT 52cIc ( 17/33) 54~/c ( 99/183) 54 lc (1 16/216) X^2=0.08 d.f.=l P=0.784 SS.ANY 58'7c ( 19/33) 63% ( 1 15/183) 62% (134/216) X^2=0.33 d.f.=l P=0.566 Figure 10 and TABLE 4.38 summarizes important SNP-phenotype association results for AVPR 1 A rs 10877970. Subjects with the AVPR 1 A rs 10877970 T allele had a strong trend for increased 28-day survival (P = 0.0586) and significantly moi-e days alive (P =
0.0349) and significantly more days alive and free of vasopressors at doses of 5 ug/min (P
= 0.0417) and 15 ug/min (P = 0.0175), inotropes (P = 0.0423) and respiratory dysfunetion (P =
0.0427). Subjects with the AVPR I A rs I0877970 T allele also showed a stronQ trend for more days alive and free of 4 of 4 SIRS criteria (P = 0.0655) cardiovascular dysfunction (P = 0.079), ventilation (P = 0.057 ), neI-u-ological dysfunction (P = 0.064) and any hepatic dysfunction (P =
0.0827). These findings indicate that Asian subjects with SIRS who had the T allele at AVPR 1 A rs 10877970 have less need of vasopressors and are at a decreased risk of severe SIRS and organ dysfunction (cardiovascular, respiratory, neurological and hepatic).

TABLE 4.38 Days alive and free of organ dysfunction (DAF) by allele of arginine vasopressin receptor I a (AVPR I A) rs 10877970 (C vs. T) in a cohort of Asian subjects with systematic inflammatory response syndrome. For all variables besicles 28-day survival, data is given as 25"' percentile /
median / 75'' percentile. For 28-day survival, data is given as % (N survived / N total). N, nurnber of sub'ects.
C T Combined Test (N=33) (N=183) (N=216) Statistic 60% 57%
SURVIVAL 42 lc (14/33) (1 10/183) ( 124/216) X^2=3.58 d.f.=1 P=0.0586 DA 4/ 12/28 7/28/28 6/28/28 F=4.51 d.f.=1,214P=0.0349 PRESS.DAF 1/9 / 26 4/ 23 / 28 2/ 21.5 / 28 F=3.72 d.f.=1,214 P=0.0551 2.75/21.5/
PRESS2.DAF 1/ 9/ 26 4/ 24 / 28 28 F=3.72 d.f.=l .214 P=0.0551 3.75/23.5/
PRESS5.DAF 1/ 9/ 27 5125 / 28 28 F=4.2 d.f.=1.214 P=0,0417 PRESS15.DAF 1/ 9/ 27 6/ 27 / 28 4.75 / 26 / 28 F=5.73 d.f.=1.214 P=0.0175 4.75 / 27.5 /
INO.DAF 3/9/28 6/28/28 28 F=4.17 d.f.=1,214 P=0.0423 MSIRS2.DAF 0/0 /7 0/3 / 21.5 0/3 / 20 F=8.5 d.f.=1,214 P=0.00393 MSIRS3.DAF 0/2 / 22 I/ 16 / 27 1 14.5 / 26 F=6.29 d.f.=1.214 P=0.0129 MSIRS4.DAF 2/7 / 28 5/ 25 / 28 4/25 / 28 F=3.19 d.f.=1.214 P=0.0757 CSIRS2.DAF 0/0 /8 O / 5/ 23 0 / 3/ 21.3 F=7.82 d.f.=1,214 P=O.00565 CSIRS3.DAF 0/3 / 20 2/ 18 / 27 I/ 16 / 26 F=7.12 d.f.=1,214 P=0.00819 CSIRS4.DAF 3/8 / 28 5/ 25 / 28 4.75 / 25 / 28 F=3.43 d.f.=1,214 P=0.0655 CVS.DAF 015121 1 / 1 3 / 27 1 / 1 1/ 26 F=3.1 I d.f.=1,214 P=0.079 RESP.DAF 0/5 / 24 0/ 14 / 27 0/ l0 / 27 F=4,16 d.f.=1,214 P=0.0427 VENT.DAF 0/1 / 19 0! i 0/ 26 0/8.5 / 26 F=3.66 d.f.=1,214 P=0.057 CNS.DAF 1/9 / 28 5/ 27 / 28 3/ 24 / 28 F=3.47 d.f:=1.2 14 P=0.064 .-' 14 P=0.0568 INR.DAF 1/9 / 28 5/ 27 / 28 4/ 25 / 28 F=3.67 d.f.= I _ ANYHEP.DAF 1 /9 / 28 4.5 / 28 / 28 2/ 20 / 28 F=3.04 d.f.=1.214 P=0.0827 lU
EXAMPLE 3: INCREASED USE OF VASOPRESSIN
Methods Cohort Selection To investigate whether genotype predicts increased use of vasopressin, a subset of Caucasian subjects with septic shock was selected for this analysis (N=543).

Data Analysis AII data analysis was carried out using statistical packages available in R (R
Core Development Group, 2005 - R Development Core Team (www.R-project.M). R: A language and environment for statistical computing. Vienna, Austria. 2005). Chi-square tests were used to identify significant associations between SNP and increased use of vasopressin as well as to identify baseline characteristics (age, gender, admittitig APACHE II score, and medical vs.
surgical admitting diaanosis) requiring post-hoc, multivariate adjustment.

Results 3.1 Leucyl/Cystinyl Aminopeptidase (LNPEP) 3.1.1 Association of CC genotype of 1LNPEP rs18059 with Use of Vasopressin It was unknown whether SNPs within the I_NPEP gene and those regions immediately upstream IO and downstream are associated with the use of vasopressin. It was found that LNPEP rs 18059 is associated with the use of vasopressin by comparing LNPEP rs18059 genotypes for vasopressin-treated subjects (N=73) with control subjects who did not receive vasopressin at any time during their ICU stay (N=366). Baseline characteristics for septic shock subjects with LNPEP rs 18059 genotypes are shown in Table 5.1. No sign ificant differences between the genotype groups were detected on admission to the ICU.

TABLE 5.1 Baseline characteristics of Caucasian ICU septic-shock subjects by leucyl/cystinyl aminopepticlase (LNPEP) t-s 18059 genotype. For age and APACHE II score, data is given as 25`' percentile I
median 175'' percentile. For all other variables, data is given as %(N /N
total). N, number of subjccts.
CC CT TT Combined Test (N=108) (N=231) (N=100) (N=439) Statistic AcE 46159171 -t8 163 72 38.75 162.5 172 48161172 F=1.1 d.f.=2.436 P=0.334 GENDER 65% ( 70/108) 64r/c ( I48/231 62cIc ( 62/100) 64% (280/439) X^2=0.2 d.f.=2 P=0.907 APACHE II 19 ~ 25 132 20.5126 131 21 125 130 20126131 F=0.39 d.f.=2.--36 P=0.679 SURGICAL 28%( 30/108) 29% ( 66/231) 25cIc ( 25/100) 28% (121/439) X^2=0.-15 d.f.=2 P=0.799 Table 5.2 shows the distribution of vasopressin administration by LNPEP
rs18059 genotype.
Subjects with the LNPEP rs18059 CC genotype were observed to have been administered vasopressin more frequently than controls compared with subjects who were LNPEP rs18059 CT
or TT (P = 0.0257) TABLE 5.2 Measure of vasopressin treatment of Caucasian ICU septic shock subjects by genotype of Ieucyl/c stinyl amino e tidase (LNPEP) rs 18059.
No Vasopressin-Vasopressin treated Combined Test (N=366) (N=73) (N=439) Statistic 25% XA2=7.32 d.f.=2 CC 221% ( 81/366) 37% ( 27/73) (108/439) P=0.0257 53%
CT 54% (198/366) 45% ( 33/73) (231/439 23 ~lc TT 24% ( 87/366) l8 lc ( l 3/73) ( l00/439) 3.1.2 Association of AA genotype of LNIPEP rs27711 with Use of Vasopressin It was unknown whether SNPs within the I_NPEP gene and those reoions immediately upstream and downstl-eam are associated with the use of vasopressin. It was found that LNPEP rs2771 I is associated with the use of vasopressin by comparing the frequency of LNPEP
rs2771 I genotypes for vasopressin-treated subjects (N=70) and control subjects who did not receive vasopressin at any time during their ICU stay (N=368). Baseline characteristics for septic shock subjects witti LNPEP rs2771 I genotypes are shown in Table 5.3. No significant differences between the (yenotype groups were detected on admission to the ICU.

IO
TABLE 5.3 Baseline characteristics of Caucasian ICU septic shock subjects by leucyl/cystinyl aminopeptidase (LNPEP) rs2771 I Qenotype. For age and APACHE II score, data is given as 25`' percentile median 175"' percentile. For all other variables, data is given as cIc (N /N
total). N, number of I S sub'ects.
AA AG GG Combined Test (N=72) (N=223) (N=143) (N=438) Statistic F=0.78 d.f.=2.435 AGE 14.5 58.5 71 48 63 72 49 163 172 48161172 P=0.46 64ck X^2=O.I I d.f.=2 GENDER 65% ( 47/72) (142/223) 63% ( 90/143) 64(7/c (279/438) P=0.945 F=0.16 d.f.=2,a35 APACHE It 19 25.5 33 20.5 126 30 21126130 20 126 i3l P=0.854 29% ( X^2=1.86 d.f.=Z
SURGICAL 218% ( 20/72) 64/223) 22ck ( 32/143) 26% (1 161438) P=0.394 Table 5.4 shows the distribution of vasopressin administration by LNPEP rs2771 1 genotype.
Subjects with the LNPEP rs2771 I AA -enotype were more frequently observed to be administered vasopressin compared to subjects with LNF'EP rs2771 I AG or GG genotypes (P =
0.0033).

TABLE 5.4 Measure of vasopressin treatment of Caucasian ICU septic shock subjects by genotype of Ieucyl/cystinyl amino e tidase (LNPEP) rs2771 1.
No Vasopressin-Vasopressin treated Combined Test (N=368) (N=70) (N=438) Statistic AA 14% ( 51/368) 30% ( 21/70) 16% ( 72/438) X^2=11.45 d.f.=2 P=0.0033 AG 53% (195/368) 40% ( 28/70) 51 clo (223/438) GG 33clc (122/368) 30% ( 21/70) 3390 (143/438) 3.1.3 Association of GG genotype of LNPEP rst0051637 with Use of Vasopressin It was unknown whether SNPs within the LNPEP gene and those regions iminediately upstream and downstream are associated with the use of vasopressin. It was found that LNPEP rs 10051,537 is associated with the use of vasopressin by comparing the frequency of LNPEP
rs 1005 1637 genotypes for vasopressin-treated subjects (N=72) with control subjects (N=361) who did not i-eceive vasopressin at any time during their ICU stay. Baseline characteristics for septic shock.
subjects with LNPEP rs10051637 genotypes are shown in Table 5.5. No significant differences between the genotype groups were detected on admission to the ICU.

TABLE 5.5 Baseline characteristics of Caucasian ICU septic shock subjects by leucyl/cystinyl aminopepticlase (LNPEP) rs 1005 1637 genotype. For age and APACHE II score, data is given as 25 i percentile median 175"' percentile. For all other variables, data is given as c (N /N
total). N. number of subjects.
AA AG GG Combined Test (N=133) (N=223) (N=77) (N=433) Statistic AGE 72 48 163 72 l3 158 ~ 71 48 61 72 F=2.05 d.f.=2,430 P=O.130 62% ( 66 Ic 66% ( 65~Ic GENDER 82/133) ( Id7/223) 51/77) (280/433) X"2=0.76 d.f.=2 P=0.682 APACI-IE II 31 21126130 19 25 1 33 20 26 31 F=0.04 d.f.=2,430 P=0.96 ? 3/c ( 2 9 % ( 29~Ic ( 27 %
SURGICAL 30/133) 64/223) 22/77) (116/433) X^2=1.75 d.f.=2 P=0.416 Table 5.4 shows the distribution of vasopressin administration by LNPEP
rsI0051637 genotype.
Subjects with the GG genotype of LNPEP i-s 10051637 were more frequently observed to be administered vasopressin (P < 0.001 ) compared to subjects who carried the AG
or AA genotyp~ of LNPEP i-s 10051637 (TABLE 5.6).
TABLE 5.6 Measure of vasopressin treatment of Caucasian ICU septic shock subjects by genotype of Ieucyl/c stin I amino e tidase (LNPEP) rs 10051637.
No Vasopressin-Vasopressin treated Combined Test (N=361) (N=72) (N=433) Statistic AA 32% 114) 26%, ( 19) 319c ( l33) X^2=14.38 d.f.=2 P<0.00 I
AG 54 Ic (194) 4U~lo ( 29) 52OIc (223) GG 15% ( 53) 33S'o ( 24) 18% ( 77) 3.2 Arginine Vasopressin Receptor la (AVPRIA) 3.2.1 Association of CT genotype of AVPRIA rs1495027 with Use of Vasopressin It was unknown whether SNPs within the A,VPR 1 A gene and those regions immediately upstream and downstream are associated with the use of vasopressin in subjects with septic shock. It wa~~

found that AVPR 1 A rs 1495027 is associat?d with the use of vasopressin by comparing the frequency of AVPRIA rs1495027 genotypes for vasopressin-treated subjects (N=72) with conl:rol subjects (N=361) who did not receive vasopressin at any time during their ICU
stay.

Baseline characteristics for septic shock subjects with AVPR 1 A rs 1495027 genotypes are shovvn in Table 5.7. No significant differences between the genotype groups were detected on admission to the ICU.

TABLE 5.7 Baseline characteristics of Caucasian ICU septic shock subjects by genotype of arginine vasopressin receptor 1 a(AVPR I A) rs 1495027. For age and APACHE II score, data is aiven as 25 i percentile I median 75't' percentile. For all other variables, data is given as rlc (N /N total). N, number of subjects.
CC CT TT Conibined Test (N=143) (N=218) (ti':=72) (N=433) Statistic AGE 48161 72 46 60 71.75 51 63.50 73 48 61 72 F=0.84 d.f.=2,430 P=0.433 GENDER 61"c ( 87/I43) 69(7r (150/2IS) 58`~(42/72) 64'Yo (279/433) X^2=3.8 d.l'.=2 P=0.15 :\PACHE 11 19.5 1 26 I 31 20 125 I 31 21.75 ~ 26 130.75 20 I 26 I 31 F=0.62 d.f.=2.430 P=0.536 SURGICAL ?-l`?c ( 35/I4-1) 28% ( 62/218) 261,^ ( 19/72) 271,1, (I 16/433) X^2=0.7 d.t.=2 P=0.705 Table 5.4 shows the distribution of vasopressin administration by AVPRIA
rs1495027 genotype.
Subjects with the AVPR 1 A rs 1495027 CT aenotype had significantly increased use of vasopressin (P = 0.0240) compared to subjects who carried either the CC ol- TT genotype of AVPR 1 A rs 1495027 (TABLE 5.8).

?O TABLE 5.8 Measure of vasopressin treatment of Caucasian ICU septic shock subjects by genotype of vaso ressin rece tor I a (AVPR I A) rs 1495027.
Vasopressin-No Vasopressin treated Combined Test (N=361) (N=72) (N=433) Statistic X^2=7.46 d.f.=?
CC 361~%(, ( 129) 19~/e ( 14) 3314c (143) P=0.0240 CT 48% ( 173) 62e% ( 45) 50~Ic (218) TT 16S,~(59) 18%( 13) 17% (72) EXAMPLE 4: BIOLOGICAL PLAUSIBILITY
Examples 1-3 show that polymorphisms of the AVP, AVPRIA and LNPEP genes are associated with altered outcome in critically iIl subjects. To further explore the relationship between inflammation and infection, the present example examines subjects with non-septic causes of systemic inflammatory response syndrome by analyzing SNP-phenotype interactions in subjects having undergone cardiopulmonary bypass surgery. If an AVP, AVPR I A, LNPEP or LRAP gene polymorphism was associated with altered survival and organ dysfunction, that polymorphism is also likely to be associated with changes in pro-inflammatory proteins such as serum granulocyte colony stimulating factor (GCSF), interleukin 8 (IL-8) and monocyte chemotactic protein I
(MCP 1).
METHODS
Cohort Selection The Biological Plausibility cohort was used for this study.
Nleasurement of Chemokine and Cytokines IO After induction of anesthesia and placement of systemic and pulmonary artery catheters that were routinely inserted for clinical purposes at SPH, blood was obtained at baseline and at 3 hours post-operatively for sertim. GCSF, MCPI and IL-8 measurements were made using ELISA.

Data Analysis IS The primary outcome variables for the Biological Plausibility cohort were change in GCSF, MCPI
and IL-8 concenti-ations from baseline to three hours after surgery. All data analysis was cai7ried out using statistical packages available in F: (R Coi-e Development Group, 2005 - R Development Core Team (www.R-project.or-,). Vienna Austria 2005). Chi-squared and Kruskal-Wallis test statistics were used to identify significant SNP-phenotype and associations, as well as to look at ?0 baseline characteristics.

Results 4.1 Leucyl/Cystinyl Aminopeptidase (LNPEP) 4.1.1 LNPEP rs18059 TABLE 6.1 tiummarizes the baseline characteristics of 69 non-septic SIRS
subjects who were successfully genotyped (LNPEP rs18059 CC (N=20) vs CT (N=36) vs TT (N=13)) at LNPEP
rs18059. No significant differences were detected between the three genotype groups on admission to the CSICU.

TABLE 6.1 Baseline characteristics of a cohort of non-septic CSICU subjects diagnosed with systematic inflamnlatory response syndrome by genotype of leucyl/cystinyl aminopeptidase (LNPEP) rs18059 (CC vs. CT vs TT).
CC CT TT Combined Test (N=20) (N=36) (N=13) (N=69) Statistic 59.25 164.5O 1 61.00 165.0O 1 60.00 166.0O 1 58.25 165.50 1 F=0.15 d.f.=2.66 AGE 73.25 70.25 72.0O 70.75 P=0.865 GENDER 70% (14) 619c (22) 77 Ic (10) 67 ic (46) X^2=I.22 d.f.=2 P=0.545 X^2=1.86 d.f.=2 SMOKER 25% ( 5) 19 Ic ( 7) 38% ( 5) 25 Ic (17) P=O. 394 X^2=0.49 l.f.=2 DIABETES 15c1c ( 3) 22qc~ ( 8) 23cIc ( 3) 20% (14) P=0.782 X^2=0.62 d.f.=2 H.TENSE 6017c ( 12) 56% (20) 46c7c ( 6) 55 Ic (38) P=0.734 0.37 10.50 0.50 10.50 1 F=0.56 d.1'.=2,64 EJEC.FRAC 0.60 0.60 0.4610.5810.60 0.50 0.50 0.60 P=0.575 1.4811.651 1.13 11.57 1 F=0.56 d.f.=2.66 BYPASS 2.02 2.00 1.33 1.73 2.45 1.3111.65 12.05 P=0.575 1.04 11.32 0.83 11.19 1 F=0.2 d.f.=2,66 CLAMP 1.57 1.69 0.93 11.43 1.78 0.9211.2911.70 P=0.822 X^2=0.22 d.f.='' APROTININ 5% ( 1 ) 8% ( 3) 8 k ( 1) 7% ( 5) P=0.897 TABLE 6.2 summarizes important SNP-biomat-ker associations. Subjects with the CC genotype had significantly smaller increase in serum GCSF levels (P = 0.0 135) post-cardiopulmonary bypass sLu'gery. These findings suggest that non-septic SIRS Subjects with the CC genotype at LNPEP rs18059 are more likely to experience a less intense chemokine (GCSF) response aftercat-diopulmonary bypass surgery.
TABLE 6.2 Biological plausibility of leucyl/cystinyl arninopeptidase association using biomarkers in a cohort I(1 of non-septic CSICU subjects diagnosed with systematic inflammatory response syndrome by venoty e of leucyl/cystinyl amino e tidase (LNPEP) rs18059. Biomarkers are measured in i;/ml.
Combined CC (N=20) CT (N=36) TT (N=13) (N=69) Test Statistic F=5.26 d.f.=2.66 GCSF.3 123/183/276 219/292/497 236/287/3~14 179/260/368 P=0.00758 GCSF.DI F=4.6 d.f.=2.66 F 108/164/266 199/287/492 210/264/330 161/249/365 P=0.0135 125.2/186.6/211 165.0/195.3/281 95.7/138.1/226 134.9/182.0/245 F=2.54d.f.=2,66 MCP I.0 .3 2 .7 2 P=0.0862 4.1.2 LNPEP rs27711 TABLE 6.3 summarizes the baseline characteristics of 69 non-septic SIRS
subjects who were successfully genotyped (AA (N=14) vs. AG/GG (N=55)) at LNPEP rs2771 1. No significant differences between the genotype groups were detected on admission to the CSICU.

TABLE 6.3 Baseline chat-actet-istics of a cohort of non-septic CSICU subjects diagnosed with systematic intlammatory response syndrome by genotype of leucyl/cystinyl aminopeptidase (LNPEP) rs2771 I (AA vs. GG/AG).
AA GG/AG Combined Test (N=14) (N=55) (N=69) Statistic AGE 60.50/66.00/71.50 58.25/65.50/70.75 F=0.52 d.f.=1,67 60.25/63.00/69.25 P=0.473 X^2=0.12 d.f.=I
GENDER 64~k ( 9) 69 7c (38) 68~'Io (47) P=0.73 X^2=O. 15 d.f.=1 SMOKER 29% ( 4) 24% (13) 25(,1c (17) P=0.702 X^2=0.24 d.f.=l DIABETES 14(-1o ( 2) 20eIc (1 1) 19 Ic (13) P=0.625 X^2=0.43 d.f.=1 H.TENSE 64% ( 9) 55c1o 0) 5790 (39) P=0.512 F=O.37 d.f.=1,65 EJEC.FRAC 0.3510.50/0.60 0.50/0.50/0.60 0.50/0.50/0.60 P=0.544 1.51225/1.63350/ 1.25850/1.65000/2.0 1.31700/1.65000/2.0 F=0.44 d.f.=1,67 BYPASS 2.06225 8300 5000 P=0.51 1 1.07900/1.33300/ 0.85850/1.21700/1.6 0.92475/1.29150/1.7 F=0.44 d.f.=I,67 CLAMP 1.61225 7500 0000 P=0.51 I
APROTININ 7%, ( I) 7 % ( 4~ 74 ( 5) X^2=0 d.f.=1 P=0.987 TABLE 6.4 summarizes impoi-tant SNP-biomarker associations observed for LNPEP
rs2771 l.
Subjects with the LNPEP rs2771 I AA (Yenotype showed a smaller change in GCSF
levels froni baseline to 3 hours post-surgery (P < 0.001) and had lower preoperative interleukin 8(IL8) levels (P = 0.05) than subjects with LNPEP rs2771 I AG or GG genotypes . These findings su"gest that non-septic SIRS Subjects with the AA genotype at LNPEP rs2771 I are more likely to experierice a less intense chemokine (GCSF) response after cardiopulmonary bypass and are more likely to have hi(,her baseline levels of IL-8.

I(1 TABLE 6.4 Biological plausibility of leucyl/cystinyl arninopeptidase association using biomarkers in a cohort of non-septic CSICU subjects diagnosed with systematic inflammatory response syndrome by (Yenoty e of leucvl/cystin I amino e tidase rs2771 I(AA vs. GG/AG).
Combined AA (N=14) GG/AG (N==55) (N=69) Test Statistic GCSF.3 I 15/ I 45/209 221 /287/44 % l 79/260/ 368 F=15.4 d.f.=1.67 P<0.00I
GCSF.DIF 103/ I 38/ 18 l 205/274/431 161 /249/365 F=14.3 d.f.= 1.67 P<0.001 IL8.0 0.0/0.0/I 2.8 O.0/13.4/21.1 0.0/7.2/20.2 F=3.89 d.f.=1,67 P=0.052~, -5 4.1.3 LNPEP rs10051637 'TABLE 6.5 summarizes the baseline characteristics of 70 non-septic SIRS
subjects who were successfully genotyped (AA/AG vs. GG) al LNPEP rs10051637. No significant differences between the genotype groups w'ere detected on admission to the CSICU.

20 TABLE 6.5 Baseline charactei-istics of a coho--t of non-<,eptic CSICU subjeets diagnosed with systematic inflammatory response syndrome by genotype of leucyl/cystinyl aminopeptidase (LNPEP) i-s10051637 (GG vs. AA/AG) AA/AG GG Combined Test (N=56) (N=14) (N=70) Statistic AGE 60.75/66.00/72.00 60.25/63.00/69.25 58.25/65.50/70.75 F=0.65 d.f.=1.68 P==0.423 GENDER 68% (38) 64% ( 9) 67% (47) X^2=0.06 d.f.=1 P=0.799 SMOKER 23 Ic (13) 29% 4) 24~'-/c (17) X^2=0. 17 d.f.=1 P=0.676 DIABETES 21 ~~c 12) 14c1c 2) 20% (14) X^2=0.36 d.f.= l P=0.55 H.TENSE 54rIc (30) 64% 9) 56% (39) X^2=0.52 d.f.=1 P=0.47 EJEC.FRAC 0.50/0.50/0.60 0.35/0.50/0.60 0.50/0.50/0.60 F=0.41 d.f.=1,66 P=
0.525 BYPASS 1.26275/1.65000/2. 1.5 1225/1.63350/ 1.31700/1.65000/ F=0.4 d.f.=1,68 P=0.527 05800 2.06225 2.05000 CLAMP 0.86275/ 1.20850/ 1. 1.07900/1.33300/ 0.92475/1.29150/ F=0.48 d. f.=1.68 P=4489 67100 1.61225 1.70000 APROTININ 7(1(,(4) 7clc ( I) 7r/c ( 5) X^2=0 d.f.=l P=l TABLE 6.6 summarizes important SNP-biomarker associations. Subjects with the LNPEP
rs 1005 1637 GG genotype showed a smaller change in serum GCSF levels from baseline to 3 hours post-surgery than subjects with the LNPEP rs 1005 1637 AG or AA genotypes (P <
0.001).
Ftirthermore, LNPEP rs10051637 AA subjects were observed to have lower baseline interleukin-8 (IL8) levels (P = 0.0443) 3 hours post- surgery. These findings suggest that non-septic SIRS
subjects with the LNPEP rs 10051637 GG genotype have a decreased chemokine (GCSF) and proinflammatory (IL-8) response after cardiopulmonary bypass.

1U TABLE 6.6 Biological plausibility of leucyl/cystinyl arninopeptidase association using biomarkers in a cohort of non-septic CSICU subjects diagnosed with systematic inflammatory response syndrome by aenotype of leucyl/cystinyl aminopeptidase (LNPEP) rs10051637 (GG vs. AA/AG).
Biomarkers are measured in Q/ml.
AA/AG Combined (N=56) GG (N=14) (N=70) Test Statistic GCSF.3 221/288/441 9 179/260/368 F=15.7 d.f.=1.68 P<0_00 1 GCSF.DI 103/138/18 F 207/279/424 I 161/249/365 F=14.6 d.f.= 1.68 P<0.00I
1L8.11 0.0/13.6/22.2 0.0/0.0/13.8 0.0/7.2/20.2 F=4.2 d.f.=1.68 P=0.0443 4.1.4 LNPEP rs38041 TABLE 6.7 summarizes the baseline characteristics of 70 non-septic SIRS
subjects who were successfully genotyped (GG/AG vs. AA) at LNPEP rs38041. No significant diffei-ences between the two genotype groups were detected on admission to the CSICU.

2(1 TABLE 6.7 Baseline characteristics of a cohort of non-septic CSICU subjects diagnosed with systematic intlammatory response syndrome by genotype of leucyl/cystinyl aminopeptidase (LNPEP) rs38041 (AA vs. GG/AG) _ AA AG/GG Combined Test (N=18) (N=52) (N=70) Statistic AGE 60.25/63.00/69.25 60.75/66.00/72.25 58.25/65.50/70.75 F=1.46 d.f.=1,68 P=0.231 GENDER 67'7c (12) 67c1c (35) 67 l0 (47) Xn2=0 d.f.=l P=0.96 SMOKER 22%(4) 25c1c ( 13) 24% (17) X^2=0.06 d.f.=1 P=0.813 DIABETES 17cIc ( 3) 21% ( I) 20% (14) X^2=O.I7 d.f.=1 P=0.682 H.TENSE 61% ( i 1) 54% (28) 56% (39) X^2=0.29 d.f.=1 P=0.593 EJEC.FRAC 0.50/0.55/0.60 0.48/0.50(0.60 0.50/0.50/0.60 F=0.02 d.f.=1,66 P=0.881 BYPASS 1.42075/1.63350/ 1.30450/1.65000/2. 1.31700/1.65000/2. F=0.12 d.f.=1.68 P=0.73 2.00000 17900 05000 CLAMP 0.93325/1.33300/ 0.87475/1.20850/1. 0.92475/1.29150/1. F=0.26 d.f_=1,68 P=0.608 1.69600 65425 70000 APROTININ 69c ( 1) 8% ( 4r 7 % ( 5) X^2=0.09 d.f.=I P-=0.762 TABLE 6.8 summa--izes important SNP-biomarker associations. Subjects with the AA genotyae had a significantly smaller change in serum GCSF levels f--om baseline to three hours post-cardiopulmonary bypass (P = 0.00226) ancl significantly lower baseline serum interleukin-8 (IL8) levels (P = 0.0417) compared to subjects with LNPEP rs38041 AG or GG. These findings suggest that non-septic SIRS subjects with LNPEP rs38041 AA have a decreased chemokine (GCSF) IU response after cardiopulmonary bypass ana lowe-- baseline serum IL-8 levels..
TABLE 6.8 Biological plausibility of leucyl/cystinyl aniinopeptidase association using biomarkers in a cohort of non-septic CSICU subjects diagnosed with systematic inflaminatory response syndrome by genotype of leucyl/cystinyl aminopeptidase rs38041 (AA vs. GG/AG). Biomarke--s are measUred in g/ml.
Combined AA (N=18) GG/AG (N=52) (N=70) Test Statistic GCSF.3 115/164/266 221/288/423 179/260/368 F=10.7 d.f.=1.68 P=0.00168 GCSF.DIF 103/154/244 211/279/415 161/249/365 F=10.1 d.f.=1.68 P=0.00226 IL8.0 0.0/0.0/ 16.0 0.0/ 13.6.122.2 0.0/7.2/20.2 F=4.31 d.f.=1,68 P=0.0417 4.2 Arginine Vasopressin (AVP;, 4.2.1. AVP rs857242 2U TABLE 6.9 summarizes the baseline characteristics of 57 non-septic SIRS
subjects who we--e genotyped at AVP rs857242. No significant differences between the genotype groups were detected on admission to the CSICU.

TABLE 6.9 Baseline characteristics of a cohort of non-septic CSICU subjects diagnosed with systematic inFlammator res onse syndrome b enot e of Arginine Vasopressin (AVP) rs857242.
AC CC Combined Test (N=11) (N=57) (N=68) Statistic AGE 60.50/65.00/71.00 60_0~:)/65_00/72.O0 58.25/65.50/70.75 F=0.O4 d.f.=I,66 P=0.837 Chisquare=0.04 d.f.=l GENDER 64% ( 7) 67% (38) 66% (45) P=0.846 Chisquare=0.l d.f.=I
SMOKER 279c ( 3) 23% ~;13) 24%(16) P=0.749 Chisquare=1.06 d.f.= I
DIABETES 9r/c ( I) 23% i 13) 21% (14) P=0.303 Chis(Juare=0.21 d.f.=I
H.TENSE 64c1c ( 7) 56cIc i32) 57% (39) P=0.645 EJEC.FRAC 0.45/0.50/0.60 0.50/0.50/0.60 0.50/0.50/0.60 F=0.02 d.f.= 1.64 P=0.897 1.O415/ I.33 30/ I.96 1.3170/ 1.6500/2.05 BYPASS 65 1.367,;)/1.6500/2.0830 00 F=I.25 d.f.=1,66 P=0.268 0.78350/ 1.03300/ I. 0.93300/ 1.2500O/ 1.63 0.92475/ 1.2915t)/ 1.
CLAMP 65850 3O0 70000 F=0.4I d.f.=1.66 P=0.525 Chisquare=0.06 d.f.=1 APROTININ 9% ( I) 7cI(: (4) 79c ( 5) P=0.8I

TABLE 6.10 summarizes important SNP-)iomarker associations foi- AVP rs857242.
Subjects with the AVP i-s857242 CC genotype showed a strong trend towards a smallei- change in GCSF levels at three hours post-cardiopulmonary bypass than subjects with the AVP rs857242 AC
genotype (p=0.0978). These findings suggest that non-septic SIRS subjects with the AVP
position rs85 7 242 CC Qenotype have a decreased chemokine (GCSF) response after cardiopulmonary bypass surgery.
TABLE 6.10 Biological plausibility of Factor V association using biomarkers in a cohort of non-septic CSICU
subjects diagnosed with systematic inflammatory response syndrome by genotype of Arginine Vaso ressin (AVP) rs857242 . Biomarkers are measured in g/ml.
I AC (N=11) CC (N=5'1) Combined (N=68) Test Statistic GCSF.3 2571319154O 180 255 3(i8 179 260 368 F=3_ 38 d.f.=1,66 P=0.0704 GCSF.DIF 257 314J519 169 240 3fi8 161 2491365 F=2.82 d.f.= l,66 P=0.0978 4.3 Arginine Vasopressin Receptor la (AVPRIA) 4.3.1 AVPRIA rs1495027 TABLE 6.11 summarizes the baseline characteristics of 69 non-septic SIRS
subjects who were successfully genotyped (CT/TT vs. CC) at AVPR I A rs 1495027. Subjects with the CC genotype had shortei- clamp time (P = 0.03) than subjects with the CT/TT genotypes.
There were no other significant differences prior to cardiopulmonary bypass surgery.

TABLE 6.11 Baseline characteristics of a cohort of nori-septic CSICU subjects diagnosed with systematic inflammatory response syndrome by genotype of arginine vasopressin receptor 1 a(AVPR I A) rs 1495027 (CC vs. CT/TT).
CC CT/TT Combined Test (N=26) (N=43) (N=69) Statistic F=1.4 l d.f.= 1 .67 AGE 58.50/64.50/68.50 61.00/66.00/73.00 58.25/65.50/70.75 P=0.239 X^2=0.02 d.f.=l GENDER 69%(18) 67% (29) 68% (47) P=0.877 X^2=0.66 d.ti.=1 SMOKER 19% ( 5) 28~Ic ( 12) 25% (17) P=0.418 X^2=2.83 d.f.=l DIABETES 31 Io ( 8) 14q, ( 6) 20% (14) P=0.0924 X^2=1.82 d.f.=I
H.TENSE 46%, 12) 6 3 % (27) 57% (39) P=0.177 F=0.35 d. F.=1,65 EJEC.FRAC 0.45/0.50/0.60 0.50,'0.50/0.60 0.50/0.50/0.60 P=O.557 1.0955/1.4415/2.033 F=3.29 d.1'.=1.67 BYPASS 0 1.4415/1.7330/2.0580 1.3170/1.6500/2.0500 P=0.0743 0.77100/0.97500/ 1.5 1.06700/ 1.30000/ 1.73 0.92475/ 1.29150/ 1.70 F=4.64 d.1'.= 1,67 CLAMP 2075 350 000 P=0.0348 Xn2=0.7=d.f.= I
APROTININ 41-/c ( I) 99c 1 4) 7"Ic ( 5) P=0.397 TABLE 6.12 summarizes important SNP-)iomarker associations for AVPRIA
rs1495027.
Subjects with the AVPR I A rs 1495027 CC genotype were observed to have lower interleukin 8 (IL8) levels at baseline (p=0.046) and at three hours post cardiopulmonary bypass (p=0.0231) and had a strong trend towards smallei- change in IL8 levels post-cardiopulnionary bypass surgery when compared to AVPR1 A rs1495027 CT or TT subjects (P = 0.0664). These findings suggest that non-septic SIRS Subjects with the AVPRIA rs1495027 CC genotype have a decreased prc+-inflammatory cytokine (IL8) response at baseline and aftei- cardiopulmonary bypass surgery. A
trend towards lower MCPI levels at baseline was also observed for subjects with the CC genotype compared with AVPRIA rs1495027 subjects with AVPRIA rs1495027 CT/TT (lenotypes P
0.09).
I 5 TABLE 6.12 Biological plausibility of arginine vasopres~in i-eceptor la association using biomarkers in a cohort of non-septic CSICU subjects diagnosed with systematic inflammatory i-esponse syndrome by genotype of arginine vasopressin receptor 1 a(AVPR 1 A) rsl495027 (CC vs.
CT/TT). Biomark,2rs are measured in Q/ml.
CC (N=26) CT/TT (N==43) Combined (N=69) Test Statistic IL8.0 0.0/0.0/16.0 0.0/15.6/21.1 0.0/7.2/20.2 F=4.13d.f.=1,67P=0.046I
IL8.3 26.0/37.6/67.2 33.7/63.6/136.3 27.9/44.9/78.4 F=5.41 d.f.=1.67 P=0.0231 IL8.DIF 21.6/27.2/58.9 24.4/47.7/116.1 22.2/35.7/67.0 F=3,48 d.f.=1.67 P=0.0664 MCP1.O 117/169/203 155/188/262 135/182/245 F=2.83 d.t.=1.67 P=0.0973 4.3.2 AVPRIA rs3803107 TABLE 6.13 summarizes the baseline characteristics of the 70 non-septic SIRS
subjects who were successfully genotyped (CT/TT vs. CC) at AVP position rs3803 107. No significant differences were detected between the two genotype groups prior to cardiopulmonary bypass surgery.

TABLE 6.13 Baseline characteristics of a cohort of non-septic CSICU subjects diagnosed with systematic inflammatory response syndrome by genotype of arginine vasopressin i-eceptor Ia (AVPRIA) rs3803107 (CT/TT vs. CC).
CC CT/TT Combined Test (N=49) (N=21) (N=70) Statistic AGE 61.00/65.00/71.00 57.00/66.00/72.00 58.25/65.50/70.75 F=0.07 d.f.=1.68 P=0.79 X^2=1.I I d.f.=I
GENDER 63% ( 31) 76r/c (16) 67 Io (47) P=0.29I
SNIOKER 2?~k (1 I) 29 c ( 6) 24%( l7) Xn2=0.3 d.f.=l P=0.584 X^2=0.O2 d.f =1 DIABETES 2O% ( 10) 19%(4) 2O(,'iC (14) P=0.896 X^2=1.46 d.f.=I
H.TENSE 51 % (2,5) 67%(14) 56%, (39) P=0.227 F=0.01 d.f.=1.66 EJEC.FRAC 0.50/0.50/0.60 0.48/0.50/0.60 0.50/0.50/0.60 P=0.934 F=0.63 d.f.=1.68 BYPASS 1.33 3/ 1.667/2.133 1.350/1.600/ 1.767 1.3 17/ 1.650/2.O50 P=0.431 0.93300/1.30000/1. 0.88300/1.13300/1.43 0.92475/1.29150/1.70 F=1.34 d.f.=1 ,68 CLAMP 75 3 0 P=0.252 X^2=0.26 d.f.=l APROTININ V4(4) 5~Ic(I) 7~/c(5) P=0.613 I(1 TABLE 6.14 summarizes important SNP-biomarker associations for AVPRIA
rs3803107.
Subjects with the AVPR 1 A rs3803 107 CC genotype had significantly higher serum MCP I
concentrations at baseline compared to those with AVPR I A rs3803 107 CT or TT(P = 0.0288).
This finding suggests that the non-septic SIRS subjects with the AVPRIA rs3803 genotype had higher MCPI levels at baseline.

TABLE 6.14 Biological plausibility of arginine vasopressin receptor l a association using biomarkers in a coho--t of non-septic CSICU subjects diagnosed with systematic inflammatory response syndromc by genotype of arginine vasopressin receptor la (AVPRIA) rs3803107 (CT/TT vs.
CC). Biomark:ers are measured in /ml.
CC (N=49) CT/TT (N=21) Combined (N=70) LTest Statistic 162.2/187.2/26 1. 78.7/133.8122.3.
MCP1.0 5 4 134.9/182.0/245.2 F=4.99 d.f.=1.68 P=o.o288 4.3.3 AVPR1A rs l0877970 TABLE 6.15 summarizes the baseline characteristics of the 69 non-septic SIRS
subjects who were successfully genotyped (CC/CT vs. TT) at AVPRlA rs10877970. No significant differences were detected between the two genotype groups prior to cardiopulmonary bypass surgery.

TABLE 6.15 Baseline characteristics of a cohort of non-septic CSICU subjects diagnosed with systernatic inflammatory response syndrome by genocype of arginine vasopressin receptor la (AVPRIA) rs10877970 (CC/CT vs. TT).
CT/CC TT Combined Test (N=20) (N=49) (N=69) Statistic F=O.?9 d.f.=1.67 AGE 57.00/66.50/70.50 61.0C/65.00/72.00 58.25/65.50/70.75 P=0.591 X^2=0.88 d.f.==I
GENDER 75~'lc (15) 63 Ic (31) 67% (46) P=0.348 X^2=0 d.f.= I
SMOKER 25"k ( 5) 24%(12) 25 k (l7) P=0.964 X^2=0.39 d.f.=:I
DIABETES -'_5"/c ( 5) 18% ( 9) 20 Ic (14) P=0.534 X^2=1.12 d.f.=: I
H.TENSE 65(/c (13) 51% (25) 55~Io (38) P=0.290 EJEC.FRAC 0.405/0.550/0.600 0.500i0.500/0.600 0.500/0.500/0.600 F=0 d.f.=1.65 P=0.967 1.3250/1.6915/2.32 1.3330/1.6500/2.033 F=0.01 d.f.=1.67 BYPASS 10 0 1.3170/ 1.65O0/2.0500 P=0.917 0.87075/ 1.3585O/ I. 093300/ I.25000/ I.7 0.92475/ 1.29 150/ l.70 F=O. 14 d.f.=1,67 CLAMP 600 17 0 P=0.7I4 X^2=0.2I d.f.=1 APROTININ 5~/c ( 1) 81/( (4) 79c ( 5) P=0.646 TABLE 6.16 summarizes important SNP-biomarker associations for AVPRIA
r510877970.
Subjects with the AVPR 1 A rs 10877970 TT genotype showed a trend towards higher serum MCP
levels (P = 0.0865) at baseline compared to subjccts with AVPRIA rs]0877970 CT
or CC. This I o finding suagests that non-septic SIRS subjects who carry either the AVPR 1 A rs 10877970 CT or CC genotypes had lower MCPI levels at baseline.

TABLE 6.16 Biological plausibility of arginine vasopres~in receptor la association using biomarkers in a cohort of non-septic CSICU subjects diagnosed with systematic inf7ammatory response syndrome by genotype of arginine vasopressin receptor la (AVPRIA) rs10877970 (CC/CT vs.
TT). Biomarkers are measured in g/ml.
CT/CC (N=20) TT (N=49) Combined (N=69) Test Statistic MCP1.0 76_4/148.81236.0 162.21187.21249.6 134.9/182.01245.2 F=3.05 d.f.=1.67 P=0.0856 SUIVIMARY
Numerous discoveries described herein show that single nucleotide polymorphisms of the vasopressin (AVP rs1410713, rs857240, rs857242) gene, the arginine vasopressin Al receptor (AVPRIA rs1495027) gene, and the leucyl/cystinyl aminopeptidatase (LNPEP i-s18059, rs2771 l, and i-s 10051637) gene are associated with response (measured as survival, organ dysfunetion and need of life support) to AVP.
>>

Furthermore, markers in the vasopressinase gene (LNPEP rs 18059, rs27711, and rs 10051637) and the vasopressin Al receptor gene (AVPRI A rs1495027) are also markers of increased use of AVP
in a cohort of critically ill subjects who have septic shock. Accordingly, clinicians more frequerntly administer infused AVP to subjects who have LNPEP genotypes rs18059 CC, rs2771 I AA and rs 10051637 GG and subjects who have the AVPR I A genotype, i-s 1495027 CT.
These genotypes also have a significantly decreased chance of survival when treated with infused AVP compared to comparable subjects who have septic shock but who are not infused with AVP
(control).

In a separate study of an independent cohort of subjects with cardiopulmonary bypass surgery, we have also found that LNPEP rs 18059 CC, LNPEP rs2771 I AA and LNPEP rs 10051637 GG arc associated with decreased inflammatory response (measured as GCSF and IL-8 response) to non-septic causes of systemic inflammatory response syndrome (subjects having cardiopulmonary bypass surgery).

The clinical utility of these discoveries is that before subjects who have SIRS, sepsis or septic shock and other inflammatory conditions listed below are considered for treatment with a vasopressin receptor agonist, they may be genotyped for single nucleotide polymorphisms of the vasopressin (AVP) gene (rs 1410713, rs857240, and rs857242), the vasopressin A
l receptor (AVPRIA) gene (rs1495027), and the vasopressinase (LNPEP) gene (rs18059, rs2771 I and rs 10051637). Subjects who have AVP rs857240 CT or rs857242 AC genotypes; the rs 1495027 TT genotype, or the LNPEP rs 18059 CC, rs2771 I AA or i-s 10051637 GG genotypes should not receive vasopressin receptor agonist(s) (e.g. V-1 reeeptor agonist, e.g. a V 1 a i-eceptor agonist, e.,,. an AVPRI agonist) because vasopressin receptor agonist(s) dramatically decreases their survival and increases the risk of organ dysfunction.

Similarly, before subjects who have SIRS, sepsis or septic shock and the conditions listed below are considered for treatment with any vasopressin receptor agonist(s), they should be g~!notyped for sin-le nucleotide polymorphisms of the vasopressin (AVP) gene (rs1410713, rs857240 and rs857242), the vasopressin A I receptor (AVPR I A) gene (rs 1495027), and the vasopressinase 3U (LNPEP) gene (rs18059, rs2771 I and rs10051637). Subjects who have the AVP
rs1410713 AA or AC, rs857240 CC or rs857242 CC genotypes; the AVPR I A rs 1495027 CC genotype, and the LNPEP rs18059 TT or rs27711 GG genotypes should receive vasopressin receptor agonist(s) (e g.
V-1 receptor agonist. e.g. a V 1 a receptor agonist, e.g. an AVPR I agonist) because vasopressin receptor agonist(s) dramatically increases their survival and decreases the risk of organ dysfunction.

Furthermore, subjects undergoing or having cardiac surgery (of all types in all ages and hypotensions), cardiac surgery requiring cardiopulmonary bypass, cardiac surgery not requiring cardiopulmonary bypass, cardiac transplantation and hypotension, dialysis-induced hypotension, autonomic neuropathy, trauma and hypoterision are also likely to be administered a vasopressin receptor agonist and should also be genotypes for single nucleotide polymorphisms of the vasopi-essin (AVP) gene (rs 1410713, rs857240, and rs857242), the vasopressin A 1 receptor (AVPR I A) gene (rs 1495027), and the vasopressinase (LNPEP) gene (rs 18059, rs2771 I and rs 10051637).
IO
Similarly. before subjects who have pregnancy-associated diuresis, diabetes insipidus and are considei-ed for treatment with vasopressin, they should be Qenotyped for single nucleotide polymoiphisms of the vasopressin (AVP) Qene (rs1410713, rs857240, and rs857242), the vasopressin A 1 receptor (AVPR I A) gene (rs 1495027), and the vasopressinase (LNPEP) gene (rs 18059, rs2771 I and rs 10051637).

TABLE 7.1 shows that subjects who have 1.he LNPEP rs 18059 CC, rs277 l I AA or rs 10051637 GG genotypes (P = 0.0398 interaction statistic of LNPEP rs 18059 TT and AVP
infusion and survival) who receive AVP infusion have decreased survival compared to subjects who have the LNPEP i-s18059 CC, rs2771 I AA or i-s100`i1637 GG genotypes who do not receive AVP infusion.
Furthermore, TABLE 7.1 shows that subjects who carry the LNPEP rs 18059 CC -enotype have a significantly increased chance of receiving AVP infusion than subjects who do not carry the LNPEP i-s 18059 CC genotype (p = 0.0257). Furthermore, subjects who carry the LNPEP rs277 11 AA genotype have a significantly increased chance of receiving AVP inftision than subjects who do not can-y the LNPEP rs2771 I AA genotype (p = 0.0033). Furthermore, subjects who carry the LNPEP i-s 10051637 GG genotype have a significantly inereased chance of receiving AVP infu~,ion than subjects who do not carry the LNPEP rs 1005 1637 GG genotype (p < 0.001).

~t) TABLE 7.1 Sunimary of Key Results of SNPs. Alleles and Genotypes of the Vaso ressinase Gene (LNPEP) LNPF,P SNP INCREASE GROUP SURVIVAL BIOLOGICAL )P
IN USE OF (%) BY GENOTYPE PLAUSIBILITY
VASO
rs 18059 Geno = CC CC CT TT CC: Smaller 0.003 increase of GCSF
P = 0.0257 CONT 67 28 15 Sig (P<0.05) 0.0398 Interaction rs277I I Geno = AA AA AG GG AA: Smaller <0.00I
increase of GCSF
P = 0.0033 CONT' 60 36 19 AA: Smaller 0.05 increase of IL-8 rs10O51637 Geno = GG GG AG AA GG: Smaller 0.001 increase of GCSF
P< 0.001 CONT 60 35 20 GG: Smaller 0.04 increase of IL-8 In addition, subjects who have the LNPEP rs 18059 CC genotype have a less pronounced rise in GCSF after cardiac surgery (p = 0.003). In addition, subjects who carry the LNPEP rs2771 1 AA
aenotype have a less pronounced rise in GCSF (p = 0.001) and IL 8(p = 0.05) after cardiac surgery. In addition, subjects who have the LNPEP rs 10051637 GG genotype have a less pronounced rise in GCSF (p = 0.001) and IL-8 (p = 0.04) after cardiac surgery.

TABLE 7.2 shows that subjects who have ~he AVP rs 1410713 CC, AVP rs857240 CT, and AVP
rs857242 AC genotypes who receive AVP infusion have decreased survival compared to subjects I U who have the AVP rs 1410713 CC, AVP rs857240 CT, and AVP rs857242 AC
genotypes who do not receive AVP infusion.

'TABLE 7.2 Summary of Key Results of SNPs, Alleles and Genotypes of the Vasopressin Gene (AVP).
AVP SNP GROUP SURVIVAL BIOLOGICAL P
(%) BY PLAUSIBILITY
GENOTYPE
rs 14 10713 CC AC AA

rs857240 CT CC

rs857242 AC CC
CONT 54 30 AC: INCREASED 0.07 GCSF

Subjects who have the AVP rs857242 AC genotype have a breater rise in GCSF (p = 0.07) after cardiac surgery than subjects w'ho do have the AVP rs857242 CC genotype.

TABLE 7.3 shows that subjects who hav,~ the AVPRIA rs1495027 TT genotype (P =
0.0466 interaction statistic of AVPRIA rs1495027 TT and AVP infusion and survival) who receive AVP
infusion have decreased survival compared to subjects who have the AVPR I A rs genotype who do not receive AVP infusion.
TABLE 7.3 Summary of Key Results of SNPs. Alleles and Genotypes of the AVPRI Gene.
AVPRI SNP INCREASE GROUP SURVIVAL BIOLOGICAL P
IN USE OF (%) BY PLAUSIBILIT
VASO GENOTYPE Y
rs 1495027 Geno = CT TT CT CC
P=O.0240 CONT 46 35 24 CT/TT: Greater 0.06 increase IL-8 Sig (P<0.05) 0.0466 Interact ion Furthermore. TABLE 7.3 shows that subjects who cai-ry the AVPRIA rs1495027 CT
genotyp2 I(1 have a significantly increased chance of receiving AVP infusion than subjects who do not carry the AV PR 1 A rs 1495027 CT genotype ( p= 0.C240).

Subjects who have the AVPR I A rs 1495027 CT/TT genotypes have a greater rise in IL-8 (p =
0.06) after cardiac surge--y than subjects who do have the AVPR l A rs 1495027 CC genotype.
Although the foregoing invention has been described in some detail by way of illustration and example foi- purposes of clarity of understanding, it will be readily apparent to those of skill in '.he art in light of the teachings of this invention that changes and modification may be made thereto without depat-ting from the spirit or scope of the appended claims.

Claims (49)

1. A method for obtaining a prognosis for a subject having, or at risk of developing, an inflammatory condition, the method comprising determining a genotype of said subject which includes one or more polymorphic sites in the subject's vasopressin pathway gene sequences or a combination thereof, wherein said genotype is indicative of an ability of the subject to recover from the inflammatory condition.

2. The method of claim 1, wherein the polymorphic site is selected from one or more of the following: rs18059; rs27711; rs38041; rs10051637; rs1410713; rs857240;
rs857242; rs10877970;
rs3803107; and rs1495027; or a polymorphic site in linkage disequilibrium thereto.

3. The method of claim 2, wherein the polymorphic site in linkage disequilibrium is selected from one or more of the following: rs2762; rs10051637; rs1477364; rs7731592;
rs7736466;
rs1363974; rs2351010; rs1423357; rs1544777; rs2161548; rs38032; rs38034;
rs38041; rs27436;
rs27306; rs27307; rs27397; rs27659; rs2771 1; rs27290; rs38030; rs27294;
rs27747; rs39602;
rs248215; rs27302; rs2278018; rs1559355; rs3734015; rs4869315; rs2247650;
rs2549781;
rs2549782; rs2161657; rs251339; rs187265; rs2548527; rs1056893; rs2548523;
rs2255546;
rs2255637; rs1019503; rs251344; rs1981846; rs10071975; rs7700332; rs38042;
rs18059; rs9127;
rs7972829; rs 10784339; rs3803107; rs 11836346; rs7308008; rs 11835545;
rs7959001;
rs11832877; rs10877977; rs2201895; rs7302323; rs10877986; rs2030106;
rs1495027;
rs10877962; rs1042615; rs16856; rs18059; rs27296; rs27300; rs27613; rs2771 1;
rs38033;
rs38035; rs38036; rs38041; rs38043; rs716848; rs1216565; rs1230358; rs1363907;
rs1974871;
rs2042385; rs2113050; rs2113189; rs2161658; rs2255633; rs2255634; rs2287988;
rs2548524;
rs2548529; rs2548530; rs2548532; rs2548533; rs2548536; rs2548538; rs2548539;
rs2548540;
rs2549783; rs2549784; rs2549790; rs2549791; rs2549794; rs2549795; rs2549796;
rs2549797;
rs2617447; rs2910686; rs2927609 rs3797796; rs3849749; rs3849750; rs4360063;
rs4869314;
rs4869316; rs6556942; rs7713127; rs7716222; rs7719705; rs 10044354; rs 10051637; rs 10058476;
rs12516666; and rs12716486.

4. The method of any one of claims 1-3, further comprising comparing the genotype so determined with known genotypes which are known to be indicative of a prognosis for recovery from:
(i) the subject's type of inflammatory condition; or (ii) another inflammatory condition.

5. The method of any one of claims 1-4, further comprising obtaining vasopressin pathway gene sequence information for the subject.

6. The method of any one of claims 1-5, wherein the genotype is determined using a nucleic acid sample from the subject.

7. The method of claim 6, further comprising obtaining the nucleic acid sample from the subject.

8. The method of any one of claims 1-7, wherein said genotype is determined using one or more of the following techniques:
(a) restriction fragment length analysis;
(b) sequencing;
(c) micro-sequencing assay;
(d) hybridization;
(e) invader assay;
(f) gene chip hybridization assays;
(g) oligonucleotide ligation assay;
(h) ligation rolling circle amplification;
(i) 5' nuclease assay;
(j) polymerase proofreading methods;
(k) allele specific PCR;
(l) matrix assisted laser desorption ionization time of flight (MALDI-TOF) mass spectroscopy;
(m) ligase chain reaction assay;
(n) enzyme-amplified electronic transduction;
(o) single base pair extension assay; and (p) reading sequence data.

9. The method of any one of claims 1-8, wherein the genotype of the subject is indicative of increased risk of death or organ dysfunction from the inflammatory condition.

10. The method of claim 9, wherein the subject is critically ill and the genotype is indicative of a prognosis of severe cardiovascular or respiratory dysfunction.

11. The method of claim 9 or 10, wherein the genotype comprises at least one of the following risk genotypes: rs18059CT; rs18059TT; rs27711GA; rs27711GG; rs38041GA;
rs38041GG;
rs 10051637GA; rs 10051637GG; rs 1410713AA; rs857240CC; rs857242CC; rs 10877970CC;
rs3803107TT; and rs1495027TT; or a polymorphic site in linkage disequilibrium thereto.

12. The method of claim 9 or 10, wherein the genotype comprises at least one of the following risk alleles: rs3803107T; and rs10877970C; or a polymorphic site in linkage disequilibrium thereto.

13. The method of any one of claims 1-8, wherein the genotype of the subject is indicative of decreased risk of death or organ dysfunction from the inflammatory condition.

14. The method of claim 13, wherein the subject is critically ill and the genotype is indicative of a prognosis of mild cardiovascular or respiratory dysfunction.

15. The method of claim 13 or 14, wherein the genotype comprises at least one of the following reduced risk genotypes: rs18059CC; rs27711AA; rs38041AA;
rs10051637AA;
rs1410713CC; rs1410713AC; rs857240TT; rs857240CT; rs857242AA; rs857242AC;
rs10877970TT; rs10877970CT; rs3803107CC; rs3803107CT; rs1495027CC and rs1495027CT; or a polymorphic site in linkage disequilibrium thereto.

16. The method of claim 13 or 14, wherein the genotype comprises at least one of the following reduced risk alleles: rs3803107C; and rs10877970T; or a polymorphic site in linkage disequilibrium thereto.

17. The method of claim 11 or 12, wherein the genotype of the polymorphic site in linkage disequilibrium is selected from one or more of the polymorphic sites and corresponding genotypes set out in TABLES 1B and 1D.

18. The method of claim 15 or 16, wherein the genotype of the polymorphic site in linkage disequilibrium is selected from one or more of the polymorphic sites and corresponding genotypes set out in TABLES 1B and 1D.

19. The method of any one of claims 1-18, wherein the inflammatory condition is selected from the group consisting of: sepsis, septicemia, pneumonia, septic shock, systemic inflammatory response syndrome (SIRS), Acute Respiratory Distress Syndrome (ARDS), acute lung injury, aspiration pneumonitis, infection, pancreatitis, bacteremia, peritonitis, abdominal abscess, inflammation due to trauma, inflammation due to surgery, chronic inflammatory disease, ischemia, ischemia-reperfusion injury of an organ or tissue, tissue damage due to disease, tissue damage due to chemotherapy or radiotherapy, and reactions to ingested, inhaled, infused, injected, or delivered substances, glomerulonephritis, bowel infection, opportunistic infections, and for subjects undergoing major surgery or dialysis, subjects who are immunocompromised, subjects on immunosuppressive agents, subjects with HIV/AIDS, subjects with suspected endocarditis, subjects with fever, subjects with fever of unknown origin, subjects with cystic fibrosis, subjects with diabetes mellitus, subjects with chronic renal failure, subjects with acute renal failure, oliguria, subjects with acute renal dysfunction, glomerulo-nephritis, interstitial-nephritis, acute tubular necrosis (ATN), subjects, subjects with bronchiectasis, subjects with chronic obstructive lung disease, chronic bronchitis, emphysema, or asthma, subjects with febrile neutropenia, subjects with meningitis, subjects with septic arthritis, subjects with urinary tract infection, subjects with necrotizing fasciitis, subjects with other suspected Group A streptococcus infection, subjects who have had a splenectomy, subjects with recurrent or suspected enterococcus infection, other medical and surgical conditions associated with increased risk of infection, Gram positive sepsis, Gram negative sepsis, culture negative sepsis, fungal sepsis, meningococcemia, post-pump syndrome, cardiac stun syndrome, myocardial infarction, stroke, congestive heart failure, hepatitis, epiglottitis, E. coli 0157:H7, malaria, gas gangrene, toxic shock syndrome, pre-eclampsia, eclampsia, HELLP syndrome, mycobacterial tuberculosis, Pneumocystic carinii, pneumonia, Leishmaniasis, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura, Dengue hemorrhagic fever, pelvic inflammatory disease, Legionella, Lyme disease, Influenza A, Epstein-Barr virus, encephalitis, inflammatory diseases and autoimmunity including Rheumatoid arthritis, osteoarthritis, progressive systemic sclerosis, systemic lupus erythematosus, inflammatory bowel disease, idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, systemic vasculitis, Wegener's granulomatosis, transplants including heart, liver, lung kidney bone marrow, graft-versus-host disease, transplant rejection, sickle cell anemia, nephrotic syndrome, toxicity of agents such as OKT3, cytokine therapy, and cirrhosis.

20. The method of any one of claims 1-19, wherein the inflammatory condition is selected from one or more of the following: SIRS, sepsis and septic shock.

21. A method for selecting a group of subjects for determining the efficacy of a candidate drug known or suspected of being useful for the treatment of an inflammatory condition, the method comprising determining a genotype at one or more polymorphic sites in a vasopressin pathway gene sequence for each subject, wherein said genotype is indicative of the subject's ability to recover from the inflammatory condition and sorting subjects based on their genotype.

22. The method of claim 21 further comprising, administering the candidate drug to the subjects or a subset of subjects and determining each subject's ability to recover from the inflammatory condition.

23. The method of claim 22, further comprising comparing subject response to the candidate drug based on genotype of the subject.

24. A method of treating an inflammatory condition in a subject in need thereof, the method comprising administering to the subject a vasopressin receptor agonist, wherein said subject has an improved response genotype in their vasopressin pathway associated gene sequence.

25. A method of treating an inflammatory condition in a subject in need thereof, the method comprising selectively not administering a vasopressin receptor agonist to the subject, wherein said subject has an adverse response genotype in their vasopressin pathway associated gene sequence.

26. A method of selecting a subject for the treatment of an inflammatory condition with a vasopressin receptor agonist, comprising the step of identifying a subject having an improved response genotype in their vasopressin pathway associated gene sequence, wherein the identification of a subject with the improved response genotype is predictive of increased responsiveness to the treatment of the inflammatory condition with the vasopressin receptor agonist.

27. A method of selecting a subject for the treatment of an inflammatory condition, comprising the step of identifying a subject having an adverse response genotype in their vasopressin pathway associated gene sequence and selectively not treating with a vasopressin receptor agonist, wherein the identification of a subject with the adverse response genotype is predictive of decreased responsiveness to the treatment of the inflammatory condition with the vasopressin receptor agonist.

28. A use of a vasopressin receptor agonist in the manufacture of a medicament for the treatment of an inflammatory condition, wherein the subjects treated have an improved response genotype in their vasopressin pathway associated gene sequence.

29. A use of a vasopressin receptor agonist in the manufacture of a medicament for the treatment of an inflammatory condition, wherein the subjects treated do not have an adverse response genotype in their vasopressin pathway associated gene sequence.

30. A use of a vasopressin receptor agonist for administration to a subject in need thereof, said subject having an improved response genotype in their vasopressin pathway associated gene sequence.

31. The method or use of any one of claims 24 to 30, further comprising determining the number of organ system failures for the subject as an assessment of subject risk.

32. The method of claim 31, wherein 2 or more organ system failures are indicative of increased subject risk.

33. The method or use of any one of claims 24-32, wherein the inflammatory condition is selected from the group consisting of: sepsis, septicemia, pneumonia, septic shock, systemic inflammatory response syndrome (SIRS), Acute Respiratory Distress Syndrome (ARDS), acute lung injury, aspiration pneumonitis, infection, pancreatitis, bacteremia, peritonitis, abdominal abscess, inflammation due to trauma, inflammation due to surgery, chronic inflammatory disease, ischemia, ischemia-reperfusion injury of an organ or tissue, tissue damage due to disease, tissue damage due to chemotherapy or radiotherapy, and reactions to ingested, inhaled, infused, injected, or delivered substances, glomerulonephritis, bowel infection, opportunistic infections, and for subjects undergoing major surgery or dialysis, subjects who are immunocompromised, subjects on immunosuppressive agents, subjects with HIV/AIDS, subjects with suspected endocarditis, subjects with fever, subjects with fever of unknown origin, subjects with cystic fibrosis, subjects with diabetes mellitus, subjects with chronic renal failure, subjects with acute renal failure, oliguria, subjects with acute renal dysfunction, glomerulo-nephritis, interstitial-nephritis, acute tubular necrosis (ATN), subjects with bronchiectasis, subjects with chronic obstructive lung disease, chronic bronchitis, emphysema, or asthma, subjects with febrile neutropenia, subjects with meningitis, subjects with septic arthritis, subjects with urinary tract infection, subjects with necrotizing fasciitis, subjects with other suspected Group A streptococcus infection, subjects who have had a splenectomy, subjects with recurrent or suspected enterococcus infection, other medical and surgical conditions associated with increased risk of infection, Gram positive sepsis, Gram negative sepsis, culture negative sepsis, fungal sepsis, meningococcemia, post-pump syndrome, cardiac stun syndrome, myocardial infarction, stroke, congestive heart failure, hepatitis, epiglottitis, E. coli 0157:H7, malaria, gas gangrene, toxic shock syndrome, pre-eclampsia, eclampsia, HELLP syndrome, mycobacterial tuberculosis, Pneumocystic carinii, pneumonia, Leishmaniasis, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura, Dengue hemorrhagic fever, pelvic inflammatory disease, Legionella, Lyme disease, Influenza A, Epstein-Barr virus, encephalitis, inflammatory diseases and autoimmunity including Rheumatoid arthritis, osteoarthritis, progressive systemic sclerosis, systemic lupus erythematosus, inflammatory bowel disease, idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, systemic vasculitis, Wegener's granulomatosis, transplants including heart, liver, lung kidney bone marrow, graft-versus-host disease, transplant rejection, sickle cell anemia, nephrotic syndrome, toxicity of agents such as OKT3, cytokine therapy, and cirrhosis.

34. The method or use of any one of claims 24-33, wherein the inflammatory condition is selected from one or more of the following: SIRS, sepsis and septic shock.

35. The method or use of any one of claims 24-34, wherein the improved response genotype is found at one or more of the following polymorphic sites: rs 18059; rs27711; rs 10051637;
rs1410713; rs857240; rs857242; and rs1495027; or a polymorphic site in linkage disequilibrium thereto.

36. The method or use of claim 35, wherein the polymorphic site in linkage disequilibrium is selected from one or more of the following: rs2762; rs10051637; rs1477364;
rs7731592;
rs7736466; rs1363974; rs2351010; rs1423357; rs1544777; rs2161548; rs38032;
rs38034; rs38041;
rs27436; rs27306; rs27307; rs27397; rs27659; rs2771 1; rs27290; rs38030;
rs27294; rs27747;
rs39602; rs248215; rs27302; rs2278018; rs1559355; rs3734015; rs4869315;
rs2247650;
rs254978 1; rs2549782; rs2161657; rs251339; rs187265; rs2548527; rs1056893;
rs2548523;

rs2255546; rs2255637; rs1019503; rs251344; rs1981846; rs10071975; rs7700332;
rs38042;
rs18059; rs9127; rs7972829; rs10784339; rs3803107; rs11836346; rs7308008;
rs11835545;
rs7959001; rs11832877; rs10877977; rs2201895; rs7302323; rs10877986; rs2030106 and rs18059;
rs27296; rs27300; rs27613; rs2771 1; rs38033; rs38035; rs38036; rs38041;
rs38043; rs716848;
rs1216565; rs1230358; rs1363907; rs1974871; rs2042385; rs2113050; rs2113189;
rs2161658;
rs2255633; rs2255634; rs2287988; rs2548524; rs2548529; rs2548530; rs2548532;
rs2548533;
rs2548536; rs2548538; rs2548539; rs2548540; rs2549783; rs2549784; rs2549790;
rs2549791;
rs2549794; rs2549795; rs2549796; rs2549797; rs2617447; rs2910686; rs2927609 rs3797796;
rs3849749; rs3849750; rs4360063; rs4869314; rs4869316; rs6556942; rs7713127;
rs7716222;
rs7719705; rs10044354; rs10051637; rs10058476; rs12516666; and rs12716486.

37. The method or use of claim 35, wherein the improved response genotype is selected from one or more of the following: rs18059CT; rs18059TT; rs27711GG; rs10051637GA;
rs10051637AA; rs1410713AC; rs1410713AA; rs857240CC; rs857242CC; rs1495027CC;
and rs1495027CT; or a polymorphic site in linkage disequilibrium thereto.

38. The method or use of claim 37, wherein the genotype of the polymorphic site in linkage disequilibrium is selected from one or more of the polymorphic sites and corresponding genotypes set out in TABLES 1B and 1D.

39. The method or use of claim 37 or 38, wherein the subject having one or more improved response genotypes is selectively administered the vasopressin receptor agonist.

40. The method or use of claim 37, wherein the subject has an adverse response genotype which is selected from one or more of the following: rs18059CC; rs27711AA;
rs10051637GG;
rs1410713CC; rs857240CT; rs857242AC; and rs1495027TT; or a polymorphic site in linkage disequilibrium thereto.

41. The method or use of claim 40, wherein the genotype of the polymorphic site in linkage disequilibrium is selected from one or more of the polymorphic sites and corresponding genotypes set out in TABLES 1B and 1D.

42. The method or use of claim 40 or 41, wherein the subject having one or more adverse response genotypes is selectively not administered the vasopressin receptor agonist.

43. The method or use of any one of claims 24-42, wherein the vasopressin receptor agonist is vasopressin.

44. Two or more oligonucleotides or peptide nucleic acids of about 10 to about nucleotides that hybridize specifically to a sequence contained in a human target sequence consisting of a subject's vasopressin pathway associated gene sequence, a complementary sequence of the target sequence or RNA equivalent of the target sequence and wherein the oligonucleotides or peptide nucleic acids are operable in determining the presence or absence of two or more polymorphism(s) or in their vasopressin pathway associated gene sequence selected from of the following polymorphic sites: rs18059; rs27711; rs38041;
rs10051637; rs1410713;
rs857240; rs857242; rs 10877970; rs3803107; and rs 1495027; or one or more polymorphic sites in linkage disequilibrium thereto.

45. The oligonucleotides or peptide nucleic acids of claim 44, wherein the one or more polymorphic sites in linkage disequilibrium thereto is selected from one or more of the following polymorphic sites: rs2762; rs10051637; rs1477364; rs7731592; rs7736466;
rs1363974; rs2351010;
rs1423357; rs1544777; rs2161548; rs38032; rs38034; rs38041; rs27436; rs27306;
rs27307;
rs27397; rs27659; rs2771 1; rs27290; rs38030; rs27294; rs27747; rs39602;
rs248215; rs27302;
rs2278018; rs1559355; rs3734015; rs4869315; rs2247650; rs2549781; rs2549782;
rs2161657;
rs251339; rs187265; rs2548527; rs1056893; rs2548523; rs2255546; rs2255637;
rs1019503;
rs251344; rs1981846; rs10071975; rs7700332; rs38042; rs18059; rs9127;
rs7972829; rs10784339;
rs3803107; rsl 1836346; rs7308008; rs11835545; rs7959001; rs11832877;
rs10877977;
rs2201895; rs7302323; rs10877986; rs2030106; rs1495027; rs10877962; rs1042615;
rs16856;
rs18059; rs27296; rs27300; rs27613; rs27711; rs38033; rs38035; rs38036;
rs38041; rs38043;
rs716848; rs1216565; rs1230358; rs1363907; rs1974871; rs2042385; rs2113050;
rs2113189;
rs2161658; rs2255633; rs2255634; rs2287988; rs2548524; rs2548529; rs2548530;
rs2548532;
rs2548533; rs2548536; rs2548538; rs2548539; rs2548540; rs2549783; rs2549784;
rs2549790;
rs2549791; rs2549794; rs2549795; rs2549796; rs2549797; rs2617447; rs2910686;
rs2927609 rs3797796; rs 3849749; rs3849750; rs4360063; rs4869314; rs4869316; rs6556942;
rs7713127;
rs7716222; rs7719705; rs10044354; rs10051637; rs10058476; rs12516666; and rs12716486.

46. Two or more oligonucleotides or peptide nucleic acids selected from the group consisting of:
(a) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:1 having a T at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:1 having a C at position 201;
(b) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:1 having a C at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:1 having a T at position 201;
(c) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:2 having a G at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:2 having a A at position 201;

(d) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:2 having an A at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:2 having a G at position 201;
(e) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:3 having an A at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:3 having a G at position 201;
(f) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:3 having a G at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:3 having an A at position 201;
(g) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:4 having a G at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:4 having an A at position 201;
(h) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:4 having an A at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:4 having a G at position 201;
(i) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:5 having an A at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:5 having a C at position 201;
(j) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:5 having a C at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:5 having an A at position 201;
(k) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:6 having an T at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:6 having a C at position 201;
(1) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:6 having a C at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:6 having an T at position 201;
(m) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:7 having an A at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:7 having a C at position 201;
(n) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:7 having a C at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:7 having an A at position 201;

(o) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:8 having a T at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:8 having a C at position 201;
(p) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:8 having a C at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:8 having a T at position 201;
(q) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:9 having a C at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:9 having a T at position 201;
(r) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO:9 having a T at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:9 having a C at position 201;
(s) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO: 10 having a T at position 201 but not to a nucleic acid molecule comprising SEQ ID NO:10 having a C at position 201;
(t) an oligonucleotide or peptide nucleic acid that hybridizes under high stringency conditions to a nucleic acid molecule comprising SEQ ID NO: 10 having a C at position 201 but not to a nucleic acid molecule comprising SEQ ID NO: 10 having a T at position 201;
(u) an oligonucleotide or peptide nucleic acid capable of hybridizing under high stringency conditions to a nucleic acid molecule comprising a first allele for a given polymorphism selected from the polymorphisms listed in TABLE 1D but not capable of hybridizing under high stringency conditions to a nucleic acid molecule comprising a second allele for the given polymorphism selected from the polymorphisms listed in TABLE 1D; and (v) an oligonucleotide or peptide nucleic acid capable of hybridizing under high stringency conditions to a nucleic acid molecule comprising the second allele for a given polymorphism selected from the polymorphisms listed in TABLE 1D but not capable of hybridizing under high stringency conditions to a nucleic acid molecule comprising the first allele for the given polymorphism selected from the polymorphisms listed in TABLE 1D.

47. An array of oligonucleotides or peptide nucleic acids attached to a solid support, the array comprising two or more of the oligonucleotides or peptide nucleic acids set out in any one of claims 44-46.

48. A composition comprising an addressable collection of two or more oligonucleotides or peptide nucleic acids, the two or more oligonucleotides or peptide nucleic acids consisting essentially of two or more nucleic acid molecules set out in SEQ ID NO: 1-264 or compliments, fragments, variants, or analogs thereof.

49. The oligonucleotides or peptide nucleic acids of any one of claims 44 to 48, further comprising one or more of the following: a detectable label; a quencher; a mobility modifier; a contiguous non-target sequence situated 5' or 3' to the target sequence or 5' and 3' to the target sequence.