CN101356287A - Methods and compositions for the assessment of cardiovascular function and disorders - Google Patents
Methods and compositions for the assessment of cardiovascular function and disorders Download PDFInfo
- Publication number
- CN101356287A CN101356287A CNA2006800507772A CN200680050777A CN101356287A CN 101356287 A CN101356287 A CN 101356287A CN A2006800507772 A CNA2006800507772 A CN A2006800507772A CN 200680050777 A CN200680050777 A CN 200680050777A CN 101356287 A CN101356287 A CN 101356287A
- Authority
- CN
- China
- Prior art keywords
- gene
- coding
- genotype
- polymorphism
- acs
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
The present invention provides methods for the assessment of risk of developing acute coronary syndrome (ACS) in smokers and non-smokers using analysis of genetic polymorphisms. The present invention also relates to the use of genetic polymorphisms in assessing a subject's risk of developing ACS. Nucleotide probes and primers, kits, and microarrays suitable for such assessment are also provided.
Description
Technical field
The present invention relates to use the analysis of genetic polymorphism and changes in gene expression to be used to assess vascular function and/or obstacle, especially for the diagnosis coronary artery disease especially procatarxis of acute coronary syndrome (ACS) and/or the method for severity.The invention still further relates to and be used to diagnose the procatarxis of the damaged blood vessels function relevant and/or the method for severity with ACS.
Background technology
Coronary artery disease (CAD) also win worry or arteriosclerotic heart disease are the primary causes of death of the U.S..According to American Heart Association, the U.S. approximately per 29 seconds just the someone CAD dependent event takes place, approximately per 1 minute just the someone die from such incident.After 40 years old the male sex the lifelong risk of coronary heart disease takes place is 49%, the women then is 32%.Follow female age to increase, this risk also almost is elevated to the male sex's lifelong risk thereupon.In addition, U.S.'s cost of being used for CAD every year is about 1,300 hundred million dollars.
The cardiovascular disorder that causes CAD can be divided into two groups, and the object of this type of obstacle also can be divided into two classes equally.This has been considered to reflect the different causes of disease of this two classes obstacle.The first group of obstacle that is referred to herein as " stable form CAD " shows as deterioration character, comprises late hair style stenocardia and exertional angina pectoris.Stable form CAD generally involves older person, with age (65 years old and more than), hypertension, diabetes, elevated cholesterol (specifically referring to high LDL cholesterol and low HDL cholesterol), lack motion or take exercise with fat relevant.
Second group of obstacle is referred to herein as acute coronary syndrome (ACS), it is believed that relevant with inflammation, patch unstable and/or smoking.ACS comprises myocardial infarction and unstable angina pectoris.Do not wish to be bound by any theory, the present patent application people thinks that genetic risk factor ratio in ACS susceptibility and/or severity is even more important in stable form CAD.
And, do not wish to be subjected to any theoretical institute fetter equally, the present patent application people thinks that the biomarker relevant with stable form CAD can not be correlated with the ACS risk or predict the ACS risk, vice versa.
Having the risk that can be used for evaluation object generation acute coronary syndrome (ACS) or the biomarker of the risk of the relevant damaged blood vessels function of ACS takes place, is desirable and favourable at this object during for the smoker especially.
The present invention relates generally to described biomarker and the purposes in the method for assessing the risk that this class obstacle takes place thereof.
The invention summary
The present invention relates generally to the contact of determining between genotype and the object generation acute coronary syndrome (ACS).As used herein, ACS includes but not limited to myocardial infarction, unstable angina pectoris and relevant acute coronary syndrome.
Therefore, the method that one aspect of the present invention provides a kind of determination object that the risk of ACS takes place, it comprises whether analysis exists one or more to be selected from down the polymorphism of group from the sample of described object:
The gene of coding chyme enzyme 1 (CMA1)-1903A/G
The gene of coding matrix metalloproteinase 12 (MMP12)-82A/G;
Be encoded into the Ser52Ser (223C/T) of the gene of fibroblast growth factor 2 (FGF2);
The Q576R A/G of the gene of coding interleukin-4 acceptor α (IL4RA);
The HOM T2437C of the gene of coding heat shock protein 70 (HSP70);
The 874A/T of the gene of the plain γ of coded interference (IFNG);
The gene of coding interleukin-4 (IL-4)-589C/T;
The gene of coding interleukin 10 (IL-10)-1084A/G (1082);
The Arg213Gly C/G of the gene of encoding superoxide dismutase 3 (SOD3);
The 459C/T Intron I of the gene of coding macrophage inflammatory protein 1 α (MIP1A);
The Asn 125 Ser A/G of the gene of coding cathepsin G;
The I249V C/T of the gene of coding chemokine (CX3C motif) acceptor 1 (CX3CR1);
The Gly 881 Arg G/C of the gene of coding Caspase (NOD2); Or
The 372T/C of the gene of coding tissue inhibitor of metalloproteinase 1 (TIMP1);
Wherein whether the existence of one or more described polymorphisms shows that the risk of ACS takes place object.
Can directly detect or be in described one or more polymorphisms of one or more polymorphisms detections of linkage disequilibrium by detection and described one or more polymorphisms.
Linkage disequilibrium (LD) is a kind of genetics phenomenon, and wherein two or various mutations or polymorphism genetic distance are nearer, make them can be total to heredity.This means in genotyping, detect the existence that a kind of existence of polymorphism can be known another by inference.(people such as Reich DE; Linkagedisequilibrium in the human genome, Nature 2001,411:199-204.)
This method can comprise that also analysis is from whether existing one or more to be selected from down other polymorphisms of group in the sample of described object:
The gene of coding transforminggrowthfactor-(TGFB1)-509C/T;
The Thr26Asn A/C of the gene of coding lymphotoxin α (LTA);
The Asp299Gly A/G of the gene of coding Toll sample acceptor 4 (TLR4);
The Thr399Ile C/T of the gene of coding TLR4;
Inhibitor-like 1 (the Nuclearfactor of kappa light polypeptide gene enhancer in B-cells inhibitor-like 1) gene (NFKBIL1) of the nf of coding B cell κ light chain polypeptide genetic enhancer-63T/A;
The gene of coding platelet derived growth factor receptor α (PDGFRA)-1630Ins/Del (AACTT/Del);
-1607 1G/2G (Del/G) of the gene of coding matrix metalloproteinase 1 (MMP1);
12 IN 5C/T of the gene of coding Thr6 PDGF BB α (PDGFA);
The gene of coding L-glutamic acid-halfcystine ligase enzyme modification subunit (GCLM)-588C/T;
The Ile132Val A/G of the gene of coding olfactory receptor analogue OR13G1 (OR13G1);
The Glu288Val A/T (M/S) of the gene of coding alpha1-antitrypsin (α 1-AT);
K469E A/G in coding intercellular adhesion molecule 1 (ICAM1) gene;
The gene of the coding related transcript 1 of HLA-B (BAT1)-23C/G;
The Glu298Asp G/T of the gene of coding nitricoxide synthase 3 (NOS3);
-668 4G/5G of the gene of coding Type 1 plasminogen activator inhibitor 1 (PAI-1); Or
The gene of coding matrix metalloproteinase 7 (MMP7)-181A/G.
Equally, can directly or by detecting the polymorphism that is in linkage disequilibrium with described one or more other polymorphisms carry out the detection of described one or more other polymorphisms.
One or more existence that are selected from down the polymorphism of group may be that the indication that the risk of ACS reduces takes place, and these polymorphisms are:
Ser52Ser (223 C/T) the CC genotype of the gene of coding FGF2;
The Q576R A/GAA genotype of the gene of coding IL4RA;
The Thr26Asn A/C CC genotype of the gene of coding LTA;
The Hom T2437C CC or the CT genotype of the gene of coding HSP70;
The Asp299GlyA/GAG or the GG genotype of the gene of coding TLR4;
The Thr399Ile C/T CT or the TT genotype of the gene of coding TLR4;
874 A/T TT genotype of the gene of coding IFNG;
The gene of coding NFKBIL1-the 63T/AAA genotype;
-1630 Ins/Del (AACTT/Del) Ins/Del or Del/Del genotype of the gene of coding PDGFRA;
-589 C/T CT or the TT genotype of the gene of coding IL-4;
-588 C/T CC genotype of the gene of coding GCLM;
-1084 A/G GG genotype of the gene of coding IL-10;
The K469E A/G AA genotype of the gene of coding ICAM1;
-23 C/G GG genotype of the gene of coding BAT1;
The Glu298Asp G/T GG genotype of the gene of coding NOS3;
The Arg213Gly C/G CG or the GG genotype of the gene of coding SOD3;
-668 4G/5G 5G5G genotype of the gene of coding PAI-1;
-181 A/G GG genotype of the gene of coding MMP7;
The Asn 125 Ser AG or the GG genotype of the gene of coding cathepsin G; Or
372 T/C TT genotype of the gene of coding TIMP1.
One or more existence that are selected from down the polymorphism of group may show that the risk that ACS takes place raises, and these polymorphisms are:
-1903 A/G GG genotype of the gene of coding CMA1;
-509 C/T CC genotype of the gene of coding TGFB1;
-82 A/G GG genotype of the gene of coding MMP12;
Ser52Ser (223C/T) CT or the TT genotype of the gene of coding FGF2;
The Q576R A/G GG genotype of the gene of coding IL4RA;
The Hom T2437C TT genotype of the gene of coding HSP70;
The Asp299Gly A/G AA genotype of the gene of coding TLR4;
The Thr399Ile C/T CC genotype of the gene of coding TLR4;
-1630 Ins/Del (AACTT/Del) Ins Ins (AACTTAACTT) genotype of the gene of coding PDGFRA;
-589 C/T CC genotype of the gene of coding IL4;
-1607 1G/2G (Del/G) Del Del (1G 1G) genotype of the gene of coding MMP1;
12 IN5 C/T TT genotype of the gene of coding PDGFA;
-588 C/T CT or the TT genotype of the gene of coding GCLM;
The Ile132Val A/G AA genotype of the gene of coding OR13G1;
Glu288Val A/T (M/S) AT of the gene of coding for alpha 1-AT or TT (MS or SS) genotype;
The gene of coding MIP1A+459C/T Intron 1 CT or TT genotype;
The Asn 125 Ser AA genotype of the gene of coding cathepsin G;
The I249V TT genotype of the gene of coding CX3CR1;
The Gly 881 Arg G/C CC or the CG genotype of the gene of coding NOD2; Or
372 T/C CC genotype of the gene of coding TIMP1;
The method of the invention is particularly useful for smoker (CS and smoker) in the past.
It should be understood that the polymorphism of two types of the method for the invention discriminatings---promptly relevant polymorphism (can be described as " protectiveness polymorphism ") and the polymorphism (can be described as " susceptibility polymorphism ") that raises and be correlated with the risk that ACS takes place with the risk reduction that ACS takes place.
Therefore, the present invention also provides evaluation object that the method for the risk of ACS takes place, and described method comprises:
Measure whether to exist and reduce relevant at least a protectiveness polymorphism with the risk that ACS takes place; And
Do not exist under at least a protectiveness polymorphism situation, whether mensuration exists and takes place the relevant at least a susceptibility polymorphism of risk rising of ACS;
Wherein the existence of one or more described protectiveness polymorphisms is that the indication that the risk of ACS reduces takes place, and does not have at least a protectiveness polymorphism and exist at least a susceptibility polymorphism then to show the risk that ACS takes place to raise.
Under the preferable case, described at least a protectiveness polymorphism is selected from:
Described at least a susceptibility polymorphism can be selected from:
In a preferred form of the invention, the existence of two or more protectiveness polymorphisms is that the indication that the risk of ACS reduces takes place.
In another preferred form of the present invention, the existence of two or more susceptibility polymorphisms shows that the risk that ACS takes place raises.
In another preferred form of the present invention, no matter whether there are one or more susceptibility polymorphisms, the existence of two or kinds of protect sexual polymorphism shows that the risk that ACS takes place reduces.
On the other hand, the invention provides the method that the risk of ACS takes place determination object, whether described method comprises acquisition results from one or more heredity tests of described object sample, and analyze and exist one or more to be selected from down the polymorphism of organizing among the described result:
-1903 A/G of the gene of coding chyme enzyme 1 (CMA1);
-82 A/G of the gene of coding matrix metalloproteinase 12 (MMP12);
Be encoded into the Ser52Ser (223C/T) of the gene of fibroblast growth factor 2 (FGF2);
The Q576R A/G of the gene of coding interleukin-4 acceptor α (IL4RA);
The HOM T2437C of the gene of coding heat shock protein 70 (HSP70);
The 874A/T of the gene of the plain γ of coded interference (IFNG);
-589 C/T of the gene of coding interleukin-4 (IL-4);
-1084 A/G (1082) of the gene of coding interleukin 10 (IL-10);
The Arg213Gly C/G of the gene of encoding superoxide dismutase 3 (SOD3);
459 C/T Intron I of the gene of coding macrophage inflammatory protein 1 α (MIP1A);
Asn 125 SerA/G of the gene of coding cathepsin G;
The I249V C/T of the gene of coding chemokine (CX3C motif) acceptor 1 (CX3CR1);
The Gly 881 Arg G/C of the gene of coding Caspase (NOD2); Or
The 372T/C of the gene of coding tissue inhibitor of metalloproteinase 1 (TIMP1); Or
With any in these polymorphisms or multiple one or more polymorphisms that are in linkage disequilibrium;
Show that wherein the result whether one or more described polymorphisms exist is the indication that the risk of ACS takes place object.
On the other hand, the invention provides the method that the risk of ACS takes place determination object, it comprises analyzes the polymorphism that one or more are selected from down group:
-1903 A/G of the gene of coding chyme enzyme 1 (CMA1);
The gene of coding matrix metalloproteinase 12 (MMP12)-82A/G;
Be encoded into the Ser52Ser (223 C/T) of the gene of fibroblast growth factor 2 (FGF2);
The Q576R A/G of the gene of coding interleukin-4 acceptor α (IL4RA);
The HOM T2437C of the gene of coding heat shock protein 70 (HSP70);
874 A/T in plain γ (IFNG) gene of coded interference;
-589 C/T of the gene of coding interleukin-4 (IL-4);
-1084 A/G (1082) of the gene of coding interleukin 10 (IL-10);
The Arg213Gly C/G of the gene of encoding superoxide dismutase 3 (SOD3);
459 C/T Intron I of the gene of coding macrophage inflammatory protein 1 α (MIP1A);
-509 C/T of the gene of coding transforminggrowthfactor-(TGFB1);
The Thr26Asn A/C of the gene of coding lymphotoxin α (LTA);
The Asp299Gly A/G of the gene of coding Toll sample acceptor 4 (TLR4);
The Thr399Ile C/T of the gene of coding TLR4;
-63 T/A of the gene of the inhibitor-like 1 (NFKBIL1) of the nf of coding B cell κ light chain polypeptide genetic enhancer;
-1630 Ins/Del (AACTT/Del) of the gene of coding platelet derived growth factor receptor α (PDGFRA);
-1607 1G/2G (Del/G) of the gene of coding matrix metalloproteinase 1 (MMP1);
12 IN 5C/T of the gene of coding Thr6 PDGF BB α (PDGFA);
Coding L-glutamic acid-halfcystine ligase enzyme is modified-588 C/T of the gene of subunit (GCLM);
The Ile132Val A/G of the gene of coding olfactory receptor analogue OR13G1 (OR13G1);
The Glu288Val A/T (M/S) of the gene of coding alpha1-antitrypsin (α 1-AT);
The K469E A/G of the gene of coding intercellular adhesion molecule 1 (ICAM1);
-23 C/G of the gene of the coding related transcript 1 of HLA-B (BAT1);
The Glu298Asp G/T of the gene of coding nitricoxide synthase 3 (NOS3);
-668 4G/5G of the gene of coding Type 1 plasminogen activator inhibitor 1 (PAI-1); Or
-181 A/G of the gene of coding matrix metalloproteinase 7 (MMP7).
The Asn 125 Ser A/G of the gene of coding cathepsin G;
The I249V C/T of the gene of coding chemokine (CX3C motif) acceptor 1 (CX3CR1);
The Gly 881 Arg G/C of the gene of coding Caspase (NOD2); Or
The 372T/C of the gene of coding tissue inhibitor of metalloproteinase 1 (TIMP1); Or
With any in these polymorphisms or multiple one or more polymorphisms that are in linkage disequilibrium.
In various embodiments, any or multiple aforesaid method comprises the amino acid whose step that analyzes now corresponding to the position of the 576th bit codon of the gene of coding IL4RA.
It is the indication that the risk reduction of ACS takes place that glutamine appears at described position.
It is the indication that the risk rising of ACS takes place that arginine appears at described position.
In various embodiments, any or multiple aforesaid method comprises the amino acid whose step that analyzes now corresponding to the position of the 26th bit codon of the gene of coding LTA.
It is the indication that the risk reduction of ACS takes place that Threonine appears at described position.
It is the indication that the risk rising of ACS takes place that l-asparagine appears at described position.
In various embodiments, any or multiple aforesaid method comprises the amino acid whose step that analyzes now corresponding to the position of the 299th bit codon of the gene of coding TLR4.
It is the indication that the risk reduction of ACS takes place that glycine appears at described position.
It is the indication that the risk rising of ACS takes place that aspartic acid appears at described position.
In various embodiments, any or multiple aforesaid method comprises the amino acid that analyzes now corresponding to the position of the 399th bit codon of the gene of coding TLR4.
It is the indication that the risk reduction of ACS takes place that Isoleucine appears at described position.
It is the indication that the risk rising of ACS takes place that Threonine appears at described position.
In various embodiments, any or multiple aforesaid method comprises the amino acid whose step that analyzes now corresponding to the position of the 132nd bit codon of the gene of coding OR13G1.
It is the indication that the risk rising of ACS takes place that Isoleucine appears at described position.
In various embodiments, any or multiple aforesaid method comprises the amino acid whose step that analyzes now corresponding to the position of the 288th bit codon of the gene of coding for alpha 1-AT.
It is the indication that the risk rising of ACS takes place that L-glutamic acid appears at described position.
In various embodiments, any or multiple aforesaid method comprises the amino acid whose step that analyzes now corresponding to the position of the 496th bit codon of the gene of coding ICAM1.
It is the indication that the risk reduction of ACS takes place that Methionin appears at described position.
In various embodiments, any or multiple aforesaid method comprises the amino acid whose step that analyzes now corresponding to the position of 298 bit codons of the gene of coding NOS3.
It is the indication that the risk reduction of ACS takes place that L-glutamic acid appears at described position.
It is the indication that the risk rising of ACS takes place that aspartic acid appears at described position.
In various embodiments, any or multiple aforesaid method comprises the amino acid whose step that analyzes now corresponding to the position of the 213rd bit codon of the gene of coding SOD3.
It is the indication that the risk reduction of ACS takes place that glycine appears at described position.
In various embodiments, any or multiple aforesaid method comprises the amino acid whose step that analyzes now corresponding to the position of the 125th bit codon of the gene of coding cathepsin G.
It is the indication that the risk reduction of ACS takes place that Serine appears at described position.
It is the indication that the risk rising of ACS takes place that l-asparagine appears at described position.
In various embodiments, any or multiple aforesaid method comprises the amino acid whose step that analyzes now corresponding to the position of the 249th bit codon of the gene of coding CX3CR1.
It is the indication that the risk rising of ACS takes place that Isoleucine appears at described position.
In various embodiments, any or multiple aforesaid method comprises the amino acid whose step that analyzes now corresponding to the position of the 881st bit codon of the gene of coding NOD2.
It is the indication that the risk rising of ACS takes place that arginine appears at described position.
In a preferred form of the invention, in conjunction with the analysis of carrying out the methods described herein risks and assumptions (comprise one or more epidemiology risks and assumptions) relevant with the risk that ACS takes place with one or more.Described epidemiology risks and assumptions includes but not limited to smoking or tobacco smoke exposure, age, sex and ACS family history.
On the other hand, the invention provides the purposes of at least a polymorphism in evaluation object generation ACS risk, wherein said at least a polymorphism is selected from:
-1903 A/G of the gene of coding chyme enzyme 1 (CMA1);
-82 A/G of the gene of coding matrix metalloproteinase 12 (MMP12);
Be encoded into the Ser52Ser (223 C/T) of the gene of fibroblast growth factor 2 (FGF2);
The Q576R A/G of the gene of coding interleukin-4 acceptor α (IL4RA);
The HOM T2437C of the gene of coding heat shock protein 70 (HSP70);
874 A/T in plain γ (IFNG) gene of coded interference;
-589 C/T of the gene of coding interleukin-4 (IL-4);
-1084 A/G (1082) of the gene of coding interleukin 10 (IL-10);
The Arg213Gly C/G of the gene of encoding superoxide dismutase 3 (SOD3);
459 C/T Intron I of the gene of coding macrophage inflammatory protein 1 α (MIP1A);
The Asn 125 Ser A/G of the gene of coding cathepsin G;
The I249V C/T of the gene of coding chemokine (CX3C motif) acceptor 1 (CX3CR1);
The Gly 881 Arg G/C of the gene of coding Caspase (NOD2); Or
The 372T/C of the gene of coding tissue inhibitor of metalloproteinase 1 (TIMP1); Or
Be in one or more polymorphisms of linkage disequilibrium with any described polymorphism.
Randomly, described purposes can be used in combination at least a other polymorphisms that are selected from down group:
The gene of coding transforminggrowthfactor-(TGFB1)-509C/T;
The Thr26Asn A/C of the gene of coding lymphotoxin α (LTA);
The Asp299Gly A/G of the gene of coding Toll sample acceptor 4 (TLR4);
The Thr399Ile C/T of the gene of coding TLR4;
-63 T/A of the gene of the inhibitor-like 1 (NFKBIL1) of the nf of coding B cell κ light chain polypeptide genetic enhancer;
-1630 Ins/Del (AACTT/Del) of the gene of coding platelet derived growth factor receptor α (PDGFRA);
-1607 1G/2G (Del/G) of the gene of coding matrix metalloproteinase 1 (MMP1);
12 IN 5C/T of the gene of coding Thr6 PDGF BB α (PDGFA);
Coding L-glutamic acid-halfcystine ligase enzyme is modified-588 C/T of the gene of subunit (GCLM);
The Ile132Val A/G of the gene of coding olfactory receptor analogue OR13G1 (OR13G1);
The Glu288Val A/T (M/S) of the gene of coding alpha1-antitrypsin (α 1-AT);
The K469E A/G of the gene of coding intercellular adhesion molecule 1 (ICAM1);
The gene of the coding related transcript 1 of HLA-B (BAT1)-23C/G;
The Glu298Asp G/T of the gene of coding nitricoxide synthase 3 (NOS3);
-668 4G/5G of the gene of coding Type 1 plasminogen activator inhibitor 1 (PAI-1);
-181 A/G of the gene of coding matrix metalloproteinase 7 (MMP7);
Or with these polymorphisms in any or multiple one or more polymorphisms that are in linkage disequilibrium.
On the other hand, the invention provides one group of nucleotide probe and/or primer that is used for the preferred process of the present invention as herein described.Under the preferable case, described nucleotide probe and/or primer are to cross over the probe and/or the primer that maybe can be used to cross over described gene pleiomorphism zone.The present invention also provides one or more nucleotide probes and/or primer, and it contains sequence any in probe as herein described and/or the primer, comprises the sequence that contains any sequence among the SEQ.ID.NO.1 to 124.
Aspect another; the invention provides the nucleic acid microarray that is used for the method for the invention; wherein said microarray comprises base material, described base material present can with the nucleotide sequence of coding one or more susceptibilities as herein described or protectiveness polymorphism or the nucleotide sequence of complementary sequence hybridization with it.
On the other hand; the invention provides the antibody microarray that is used for the method for the invention; wherein said microarray comprises base material; described base material present can with gene expression product bonded antibody; when relevant with susceptibility as herein described or protectiveness polymorphism, described expression of gene can raise or reduce.
On the other hand, the invention provides the method for the object for the treatment of the risk rising that ACS takes place, it is included in genotype or phenotypic level repeats the existence of protectiveness polymorphism and/or the step of functional effect in described object.
Aspect another, the invention provides the method for the object for the treatment of the risk rising that ACS takes place, described object has detectable susceptibility polymorphism, it or raise or reduce certain expression of gene, make the physiologically active concentration of described expressing gene product exceed beyond the normal range for described object age and sex, the physiologically active concentration that described method comprises the described product that recovers genetic expression to the normal range for described object age and sex with interior step.
On the other hand, the invention provides treatment because of there being the method for estimating the polymorphism of ACS susceptible is made the object of the risk rising that ACS takes place, it comprises the functional effect described object from genotype level or the phenotypic level described polymorphism of reverse.
Again on the one hand, the invention provides the method for the object for the treatment of the risk rising that ACS takes place, for described object, determined to be present in the coding MMP12 gene promoter-the GG genotype at 82A/G pleomorphism site place, described method comprises using to described object can regulate the active medicament of described object MMP12.
In one embodiment, described medicament is a kind ofly to increase that one or more tissue inhibitor of metalloproteinase (TIMP) express or active medicament, is preferably among TIMP1, TIMP2, TIMP3 or the TIMP4 one or more expression or activity.In another embodiment, described medicament is a kind of one or more expression that combines MMP with film or active medicaments that reduce.In another embodiment, described medicament is the MMP inhibitor, described MMP inhibitor is selected from 4 under the preferable case, 5-dihydroxyanthraquinone-2-carboxylic acid (AQCA), anthraquinone-mercaptoethylamine (anthraquinyl-mercaptoethyamine), anthraquinone-L-Ala hydroxamic acid (anthraquinyl-alanine hydroxamate) and their derivative.
On the other hand, the invention provides the method for the object for the treatment of the risk rising that ACS takes place, it is for described object, determined to be present in the CC genotype at 372T/C pleomorphism site place in the coding TIMP1 gene, described method comprises using to described object can regulate the active medicament of described object TIMP1.
In one embodiment, described medicament is that a kind of TIMP1 of increasing expresses or active medicament.
On the other hand; the invention provides the method for expression of screening regulatory gene and/or active compound; when described gene is relevant with susceptibility or protectiveness polymorphism; it is expressed and can raise or downward modulation when not relevant with described polymorphism with described gene (expression level compare), and described method comprises the following steps:
Candidate compound is raised with genetic expression or the susceptibility that downward modulation is relevant or the cells contacting of protectiveness polymorphism with containing to be determined; And
Use described candidate compound contact back to measure described expression of gene,
Wherein with before the contact procedure compare, the changes of expression level after the contact procedure represents that described compound regulates described expression of gene and/or active ability.
Under the preferable case, described cell behaviour vascular cell more preferably is people's blood vessel epithelial cell, and it is confirmed to exist described polymorphism by prescreen.
Under the preferable case, described cell comprises and the relevant susceptibility polymorphism of described genetic expression rise that described screening is used to reduce the candidate compound of described genetic expression.
Perhaps, described cell comprises the susceptibility polymorphism relevant with described down regulation of gene expression, and described screening is used to raise the candidate compound of described genetic expression.
In another embodiment, described cell comprises and the relevant protectiveness polymorphism of described genetic expression rise that described screening is used for further raising the candidate compound of described genetic expression.
Perhaps, described cell comprises the protectiveness polymorphism relevant with described down regulation of gene expression, and described screening is used for further reducing the candidate compound of described genetic expression.
On the other hand, the invention provides the method for expression of screening regulatory gene and/or active compound, it was expressed and can raise or downward modulation when described gene was relevant with susceptibility or protectiveness polymorphism, and described method comprises the following steps:
With candidate compound with contain the cells contacting of gene, when this gene is relevant with susceptibility or protectiveness polymorphism its express can rise or reduce, but this expression of gene neither raises also and does not cut in described cell; And
Use described candidate compound contact back to measure described expression of gene,
Wherein with before the contact procedure compare, the variation of the gene expression dose after the contact procedure represents that described compound regulates described expression of gene and/or active ability.
Under the preferable case, it was expressed and can reduce when described gene was relevant with the susceptibility polymorphism, in case described screening is used for raising at described cell the candidate compound of described genetic expression.
Under the preferable case, described cell behaviour vascular cell more preferably is people's blood vessel epithelial cell, and it has been confirmed the existence and the baseline expression level of described gene by prescreen.
Perhaps, it was expressed and can raise when described gene was relevant with the susceptibility polymorphism, and described screening is used for the candidate compound in the described genetic expression of described cell downward modulation.
In another embodiment, it was expressed and can raise when described gene was relevant with the protectiveness polymorphism, and described screening is used for raising at described cell the candidate compound of described genetic expression.
Perhaps, it was expressed and can reduce when described gene was relevant with the protectiveness polymorphism, and described screening is used for the candidate compound in the described genetic expression of described cell downward modulation.
Aspect another, the invention provides the risk of assessing existence generation ACS or suffer from the possible reactive method of the object of ACS prevention or treatment processing, described processing relates to physiologically active concentration with gene expression product and returns to for described object age and sex in the due normal range of institute, described method comprise detect susceptibility polymorphism in the described object existence whether, when described susceptibility polymorphism exists or rise or reduce described expression of gene, make the physiologically active concentration of described expressing gene product exceed beyond the described normal range, the existence that wherein detects described polymorphism represents that described object may respond described processing.
On the other hand, the invention provides the test kit that the risk of ACS takes place evaluation object, described test kit comprises whether analysis exists the device of one or more polymorphisms disclosed herein from the sample of described object.
The accompanying drawing summary
Fig. 1: illustrate at SNP fractional ACS frequency from 11 SNP group.
Fig. 2: the SNP fractional ACS frequency at 15 SNP group is shown.
Fig. 3: illustrate according to the SNP mark that is derived from 11 SNP group and have the logarithm advantage of ACS.
Fig. 4: illustrate at SNP fractional ACS frequency from alternate 11 SNP group.
Preferred implementation is described
Use case control study, the smoker of ACS has relatively been taken place and the candidate gene of the contrast of donating blood in the frequency of several genetic variants (polymorphism).These candidate gene great majority have the functional effect of affirmation (maybe may confirm) to genetic expression or protein function.Particularly, the polymorphism frequency of donating blood contrast, resistance smoker (resistant smoker) and suffering from the smoker of ACS compares.
In a kind of embodiment as herein described, identify 20 susceptibility genetic polymorphisms and 20 protectiveness genetic polymorphisms.These polymorphisms are as follows:
Gene pleiomorphism genotype phenotype
CMA1-1903A/G GG susceptibility
TGFB1-509C/T CC susceptibility
MMP12-82A/G GG susceptibility
FGF2 Ser52Ser223C/T CT/TT susceptibility
The CC protectiveness
IL4RA Q576RA/G GG susceptibility
The AA protectiveness
LTA Thr26AsnA/C CC protectiveness
HSP70 Hom T2437C CC/CT protectiveness
The TT susceptibility
TLR4 Asp299GlyA/G AG/GG protectiveness
The AA susceptibility
TLR4 Thr399IleC/T CT/TT protectiveness
The CC susceptibility
IFNG 874A/T TT protectiveness
NFKBIL1-63T/A AA protectiveness
PDGFRA-1630I/D, AACTT/Del I/Del, Del/Del protectiveness
The II susceptibility
IL4-589C/T CT/TT protectiveness
The CC susceptibility
MMP1-16071G/2G, Del/G Del.Del ie1G1G susceptibility
PDGFA 12IN5C/T TT susceptibility
GCLM-588C/T CT/TT susceptibility
The CC protectiveness
OR13G1 Ile132ValA/G AA susceptibility
IL-10-1084A/G (1082) GG protectiveness
α 1-ATS Glu288ValA/T (M/S) AT/TT MS/SS susceptibility
Allelotrope
ICAM1 K469EA/G AA protectiveness
BAT1-23C/G GG protectiveness
NOS3 Glu298AspG/T GG protectiveness
SOD3 Arg213GlyC/G CG/GG protectiveness
PAI-1-6684G/5G 5G5G protectiveness
MIP1A+459C/TIntron1 CT/TT susceptibility
MMP7-181A/G GG protectiveness
The Asn125Ser AG/GG of cathepsin G protectiveness
The AA susceptibility
CX3CR1 I249V TT susceptibility
NOD2 Gly881ArgG/C CC/CG susceptibility
TIMP1 372T/C TT protectiveness
The CC susceptibility
The existence of susceptibility genetic polymorphism is that the indication that the risk of ACS raises takes place.On the contrary, the existence of protectiveness genetic polymorphism represents that the risk that ACS takes place reduces.
As used herein, the risk of ACS " takes place " and means the possibility that faces risk object generation ACS in phrase, and comprises procatarxis and potential morbidity to disease.Therefore, phrase " risk that ACS takes place raises " means genetic predisposition or trend that the object that carries this rising risk has generation ACS.This does not represent this object reality generation at any time ACS, only show with not having and compare that the possibility that ACS takes place for he or she is bigger with raise relevant polymorphism or have of the risk that ACS takes place with general population that the risk that ACS takes place reduces the polymorphism of being correlated with.Carry the object that ACS rising risk takes place and comprise having for example object of trend or preference of ACS procatarxis, its vascular function when assessing.The object that for example has ACS incidence inheritance tendency but have the normal blood vessels function, be in the object of potential risk, comprise object with the slight downtrending of vascular function, as they might suffer from ACS to continue smoking, and object with potential ACS morbidity, they have the trend that vascular function worsens, this during with assessment the ACS state of an illness of discovery consistent.
Similar with it, phrase " reduction of generation ACS risk " means the object that carries this reduction risk and has genetic predisposition or the trend that does not take place or ACS takes place less.This does not represent that this object at no time ACS can take place, only show with having and compare that the possibility that ACS takes place for he or she is littler with raise relevant polymorphism or do not have of the risk that ACS takes place with general population that the risk that ACS takes place reduces the polymorphism of being correlated with.
Be understood that, in the present invention, the probability that two or more alternatively forms (for example allelotrope or genetic marker) that term " polymorphism " means a chromosomal foci occur in same people simultaneously is greater than the probability (usually greater than 1%) of random mutation, and these alternatively forms have different nucleotide sequences or have the repetition nucleotide units of variable number.Referring to
Www.ornl.gov/sci/techresources/Human Genome/publicat/97pr/09gloss.html#p. therefore, term " polymorphism " means heritable variation in this article, comprises mononucleotide replacement, Nucleotide insertion and disappearance, tumor-necrosis factor glycoproteins (as little satellite) and all or part of genetically deficient (as null mutation).As used herein, term " polymorphism " also comprises genotype and haplotype.Genotype is the genetic composition at certain specific site or certain group specific site place.Haplotype is one group and is present in closely linked genetic marker on the karyomit(e), and they are difficult for by heavy constituent from, often heredity together, and may be in the linkage disequilibrium.Haplotype can identify by the pattern such as the SNP of polymorphism.Similar with it, term " single nucleotide polymorphism " or " SNP " comprise that in linguistic context of the present invention single nucleotide base replaces and polymorphism is lost and inserted in shortage.
Can be to reduce or rising by analyzing from whether existing the polymorphism that is selected from down group to come the risk that ACS takes place diagnosis object in the sample of described object:
The gene of coding chyme enzyme 1 (CMA1)-1903A/G;
The gene of coding matrix metalloproteinase 12 (MMP12)-82A/G;
Be encoded into the Ser52Ser (223C/T) of the gene of fibroblast growth factor 2 (FGF2);
The Q576R A/G of the gene of coding interleukin-4 acceptor α (IL4RA);
The HOM T2437C of the gene of coding heat shock protein 70 (HSP70);
The 874A/T of the gene of the plain γ of coded interference (IFNG);
In coding interleukin-4 (IL-4) gene-589C/T;
The gene of coding interleukin 10 (IL-10)-1084A/G (1082);
The Arg213Gly C/G of the gene of encoding superoxide dismutase 3 (SOD3);
The 459C/T Intron I of the gene of coding macrophage inflammatory protein 1 α (MIP1A);
The Asn 125 Ser A/G of the gene of coding cathepsin G;
The I249V C/T of the gene of coding chemokine (CX3C motif) acceptor 1 (CX3CR1);
The Gly 881 Arg G/C of the gene of coding Caspase (NOD2); Or
The 372T/C of the gene of coding tissue inhibitor of metalloproteinase 1 (TIMP1); Or any or multiple polymorphism is in the polymorphism of linkage disequilibrium in one or more and last group.
These polymorphisms also can be united two or more and analyzed, or together analyze with other polymorphisms (being included in top listed polymorphism) that the ACS risk takes place indicated object.
The detection that relates to the polymorphism combination (comprises that high throughput testing (as using the detection of microarray) is preferred.
The statistical study especially statistical results show hereditary check of the present invention of these polymorphism combined effects can be used to measure the risk quotient of any object (comprising the smoker), is in the object of the risk of higher generation ACS especially for evaluation.This class combinatory analysis can only be the combination of susceptibility polymorphism, only is the combination of protectiveness polymorphism or the combination of the two.Analyzing can also proceed step by step, and whether the existence of wherein at first analyzing the protectiveness polymorphism only continues to analyze the susceptibility polymorphism when the unprotect sexual polymorphism.
Therefore, by the frequency of these polymorphisms of systems analysis in the object colony that clearly defines (comprising smoker as described herein and non-smoker), might set up some gene and protein and differentiate that with related also raising the between the ACS morbidity ability of the risk rising of relevant damaged blood vessels function of ACS and ACS takes place which class object based on the prediction purpose.
Result of the present invention shows that the minority smoker's that ACS takes place risk raises really, because they have one or more susceptibility polymorphisms and seldom or do not have a protectiveness polymorphism defined herein.The noxious stimulus and the oxygenant effect that it is believed that the existence of one or more susceptibility polymorphisms and smoking join together to make this group smoker height susceptible in ACS takes place.Other risks and assumptions for example also can exert an influence to the risk status of object in family history, age, body weight, bag year (pack year) etc., and these risks and assumptions can be assessed in conjunction with genetic analysis as herein described.
Can directly detect described one or more polymorphisms or detect described one or more polymorphisms by detecting one or more polymorphisms that are in linkage disequilibrium with described one or more polymorphisms.Discuss as mentioned, linkage disequilibrium is a kind of genetics phenomenon, and wherein two or more sudden changes or polymorphism genetic distance are nearer, make them can be total to heredity.This means when genotyping, detect the existence that a kind of existence of polymorphism can be known another by inference.(people such as Reich DE; Linkagedisequilibrium in the human genome, Nature 2001,411:199-204.)
This paper has provided the aforementioned example that it is reported the polymorphism that is in linkage disequilibrium, these examples comprise MMP12-82 A/G shown in this paper embodiment 1 and the table 33 and MMP1-1607 1G/2G (Del/G) polymorphism, LTA Thr26Asn A/C and NFKBIL 1-63T/A polymorphism and TLR4Asp299Gly A/G and Thr399Ile C/T polymorphism.
It is evident that, raise or reduce the biomarker that polymorphism that relevant polymorphism is in linkage disequilibrium also can be used as generation ACS risk with the risk that ACS takes place with one or more other.The listed data sheet of this paper where there is light is very similar in the frequency of the SNP of linkage disequilibrium.Therefore, the SNP of these genetic linkages can combine with polymorphism analysis and be used to extrapolate the risk level that is similar to the risk level that calculates from former SNP.This paper embodiment 2 has provided a kind of example of this alanysis, and a kind of SNP that wherein is in LD is replaced by another kind of SNP.
Therefore it is evident that one or more polymorphisms that are in linkage disequilibrium with polymorphism as referred to herein can obtain identifying by for example public database.This paper table 35 has provided this class and it is reported the example that is in the polymorphism of linkage disequilibrium with polymorphism as referred to herein.
Also it is evident that, may have multiple naming method usually for any given polymorphism.For example, it is believed that the polymorphism of Arg 213 Gly that this paper is called the gene of the SOD3 that encodes differently is called Arg 312 Gln ,+760 G/C and Arg 231 Gly (rs1799895).When mentioning susceptibility as herein described or protectiveness polymorphism, the present invention also considers the interchangeable another name of this class.
The method of the invention relates generally to the detection and the evaluation of the above-mentioned polymorphism relevant with ACS.These polymorphisms are generally single nucleotide polymorphism.Generally speaking, single nucleotide polymorphism (SNP) is single sequence change or the point mutation that causes heritable variation between the individuality.The occurrence frequency of SNP in human genome is approximately in per 100 to 300 bases 1, and it can occur in coding region or non-coding region.Because the redundancy of genetic code, the SNP of coding region may or may not can change the aminoacid sequence of protein.The SNP that is positioned at non-coding region can be for example by changing genetic expression and influence genetic transcription, processing and translation as promotor, transcription factor binding site point, processing site, ribosome bind site as modifying the regulation and control zone.
SNP helps extensive related genetic research, and people have had very big interest to discovery and the detection of SNP recently.SNP shows the bright prospects as the marker of many phenotypic characters (comprising potential proterties), and the tendency of for example falling ill and severity, healthy tendency and drug responsiveness for example comprise the susceptibility to adverse drug reaction.Understand related and individuality between certain specific SNP and the phenotypic character and whether carry described specific SNP and can realize that targeting diagnosis, prevention and treatment use, handle and increase the understanding of morbid state and finally promote for example discovery of individualized treatment scheme of more effective treatment to realize better disease.
Really, made up at present many databases of known SNP, some SNP has wherein also been made up the database of many biological effects related with SNP.For example, NCBI snp database " dbSNP " is integrated into the Entrez system of NCBI, can use the method identical with GenBank with other Entrez databases such as PubMed to inquire about.This database has been included the SNP more than 1,500,000 that draws on the human genomic sequence.Every dbSNP record comprises the contiguous sequence (sequence context) (sequence promptly) of polymorphism, polymorphism occurrence frequency (colony or individuality) and be used to measure experimental technique, scheme and the condition of variation also comprises the data of the SNP related with the particular phenotype proterties.
To small part is also to put into the method that SNP can be reliably identified in research and development apace because SNP, has big quantity research input to health and healthy potential impact.This is not a gravy jobs, and at least in part because human genome DNA's complicacy, only the monoploid genome just has 3 * 109 base pairs, also has relevant susceptibility in addition and differentiates requirement.
The genotyping method that is used to detect SNP well known in the art comprises dna sequencing, need the allele-specific hybridization of primer or probe, the Nucleotide allele-specific is incorporated into and near or contiguous polymorphism bonded primer (being commonly referred to " single-basic extension " or " micrometering preface "), the oligonucleotide allele-specific connects (connection) (connection chain reaction or connection padlock probe), the allele-specific cutting (restriction fragment length polymorphism analysis or RFLP) that oligonucleotide or PCR product carry out through restriction enzyme or chemical or other agent, distinguish the allelotrope dependency difference of electrophoresis or chromatography mobility or mass spectrum by the structure specific enzymes that comprises invasive structure specific enzymes.When SNP is positioned at the coding region and cause amino acid to change, also can use the amino acid variation analysis.
Dna sequencing allows directly to measure and identify SNP.During screening, full genome even the general advantage that surpasses specificity and accuracy aspect of target subgene group order-checking inherent difficulty.
The micrometering preface relates to the dna sequence dna that allows SNP site in the test sample that primer hybridization studies to being adjacent to.Four kinds of not the fluorescence dideoxy nucleotide of isolabeling (A, C, G or T) and archaeal dna polymerase prolongation primers are carried in use.Having only in four kinds of Nucleotide in a kind of (under the homozygote situation) or four kinds of Nucleotide has two kinds (under heterozygote situations) to be integrated.The base complementrity of integrating is in the Nucleotide that is positioned at the SNP site.
The many methods that are used for the SNP detection at present relate to locus specificity hybridization and/or allele-specific hybridization.These methods are attached on the target sequence that contains purpose SNP with mainly relying on the oligonucleotide distinctiveness.Affymetrix (Santa Clara, Calif.) and Nanogen Inc. (San Diego, technology Calif.) is particularly famous, it is more much lower than the complete paired two strands of base that these technology utilize this fact promptly to contain the dna double chain stability of single base mismatch.Existence by fluoroscopic examination pairing duplex.
Hybridize by locus specificity and to detect or to identify target amplification that the most methods of SNP need be undertaken by for example PCR method to increase susceptibility and specificity (for example referring to U.S. Patent No. 5,679,524, the open WO 98/59066 of PCT, the open WO 95/12607 of PCT).U.S. Patent application 20050059030 (integral body is incorporated this paper into) has been described a kind of method that detects single nucleotide polymorphism among the human total DNA, and it does not need amplification in advance or reduces complexity with enriched target sequence optionally, need not any enzyme reaction yet.Described method has been used the single step hybridization that relates to two hybridisation events.First part's target sequence hybridizes on the capture probe, and the described target sequence of second section hybridizes on the detection probes.Two hybridisation events occur in the same reaction, and the order that hybridization takes place is not vital.
U.S. Patent application 20050042608 (integral body is incorporated this paper into) has been described the improvement to people such as Thorp (U.S. Patent No. 5,871,918) electrochemically detecting nucleic acid hybridizing method.In brief, the design capture probe, wherein every probe all has different SNP bases and has one section probe sequence in the every side of described SNP base.The probe base complementrity is in the corresponding target sequence adjacent with the SNP site.Every capture probe is fixed on the different electrodes, and this electrode has nonconducting skin on the conduction working-surface of matrix.Use transition metal complex after testing the redox reaction at each electrode place detect hybridization degree between every capture probe and the described nucleic acid target.Utilize these differences of different anodizing speed to determine whether selected nucleic acid target has single nucleotide polymorphism in selected SNP site.
Use MEGATYPE
TM(Hayward, Calif.) technology can be carried out genotyping to a large amount of SNP from big and small genetic material storehouse to the Lynx Therapeutics of technology simultaneously.Two colony's genomes that this technology uses fluorescently-labeled probe relatively to collect can detect and reclaim and cross over the dna fragmentation of distinguishing these two SNP of colony, and need not to carry out in advance the SNP mapping or understand SNP.
Exist many other to be used to detect and identify the method for SNP.These methods comprise uses mass spectrum for example to measure probe with SNP hybridization.This technology changes because of the speed that it carries out, and this technology of functional quality coded markings can realize that the processing of several samples can realize the high-throughput of 40,000 SNP to every day every day.A kind of preferred embodiment is to use mass spectroscopy to comprise the nucleotide sequence of polymorphism of the present invention, and for example this nucleotide sequence comprises the promotor of COX2 gene or complementary sequence.Described mass spectrometry method is known for those skilled in the art, and genotyping method of the present invention can be revised the mass spectrometric detection that is used for polymorphism of the present invention, COX2 promotor polymorphism for example of the present invention.
Also can analyze and determine SNP by ligation-bit.This analyzes the primer that needs two to hybridize with target, wherein has a Nucleotide gap between two primers.Each of four kinds of Nucleotide is joined in the independent reaction mixture that contains archaeal dna polymerase, ligase enzyme, target DNA and primer.Polysaccharase adds Nucleotide with 3 ' of SNP complementary first primer to be held, and ligase enzyme connects together the primer of two vicinities then.After the sample heating, if connect, longer primer will still be in the hybridization state and can detect signal such as fluorescent signal this moment.The further discussion of these methods is found in United States Patent (USP) 5,919,626; 5,945,283; 5,242,794 and 5,952, No. 174.
United States Patent (USP) 6,821,733 (integral body is incorporated this paper into) were described the method that detects two sequence of nucleic acid molecules differences, and it comprises the following steps: two nucleic acid are contacted under the condition that allows formation four-way mixture (four-waycomplex) and branch migration; With four-way mixture and labelled molecule and detection molecules detection molecules can with labelled molecule or four-way mixture bonded condition under contact; And measure and to be exposed to combining between the labelled molecule and detection molecules before and after the four-way mixture.The competition that combines detection molecules between four-way mixture and the labelled molecule shows two kinds of differences between the nucleic acid.
Method based on protein and proteomics also is suitable for polymorphism detection and analysis.Can detect by the described protein of direct analysis and to cause marking protein to change or change related polymorphism with marking protein.This for example generally need by gel electrophoresis or HPLC separate the different proteins in the duplicate samples and for example be derived from as chemistry order-checking or more common mass spectrum evaluation by NMR or protein sequencing as described in sample as described in protein or peptide.Proteomics method is learned and is known by technical field, has wide automatization prospect.For example, integrated system is as the ProteomIQ from Proteome Systems
TMSystem provides the high-throughput platform for Proteomic analysis, and it combines specimen preparation, protein separation, IMAQ and analysis, protein processing, mass spectrum and bioinformatics technique.
Most proteomics methods of identification of proteins utilize mass spectrum, comprise ion trap mass spectrometry, liquid chromatography (LC) (LC) and LC/MSn mass spectrum, gas chromatography (GC) mass spectrum, Fourier Transform Ion cyclotron Resonance mass spectrograph (FT-MS), MALDI-TOF mass spectrum and ESI mass spectrum and their deriving method.The mass-spectrometry method also is useful for proteinic posttranslational modification as phosphorylation or glycosylated mensuration, therefore can be used for measuring causing the protein post-translational modification variation or changing related polymorphism with protein post-translational modification.
Correlation technique is also known, comprise that for example the protein processing units is as " chemicals ink-jet printer ", it comprises the piezoelectricity printing technique, allows by enzyme or chemicals are directly injected to selected protein spot the protein example from 2-D PAGE gel electrotransfer to film to be carried out original position enzyme or chemical digestion.Behind digestion of protein original position and the incubation, described film can directly be placed on and carry out peptide analysis in the mass spectrograph.
Develop many variable methods of nucleic acid conformation that depend on and detected SNP.
For example, single strand conformation polymorphism (SSCP, people such as Orita., PNAS 1989 86:2766-2770) be a kind of method that in solution, forms the secondary structure ability that relies under certain condition of single-chain nucleic acid.Secondary structure depends on that base constitutes and can change by the mononucleotide replacement, thereby causes the difference of electrophoretic mobility under non-sex change condition.General by radioautograph (if carrying radio-labeling), band silver dye, detectable label probe fragment hybridization or use fluorescence PCR primer (with after for example automated DNA sequenator detection) that various polymorphisms (polymorph) are detected.
The technical field that is improved to of SSCP is known, and comprises the different gel electrophoresis condition of using, for example differing temps or adding additive and different gel matrixs.Other of SSCP are changed to the technician and know, comprise RNA-SSCP, restriction enzyme fingerprint-SSCP, two deoxidation fingerprints (dideoxy sequencing combines with SSCP's), the two-way pair of deoxidation fingerprint (wherein adopting two relative primers to carry out two deoxidation termination reactions simultaneously) and fluorescent PCR-SSCP (PCR product multiple fluorescence dye on inner marker wherein, the available constraints enzyme digests, and carries out SSCP then, and analyzes can detecting on the automated DNA sequenator of fluorescence dye).
Utilize the additive method of the different mobility of different nucleic acid constructs to comprise denaturing gradient gel electrophoresis (DGGE), temperature gradient gel elec-trophoresis (TGGE) (TGGE) and heteroduplex analysis (HET).The dissociated variation of double-stranded DNA herein (for example because base mispairing) causes the variation of electrophoretic mobility.The variation of these mobilities is used to detect nucleotide diversity.
Sex change high pressure liquid chromatography (HPLC) (HPLC) is another method that is used to detect SNP, it uses the HPLC method known in this area to detect homoduplex and heteroduplex with different rates wash-out on the HPLC post as the alternative method of above-mentioned separation method (example gel electrophoresis), thereby can detect the mispairing and the SNP of Nucleotide.
But another method that detects SNP depends on the different susceptibility to various doses of cuttings comprising chemical chop agent and hydrolase nucleic acid of strand and double-strandednucleic acid.For example, RNase A is to the intravital mispairing cutting of RNA:DNA heteroduplex, phage T4 endonuclease YII or T7 endonuclease I are to the cutting of heteroduplex, lyase I is to the cutting of the hairpin loop 5 ' end of joint between strand and the double-stranded DNA and be generally used for chemical chop agent in the Maxam-Gilbert order-checking chemistry and the modification of the mispairing Nucleotide of heteroduplex inside is technical field knows.
Other examples comprise the protein translation test (PTT) that is used to separate the terminator codon that the factorial variation produces, and variation causes the protein of translating of crossing early stopping and shortening and uses the mispairing conjugated protein.By will be for example the component MutS albumen of e. coli dna mismatch repair system or human hMSH2 and GTBP protein binding to the double-stranded DNA heteroduplex that contains base mismatch, detect variation.The dna double chain then with the conjugated protein together incubation of mispairing, detect variation through mobility shift assay.For example, a kind of simple mensuration is based on this fact, i.e. the conjugated protein heteroduplex that is attached to of mispairing protects heteroduplex to avoid the degraded of exonuclease.
Those skilled in the art can understand that specific SNP especially is positioned at the regional SNP as promotor of generegulation and can associates with the genetic expression that changes.Also can cause genetic expression to change when SNP is positioned at the coding region of gene of protein coding, for example SNP and the codon with different codon usages are related also thereby with different tRNA abundance when related.The genetic expression of this change can be measured by method well known in the art, and therefore can be used to detect this class SNP.Equally, when SNP was positioned at the coding region of gene and cause non-synonym aminoacid replacement, this replacement can cause the variation of gene product function.Equally, when gene product was RNA, this SNP can cause the variation of rna gene product function.For example any variation of this class of activity or the detected function of functional assays can be used to detect this class SNP.
Above-mentionedly be used to detect and identify that the method for SNP can be used for the method for the invention.
Certainly, in order to detect according to the present invention and to identify SNP, obtain to contain the sample of detected materials on one's body from object.Described sample can be for may containing any sample of target SNP (or the target polypeptide under some occasion), and can obtain from (blood, urine, the saliva etc.) biopsy of any body fluid or other tissue preparations.
According in numerous methods well known in the art any can be from sample DNA isolation or RNA.Tijssen for example; Laboratory Techniques in Biochemistry and MolecularBiology:Hybridization with nucleic acid probes Part 1:Theory and Nucleicacid preparation, Elsevier, New York, N.Y.1993 and Maniatis, T., Fritsch, E.F.and Sambrook, J., Molecular Cloning Manual 1989 has described the method for purification of nucleic acid.
For whether auxiliary detection polymorphism/SNP exists, can provide nucleic acid probe and/or primer.This class probe has special at the nucleotide sequence that confirms that karyomit(e) that whether polymorphism exists changes, and the material that preferably sends detectable signal when being attached to the target pleomorphism site carries out mark.
Nucleic acid probe can be genomic dna or cDNA or mRNA, or the material of any RNA sample or DNA sample, peptide nucleic acid(PNA) for example, branched DNA etc.Probe can be that justice or antisense polynucleotides probe are arranged.When target polynucleotide was two strands, probe can be justice or antisense strand.When target polynucleotide was strand, probe was the complementary strand.
Can prepare described probe by many synthetic or enzyme schemes well known in the art.The chemical process of can the use technology field knowing (people such as Caruthers., Nucleic Acids Res., Symp.Ser., 215-233 (1980)) all or part of synthetic described probe.Perhaps, can be by all or part of synthetic described probe of enzymatic mode.
Can nucleotide analog be incorporated in the probe by this method well known in the art.Unique requirement is that the nucleotide analog of integrating must carry out base pairing with target nucleotide sequences.For example, some guanylic acid can be replaced by the xanthoglobulin that carries out base pairing with the cytosine(Cyt) residue.But these base pairs do not have the base pair between guanine and the cytosine(Cyt) stable.Perhaps, adenine nucleotide can be replaced by 2,6-diaminopurine, and the latter can form the base pair stronger than base pair between the adenine and thymine.
In addition, probe can comprise by chemical process or Enzymology method deutero-Nucleotide.Typical chemically modified comprises with acyl group, alkyl, aryl or amino deriving of carrying out.
Probe can be fixed on the base material.Preferred substrate is any suitable hard or the upholder of semi-rigid, and it comprises film, filter paper, chip, slide, wafer, magnetic bead or non-magnetic bead, gel, pipeline, plate, polymkeric substance, particulate and kapillary.Base material can have many surface shapes, for example well (well), canal (trench), pin, groove (channel) and pore (pore), and polynucleotide probes can be in conjunction with thereon.Base material is optically transparent under the preferable case.
And probe need not directly to be attached on the matrix, only needs to be attached on the matrix by the joint group.The joint group generally is about 6 to 50 atoms, for the probe that is connected provides exposed space.Preferred joint group comprises ethylene glycol oligomer, diamines, diacid etc.One of reactive group on the stromal surface and terminal portions of joint react so that joint is connected on the matrix.Another terminal portions of joint functionalised and is used for bonding probes then.
Can be distributed to substrate surface or preformed dna fragmentation or clone are distributed to substrate surface probe is connected to base material by being used for probe synthetic reagent.Typical divider comprises the micropipet that solution is transported to base material, and it uses automatic system with the position of control micropipet with respect to base material.Can there be the plurality of distribution device to make reagent can be transported to conversion zone simultaneously.
Nucleic acid microarray is preferred.This class microarray (comprising nucleic acid chip) is known (referring to for example United States Patent (USP) 5,578,832 for technical field; 5,861,242; 6,183,698; 6,287,850; 6,291,183; 6,297,018; 6,306,643; With 6,308, No. 170, wherein incorporate this paper by reference into for every piece).
Perhaps, can make the antibody microarray.The making of this class microarray is basically as Schweitzer﹠amp; Kingsmore, " Measuring proteins on microarrays ", Curr Opin Biotechnol 2002; 13 (1): 14-9; People such as Avseekno., " Immobilization of proteins in immunochemicalmicroarrays fabricated by electrospray deposition ", Anal Chem 2,001 15; 73 (24): 6047-52; Huang, " Detection of multiple proteins in an antibody-based proteinmicroarray system, Immunol Methods 2,001 1; 255 (1-2): 1-13 describes.
The present invention considers that also preparing test kit is used for the present invention.Suitable test kit comprises according to the present invention in suitable containers and packaged material and comprises all ingredients that uses in pipe, bottle and shrink packaging and the blowing packing.
The material that is applicable to exemplary kit of the present invention comprises one or more following materials: renaturation is attached to the gene specific PCR primer of the DNA that is positioned at purpose genetic polymorphism both sides or cDNA sequence domains to (oligonucleotide), distinguished sequence structural domain among amplifiable gene group DNA or the cDNA and need not carry out the reagent of PCR, (the restriction enzyme for example of the required reagent of various possible allelotrope in the sequence domains of differentiation by PCR or non-PCR amplification, preferred renaturation is attached to a kind of allelic oligonucleotide of polymorphism, comprise and modifiedly contain amplification from the enzyme of the signal of oligonucleotide or the oligonucleotide of fluorescence chemical group, they make the allelic differentiation stronger), physical sepn is derived from the required reagent of various allelotrope products and (for example is used for electrophoretic agarose or polyacrylamide and damping fluid, the HPLC post, the SSCP gel, the methane amide gel or be used for the medium carrier of MALDI-TOF).
Being understood that the method for the invention can combine with the analysis of other known risks and assumptions related with ACS carries out.This class risks and assumptions comprises and the relevant epidemiology risks and assumptions of risk rising that ACS takes place.This class risks and assumptions includes but not limited to smoking and/or tobacco smoke exposure, age, sex and family history.When the risk of ACS took place evaluation object, these risks and assumptions can be used to promote the analysis of one or more polymorphisms as herein described.
Forecasting Methodology of the present invention allows the suitability of many therapeutic interventions of assessment and/or treatment plan and allows given object is carried out these therapeutic interventions and/or treatment plan.The simplest method can be to carry out the power that mode of life changes for object provides in these therapeutic interventions and/or the treatment plan, and the power of smoking cessation for example can be provided when the method for the invention when liking the CS.
Come the mode of predicted treatment intervention or processing according to the biological effect of the character of polymorphism and described polymorphism.For example, when the susceptibility polymorphism was related with the variation of genetic expression, intervention or processing were preferably used for recovering the normal expression of described gene, for example by using the medicament that can regulate described genetic expression.When polymorphism with the reduction of gene express when related, treatment can comprise the medicament that gives to increase described genetic expression, on the contrary, when polymorphism and expression of gene rising were related, treatment can comprise used the medicament that can reduce described genetic expression.Expressing useful method for regulatory gene is known by technical field.For example, raise when related, can use the treatment of RNAi for example or antisense method to reduce the abundance of mRNA, thereby reduce described expression of gene in polymorphism and genetic expression.Perhaps, thus treatment can comprise the method for the compensatory described gene unconventionality expression of activity that is used for for example regulating described gene product.
When the gene product level of the gene product function of susceptibility polymorphism and reduction or reduction is related, therapeutic intervention or processing can comprise to be promoted or alternative described function, or the amount of the interior gene product of additional subject, for example by using the functional analogue of described gene product or described gene product.For example, when the enzyme function association of polymorphism and reduction, treatment can comprise to object uses organized enzyme or organized enzyme analogue.Equally, when the gene product function association of polymorphism and rising, therapeutic intervention or handle can comprise and reduces described function, for example maybe can reduce the medicament of described gene product level in subject by the inhibitor of using described gene product.For example, when the enzyme function association of SNP allelotrope or genotype and rising, treatment can comprise to object uses enzyme inhibitors.
Equally, when the rise of protectiveness polymorphism and specific gene or enzyme or other protein expressions were related, treatment can be used for simulating this rise or the expression of the individuality that lacks described resistant gene type, and/or gives this class individual this enzyme or other protein carried.And when the downward modulation of protectiveness polymorphism and specific gene or enzyme or other protein expressions reduce or disappear when related, desirable treatment can be used for simulating this class situation of the individuality of the described protective gene type of shortage.
The relation that (otherwise or) take place between the susceptibility of ACS for the various polymorphisms of above-mentioned evaluation and object can also be applied to the design and/or the screening of candidate therapy.This is particularly like this when showing in rise or the downward modulation by genetic expression of the polymorphism of prediction susceptibility.In this case, can easily detect the effect that candidate therapy raises or reduces this class.
For example, in one embodiment existing people's blood vessel organ and cell culture are carried out the genotypic screening of above-mentioned SNP.(for people's blood vessel organ and cell cultures, for example see also: Clare WiseED., Epithelial Cell Culture Protocols, 2002, ISBN 0896038939, Humana PressInc.NJ; Endothelial Cell Culture, Roy Bicknell, ED., 1996, ISBN 0521550246, Cambridge University Press, UK; Cell Culture Models of Biological Barriers, Claus-Michael Lehr, ED., 2002, ISBN 0415277248, Taylor and Francis, UK; Wherein each piece method integral body is by reference incorporated this paper into).Select to represent the culture of genes involved type group and the culture of supposition " normally " with regard to gene expression dose, this expression of gene or rise or downward modulation in the presence of polymorphism.
The sample of this class culture is exposed to candidate therapeutic compound library and screening: (a) downward modulation of the gene that raises under the normal circumstances in the susceptible gene type; Or the rise of the gene of (b) in the susceptible gene type, reducing under the normal circumstances.Change the adjusting of the gene in the culture with susceptible gene type and/or the ability of effect according to compound and select compound.
Equally, when polymorphism is that a kind of physiologically active concentration that can cause the expressing gene product when it exists is when exceeding polymorphism beyond object (age and the sex are proofreaied and correct) normal range, and when the preventative or therapeutic method of the physiologically active concentration level of exist to recover expressing gene product to normal range, can screen individual subject and benefit from the possibility of this restorative method to determine it.The screening of this class comprises and comes by arbitrary method described herein whether polymorphism exists in the detected object body, and wherein existing the object of described polymorphism to be accredited as is the individuality that possible benefit from treatment.
Now with reference to following non-limiting examples the present invention is described in more detail.
The case association study
Foreword
The case-control association study allows selected control group, and wherein the coupling of important risks and assumptions is vital.In this research, comparative diagnoses suffers from the smoker of ACS and does not suffer from the smoker of ACS.This unique control group is a height correlation, because the smoker that can not select ACS to be free from risk in advance, although the smoker of ACS never can take place in i.e. smoking.Have de-luxe compartment year history and the smoker of normal cardiovascular function be used as " low risk " smoker group, this is can not identify more low-risk smoker's group because the present patent application people thinks under existing knowledge.Without wishing to be bound to any theory, the present patent application people thinks that this method allows the low penetrance and the high-frequency polymorphism that may improve the risk that ACS takes place are carried out more strict comparison.Without wishing to be bound to any theory equally, the present patent application people also thinks and may exist protection to a certain degree to avoid the polymorphism of ACS, only is only significantly during as control group (comparator group) when the smoking formation with normal cardiovascular function.Therefore, with have normal cardiovascular function and diagnosis have the smoker of ACS to compare, suffer from the frequency that the ACS smoker has these polymorphisms and estimate lower.
15 bag years of smoking are at least recruited in this research and diagnosis has acute coronary syndrome European descendants' object of (ACS comprises acute myocardial infarction and unstable angina pectoris).Object meets following standard: the clinical manifestation when accepting tertiary care hospital for medical treatment (medical history, ECG, heart biology marker are measured) diagnosis suffers from ACS.The CAG of suffering from the object of ACS confirms the existence of coronary atherosclerosis disease.The object age of suffering from ACS is between 40-60 between year, and is European descendants.148 routine objects have been raised in research, and wherein 85% is the male sex, mean F EV1/FVC (± 1SD) be 74% (± 8), mean F EV1 accounts for 94 (± 15) of predictor percentage ratio.Mean age, every day cigarette number and Bao Nianshi be respectively 50 (± 3) year, 22 cigarette/skies (± 8) and 31 wrap year (± 11).Also studied 460 European objects in addition, they are 15 bag years of smoking at least, never suffer from stenocardia, pectoralgia, heart attack or previously are diagnosed with ischemic heart disease.This control group has been recruited smoker's and CS the volunteer of community in the past, and wherein 55% is made up of the male sex, mean F EV1/FVC (± 1SD) be 75% (± 9), mean F EV1 accounts for predictor per-cent is 98 (± 12).Mean age, every day cigarette number and Bao Nianshi be respectively 60 (± 10) year, 23 cigarette/skies (± 11) and 40 wrap year (± 11).
This studies show that, compares the higher polymorphism of acute coronary syndrome patient frequency with the resistance smoker and may reflect that the susceptibility to life-threatening acute coronary syndrome takes place raises.Equally, the patient compares with acute coronary syndrome, and the polymorphism that resistance smoker's frequency is higher may reflect provide protection.
The summary of ACS formation and resistant control smoker characteristics
Mean parameter (1SD) | Acute coronary syndrome N=148 | Resistance smoker N=460 | Difference |
Masculinity proportion (%) | 85% | 55% | P<0.05 |
Age (year) | 50(3) | 60(10) | P<0.05 |
Bag year | 31(11) | 40(21) | P<0.05 |
Cigarette number/sky | 22(8) | 23(11) | ns |
FEV1(L) | 3.3(0.7) | 2.7(0.6) | P<0.05 |
Prediction FEV1% | 94(15) | 98%(12) | P<0.05 |
FEV1/FVC | 74(8) | 75(9) | P<0.05 |
Mean value and 1SD
The genotyping method
Use Sequenom Autoflex mass spectrograph to carry out the polymorphism genotyping
From whole blood sample, extract genomic dna (Maniatis, T., Fritsch, E.F. and Sambrook, J., Molecular Cloning Manual.1989).With the genomic dna five equilibrium (10ng/ul concentration) of purifying to 96 orifice plates, at Sequenom
TM(the Sequenom of system
TMAutoflex mass spectrograph and Samsung 24 pin nano-dispersed devices) go up and adopt following sequence, amplification condition and method that it is carried out genotyping.
Use following condition to be used for the PCR multiple reaction: final concentration is 10 * damping fluid 15mM MgCl
21.25 *, 25mM MgCl
21.625mM, dNTP mixture 25mM 500 μ M, primer 4 μ M100nM, Taq polysaccharase (Quiagen warm start) 0.15U/ reaction, genomic dna 10ng/ μ l.Cycle index be 95 ℃ following 15 minutes, at 5 ℃ of 15s, 56 ℃ of 30s, 72 ℃ of following 45 circulations of 30s are extended at last and were finished reaction in 3 minutes.We have used 35 ℃ of shrimp alkaline phosphotases of 30 minutes of following incubation (SAP) to handle (each PCR reaction adds 2 μ l to 5 μ l) and extension (SAP handles the back and adds 2 μ l to 7 μ l), and wherein following volume is adopted in each reaction: water, 0.76 μ l; HME 10 * stop buffer, 0.2 μ l; HME primer (10 μ M), 1 μ l; Mass Extend enzyme, 0.04 μ l.The full name of SNP and candidate gene sees table 1-26.
The Sequenom condition of PCR and mass spectrograph genotyping
SNP_ID SNP title the 2nd PCRP the one PCRP
PDGFA PDGFA 12 ACGTTGGATGAAGGCTCTGA ACGTTGGATGATCCGGATTATCG
IN5C/T AGACCTGTTC[SEQ.ID.NO.1] GGAAGAG[SEQ.ID.NO.2]
RS1758 1-antitrypsin ACGTTGGATGCTTGGTGATG ACGTTGGATGTCTTCTTCCTGCC
0 S-allele ATATCGTGGG[SEQ.ID.NO.3] TGATGAG[SEQ.ID.NO.4]
RS1799 NOS3 298 ACGTTGGATGAAACGGTCGC ACGTTGGATGGGGCAGAAGGAA
983 G/T TTCGACGTG[SEQ.ID.NO.5] GAGTTC[SEQ.ID.NO.6]
RS1800 TGFB1 -509 ACGTTGGATGTACAGGTGTC ACGTTGGATGAAGAGGGTCTGT
469 C/T TGCCTCCTGA[SEQ.ID.NO.7] CAACATGG[SEQ.ID.NO.8]
RS1151 OG13G1 132 ACGTTGGATGATAGCCATGAC ACGTTGGATGGGCCATTTGTTTC
640 A/G CATGCTGAG[SEQ.ID.NO.9] CCTCTTC[SEQ.ID.NO.10]
RS2276 MMP12 -82 ACGTTGGATGTTGAGATAGAT ACGTTGGATGGTCCGGGTTCTG
109 A/G CAAGGGATG[SEQ.ID.NO.11] TGAATATG[SEQ.ID.NO.12]
RS4986 TLR4 299 ACGTTGGATGAGCATACTTAG ACGTTGGATGCACACTCACCAG
790 A/G ACTACTACC[SEQ.ID.NO.13] GGAAAATG[SEQ.ID.NO.14]
RS1800 IL-10 -1084 ACGTTGGATGATTCCATGGA ACGTTGGATGGACAACACTACTA
896 A/G GGCTGGATAG AGGCTTC[SEQ.ID.NO.16]
[SEQ.ID.NO.15]
RS5498 ICAM1 ACGTTGGATGACTCACAGAG ACGTTGGATGTGTCACTCGAGA
K469E A/G CACATTCACG[SEQ.ID.NO.17] TCTTGAGG[SEQ.ID.NO.18]
RS1449 FGF2 ACGTTGGATGAGGCGGCGTC ACGTTGGATGCTCGGCCGCTCT
683 Ser52Ser C/T CGCGGAGACA TCTGTCC[SEQ.ID.NO.20]
[SEQ.ID.NO.19]
RS2239 BAT1-23C/G ACGTTGGATGTTACCTAAACA ACGTTGGATGAAGCCTGCAACC
527 GGGAGAGCG[SEQ.ID.NO.21] GGAAGTG[SEQ.ID.NO.22]
RS1799 SOD3 ACGTTGGATGCTCAGGCGGC ACGTTGGATGAGGCGCGGGAG
895 Arg213Gly CTTGCACTC[SEQ.ID.NO.23] CACTCAGA[SEQ.ID.NO.24]
C/G
RS1800 CMA1 -1903 ACGTTGGATGGCTCCACAGC ACGTTGGATGTTCCATTTCCTCA
875 A/G ATCAAGATTC[SEQ.ID.NO.25] CCCTCAG[SEQ.ID.NO.26]
RS1719 MIP1A +459 ACGTTGGATGGGTTCAAGAA ACGTTGGATGAGCTCTGTCCCT
134 C/T GTCATACCCC[SEQ.ID.NO.27] TGGATGTC[SEQ.ID.NO.28]
RS2243 IL-4-589C/T ACGTTGGATGCGACCTGTCC ACGTTGGATGGAATAACAGGCA
250 TTCTCAAAAC[SEQ.ID.NO.29] GACTCTCC[SEQ.ID.NO.30]
RS1801 IL-4RA ACGTTGGATGGAAATGTCCT ACGTTGGATGACCCTGCTCCAC
275 Q576R A/G CCAGCATGGG CGCATGTA[SEQ.ID.NO.32]
[SEQ.ID.NO.31]
RS2227 HASP70Hom ACGTTGGATGTGATCTTGTTC ACGTTGGATGCGAGGTGACGTT
956 T2437C ACCTTGCCG[SEQ.ID.NO.33] TGACATTG[SEQ.ID.NO.34]
RS1799 MMP1 -1607 ACGTTGGATGCTTCAGTATAT ACGTTGGATGGTTATGCCACTTA
750 1G/2G CTTGGATTG[SEQ.ID.NO.35] GATGAGG[SEQ.ID.NO.36]
RS1788 MMP7 -181 ACGTTGGATGGGAGTCAATTT ACGTTGGATGCATCGTTATTGGC
0821 A/G ATGCAGCAG[SEQ.ID.NO.37] AGGAAGC[SEQ.ID.NO.38]
RS4986 TLR4399C/T ACGTTGGATGAGCCCAAGAA ACGTTGGATGAGGTTGCTGTTC
791 GTTTGAACTC[SEQ.ID.NO.39] TCAAAGTG[SEQ.ID.NO.40]
RS1041 LTAThr26Asn ACGTTGGATGGAGGTCAGGT ACGTTGGATGACCCCAAGATGC
981 A/C GGATGTTTAC[SEQ.ID.NO.41] ATCTTGCC[SEQ.ID.NO.42]
PDGFR PDGFRA ACGTTGGATGGGCAACTAGC ACGTTGGATGCAGAGTGCGGAA
A -1630I/D CTAAAAACCC[SEQ.ID.NO.43] TAAAAGGC[SEQ.ID.NO.44]
GCLM GCLM -588 ACGTTGGATGTGAGGTAGAC ACGTTGGATGAAGAGACGTGTA
C/T ACCGCCTCC[SEQ.ID.NO.45] GGAAGCCC[SEQ.ID.NO.46]
RS2430 IGN-G 874 ACGTTGGATGCAGACATTCA ACGTTGGATGGATAGTTCCAAAC
561 A/T CAATTGATT[SEQ.ID.NO.47] ATGTGCG[SEQ.ID.NO.48]
RS2071 NFKBIL1 -63 ACGTTGGATGTAACGCCCCT ACGTTGGATGACTCCAGGCTGG
592 T/A CACAGTTCAC[SEQ.ID.NO.49] AGGAAATG[SEQ.ID.NO.50]
PAI1 PAI-1 -668 ACGTTGGATGCACAGAGAGA ACGTTGGATGTCTTGGTCTTTCC
4G/5G GTCTGGACAC CTCATCC[SEQ.ID.NO.52]
[SEQ.ID.NO.51]
Rs20668 Caspase ACGTTGGATGGTCTGTTGAC ACGTTGGATGTGGTGATCACCC
45 TCTTTTGGC[SEQ.ID.NO.105] AAGGCTTC[SEQ.ID.NO.106]
rs37323 CX3CR1 ACGTTGGATGCATAGAGCTTA ACGTTGGATGTGATCCTTCTGGT
79 AGCGTCTCC[SEQ.ID.NO.107] GGTCATC[SEQ.ID.NO.108]
Organize the CGTTGGATGTCAGTCCCTC ACGTTGGATGAGAAGAGTCAGA of egg cathepsin A
White enzyme G G Asn125Ser CTGGGCTCTA CGGAATCG[SEQ.ID.NO.110]
[SEQ.ID.NO.109]
rs65202 TIMP1 ACGTTGGATGGACTCTTGCA ACGTTGGATGAGTGTAGGTCTT
77 CATCACTACC GGTGAAGC[SEQ.ID.NO.112]
[SEQ.ID.NO.111]
The result
Chyme enzyme 1 (CMA)-1903A/G polymorphism allelotrope and genotype frequency of table 1.ACS patient and resistance smoker
*Chromosome number (2n)
The genotype GG of ACS smoker antagonism smoker contrast is to AG/AA, odds ratio (OR)=1.9,95% confidence limit 1.2-3.0, χ
2(Mantel-Haenszel)=8.23, p=0.004,
GG genotype=susceptibility
The allelotrope G of ACS smoker antagonism smoker contrast is to A, odds ratio (OR)=1.4,95% confidence limit 1.1-1.9, χ
2(Mantel-Haenszel)=6.52, p=0.01,
G allelotrope=susceptibility
Transforminggrowthfactor-(TGFB1)-509C/T polymorphism allelotrope and genotype frequency of table 2.ACS patient and resistance smoker
*Chromosome number (2n)
The genotype CC of ACS smoker antagonism smoker contrast is to CT/TT, odds ratio (OR)=1.5,95% confidence limit 1.0-2.2, χ
2(Mantel-Haenszel)=3.96, p=0.05,
CC genotype=susceptibility
The allele C of ACS smoker antagonism smoker contrast is to T, odds ratio (OR)=1.4,95% confidence limit 1.0-1.8, χ
2(Mantel-Haenszel)=3.79, p=0.05,
C allelotrope=susceptibility
Matrix metalloproteinase 12 (MMP12)-82A/G polymorphism allelotrope and genotype frequency of table 3.ACS patient and resistance smoker.
*Chromosome number (2n)
The genotype GG of ACS smoker antagonism smoker contrast is to AA/AG, odds ratio (OR)=3.2,95% confidence limit 0.8-13, χ
2(Mantel-Haenszel)=3.76, p=0.05,
GG genotype=susceptibility
Table 4.ACS patient and resistance smoker's fibroblast growth factor 2 (FGF2) Ser 52 Ser (223C/T) polymorphism allelotrope and genotype frequency
*Chromosome number (2n)
The genotype CT/TT of ACS smoker antagonism smoker contrast is to CC, odds ratio (OR)=1.5,95% confidence limit 0.9-2.5, χ
2(Mantel-Haenszel)=3.1, p=0.08,
CT/TT genotype=susceptibility (CC protectiveness)
The allelotrope T of ACS smoking antagonism smoker contrast is to C, odds ratio (OR)=1.5,95% confidence limit 0.9-2.3, χ
2(Mantel-Haenszel)=3.24, p=0.07,
T allelotrope=susceptibility
Table 5.ACS patient and resistance smoker's interleukin-4 α (IL4RA) Q576R A/G polymorphism allelotrope and genotype frequency.
*Chromosome number (2n)
The genotype GG of ACS smoker antagonism smoker contrast is to AA/AG, odds ratio (OR)=2.71,95% confidence limit 1.1-6.9, χ
2(Mantel-Haenszel)=5.52, p=0.02,
GG genotype=susceptibility
The frequency of genotypes AA of ACS smoker antagonism smoker contrast is to AG/GG, odds ratio (OR)=0.47,95% confidence limit 0.07-1.0, χ
2(Mantel-Haenszel)=3.45, p=0.05,
AA genotype=protectiveness
The allelotrope G of ACS smoker antagonism smoker contrast is to A, odds ratio (OR)=1.5,95% confidence limit 1.1-2.0, χ
2(Mantel-Haenszel)=5.56, p=0.02,
G allelotrope=susceptibility
Table 6.ACS patient and resistance smoker's lymphotoxin α (LTA) Thr26Asn A/C polymorphism allelotrope and genotype frequency.
*Chromosome number (2n)
The genotype CC of ACS smoker antagonism smoker contrast is to AA/AC, odds ratio (OR)=0.66,95% confidence limit 0.4-1.0, χ
2(Mantel-Haenszel)=4.28, p=0.04,
CC genotype=protectiveness
LTA Thr26Asn A/C and NFKBIL1-63T/A are in linkage disequilibrium
Table 7.ACS patient and resistance smoker's heat shock protein(HSP) (HSP) 70 Hom T2437C C/T polymorphism allelotrope and genotype frequencies
*Chromosome number (2n)
The genotype CC/CT of ACS smoker antagonism smoker contrast is to TT, odds ratio (OR)=0.66,95% confidence limit 0.43-1.0, χ
2(Mantel-Haenszel)=4.33, p=0.04,
CC/CT genotype=protectiveness (TT=susceptibility)
The allele C of ACS smoker antagonism smoker contrast is to T, odds ratio (OR)=0.65,95% confidence limit 0.5-0.9, χ
2(Mantel-Haenszel)=5.75, p=0.02,
C allelotrope=protectiveness
Table 8a.ACS patient and resistance smoker's Toll sample acceptor 4 (TLR4) Asp 299Gly A/G polymorphism allelotrope and genotype frequency.
*Chromosome number (2n)
The genotype AG/GG of ACS smoker antagonism smoker contrast is to AA, odds ratio (OR)=0.54,95% confidence limit 0.3-1.1, χ
2(Mantel-Haenszel)=3.27, p=0.07,
AG/GG genotype=protectiveness (AA=susceptibility)
TLR4 Asp299Gly A/G and TLR4 Thr399Ile C/T are in linkage disequilibrium
Table 8b.ACS patient and resistance smoker's Toll sample acceptor 4 (TLR4) Thr 399Ile C/T polymorphism allelotrope and genotype frequency.
*Chromosome number (2n)
The genotype CT/TT of ACS smoker antagonism smoker contrast is to CC, odds ratio (OR)=0.54,95% confidence limit 0.3-1.1, χ
2(Mantel-Haenszel)=3.67, p=0.06,
CT/TT genotype=protectiveness (CC=susceptibility)
TLR4 Thr399Ile C/T and TLR4 Asp 299Gly A/G are in linkage disequilibrium
Table 9.ACS patient and resistance smoker's interferon-gamma (IFNG) 874A/T polymorphism allelotrope and genotype frequency.
*Chromosome number (2n)
The genotype TT of ACS smoker antagonism smoker contrast is to AA/AT, odds ratio (OR)=0.57,95% confidence limit 0.3-0.96, χ
2(Mantel-Haenszel)=4.98, p=0.03,
TT genotype=protectiveness
Nf (the NFKBIL1)-63T/A polymorphism allelotrope and the genotype frequency of table 10.ACS patient and resistance smoker B cell K light chain polypeptide genetic enhancer.
*Chromosome number (2n)
The frequency of genotypes AA of ACS smoker antagonism smoker contrast is to AT/TT, odds ratio (OR)=0.73,95% confidence limit 0.5-1.1, χ
2(Mantel-Haenszel)=2.66, p=0.10,
AA genotype=protectiveness
NFKBIL1-63 T/A and LTA Thr26Asn are in linkage disequilibrium
Table 11.ACS patient and resistance smoker's platelet derived growth factor receptor α (PDGFRA)-1630 insertion/disappearance) AACTT/Del polymorphism allelotrope and genotype frequency
*Chromosome number (2n): I=inserts AACTT, the D=disappearance
The genotype ID/DD of ACS smoker antagonism smoker contrast is to II, odds ratio (OR)=0.68,95% confidence limit 0.5-1.0, χ
2(Mantel-Haenszel)=3.69, p=0.05,
ID/DD genotype=protectiveness (II susceptibility)
Interleukin-4 (IL-4)-589C/T polymorphism allelotrope and genotype frequency of table 12.ACS patient and resistance smoker.
*Chromosome number (2n)
The genotype CT/TT of ACS smoker antagonism smoker contrast is to CC, odds ratio (OR)=0.68,95% confidence limit 0.42-1.1, χ
2(Mantel-Haenszel)=2.57, p=0.11,
CT/TT genotype=protectiveness (CC=susceptibility)
Table 13.ACS patient and resistance smoker's matrix metalloproteinase 1 (MMP1)-1607 1G/2G polymorphism allelotrope and genotype frequency.
*Chromosome number (2n)
The genotype 1G1G of ACS smoker antagonism smoker contrast is to 1G2G/2G2G, odds ratio (OR)=1.4,95% confidence limit 0.9-2.1, χ
2(Mantel-Haenszel)=2.44, p=0.12,
1G1G genotype=susceptibility
Table 14.ACS patient and resistance smoker's thrombocyte derivation growth factor ' alpha ' (PDGFA) 12 IN 5C/T polymorphism allelotrope and genotype frequencies
*Chromosome number (2n)
The genotype TT of ACS smoker antagonism smoker contrast is to CT/CC, odds ratio (OR)=1.4,95% confidence limit 0.9-2.2, χ
2(Mantel-Haenszel)=2.21, p=0.14,
TT genotype=susceptibility
Table 15.ACS patient and resistance smoker's L-glutamic acid-halfcystine ligase enzyme is modified subunit (GCLM)-588C/T polymorphism allelotrope and genotype frequency
*Chromosome number (2n)
The genotype CT/TT of ACS smoker antagonism smoker contrast is to CC, odds ratio (OR)=1.4,95% confidence limit 0.9-2.0, χ
2(Mantel-Haenszel)=2.34, p=0.13,
CT/TT genotype=susceptibility (CC protectiveness)
Table 16.ACS patient and resistance smoker's olfactory receptor analogue OR13G1 Ile132Val A/G polymorphism allelotrope and genotype frequency.
*Chromosome number (2n)
The frequency of genotypes AA of ACS smoker antagonism smoker contrast is to AG/GG, odds ratio (OR)=1.4,95% confidence limit 0.9-2.1, χ
2(Mantel-Haenszel)=2.20, p=0.14,
AA genotype=susceptibility
Table 17.ACS patient and resistance smoker's interleukin 10 (IL-10)-1084 A/G polymorphism allelotrope and genotype frequency.
*Chromosome number (2n)
The genotype GG of ACS smoker antagonism smoker contrast is to AA/AG, odds ratio (OR)=0.74,95% confidence limit 0.5-1.2, χ
2(Mantel-Haenszel)=1.74, p=0.19,
GG genotype=protectiveness
Table 18.ACS patient and resistance smoker's alpha1-antitrypsin S-allele Glu 288 Val A/T (M/S) polymorphism allelotrope and genotype frequencies
*Chromosome number (2n)
The genotype AT/TT of ACS smoker antagonism smoker contrast is to AA, odds ratio (OR)=1.5,95% confidence limit 0.8-2.7, χ
2(Mantel-Haenszel)=1.95, p=0.16,
AT/TT genotype=susceptibility
Table 19.ACS patient and resistance smoker's intercellular adhesion molecule 1 (ICAM1) K469E A/G polymorphism allelotrope and genotype frequency.
*Chromosome number (2n)
The frequency of genotypes AA of ACS smoker antagonism smoker contrast is to AG/GG, odds ratio (OR)=0.70,95% confidence limit 0.5-1.1, χ
2(Mantel-Haenszel)=2.91, p=0.09,
AA genotype=protectiveness
The table related transcript 1 of 20.ACS patient (BAT1)-23C/G polymorphism allelotrope and genotype frequency with resistance smoker's HLA-B.
*Chromosome number (2n)
The genotype GG of ACS smoker antagonism smoker contrast is to CC/CG, odds ratio (OR)=0.71,95% confidence limit 0.5-1.1, χ
2(Mantel-Haenszel)=2.88, p=0.09,
GG genotype=protectiveness
Table 21.ACS patient and resistance smoker's nitricoxide synthase 3 (NOS3) Glu298Asp G/T polymorphism allelotrope and genotype frequency.
*Chromosome number (2n)
The genotype GG of ACS smoker antagonism smoker contrast is to GT/TT, odds ratio (OR)=0.72,95% confidence limit 0.5-1.1, χ
2(Mantel-Haenszel)=2.79, p=0.09,
GG genotype=protectiveness
Table 22.ACS patient and resistance smoker's superoxide-dismutase 3 (SOD3) Arg213Gly C/G polymorphism allelotrope and genotype frequency.
*Chromosome number (2n)
The genotype CG/GG of ACS smoker antagonism smoker contrast is to CC, odds ratio (OR)=0.23,95% confidence limit 0.01-1.7, χ
2(Mantel-Haenszel)=2.31, p=0.13,
CG/GG genotype=protectiveness
*Chromosome number (2n)
#Identical with PAI-1-6754G/5G polymorphism
The genotype 5G5G of ACS smoker antagonism smoker contrast is to 4G5G/4G4G, odds ratio (OR)=0.72,95% confidence limit 0.4-1.2, χ
2(Mantel-Haenszel)=1.7, p=0.19,
5G5G genotype=protectiveness
Table 24.ACS patient and resistance smoker's macrophage inflammatory protein 1 alpha (MIP1A) 459 C/T polymorphism allelotrope and genotype frequencies
*Chromosome number (2n)
The genotype CT/TT of ACS smoker antagonism smoker contrast is to CC, odds ratio (OR)=1.31,95% confidence limit 0.9-2.0, χ
2(Mantel-Haenszel)=1.81, p=0.18,
CT/TT genotype=susceptibility
The allelotrope T of ACS smoker antagonism smoker contrast is to C, odds ratio (OR)=1.33,95% confidence limit 0.9-1.9, χ
2(Mantel-Haenszel)=2.87, p=0.09,
T allelotrope=susceptibility
Table 25.ACS patient and resistance smoker's matrix metalloproteinase 7 (MMP7)-181 A/G polymorphism allelotrope and genotype frequency.
*Chromosome number (2n)
The genotype GG of ACS smoker antagonism smoker contrast is to AA/AG, odds ratio (OR)=0.70,95% confidence limit 0.4-1.2, χ
2(Mantel-Haenszel)=1.73, p=0.19,
GG genotype=protectiveness
Table 26.ACS patient and resistance smoker's the Asn125Ser A/G of cathepsin G polymorphism allelotrope and genotype frequency.
*Chromosome number (2n)
The genotype AG/GG of ACS smoker antagonism smoker contrast is to AA, odds ratio (OR)=0.58,95% confidence limit 0.27-1.22, χ
2(Mantel-Haenszel)=2.36, p=0.12,
AG/GG genotype=protectiveness (AA susceptibility)
Table 27.ACS object and resistance smoker's chemokine (CX3C motif) acceptor 1 (CX3CR1) I249V C/T polymorphism allelotrope and genotype frequency.
Chromosome number (2n)
The genotype TT vs CC/CT of ACS smoker vs resistance smoker contrast, odds ratio (OR)=1.5,95% confidence limits=0.82-2.81, χ
2(Mantel-Haenszel)=2.04, p=0.15,
TT genotype=susceptibility
Table 28.ACS patient and resistance smoker's Caspase (NOD2) Gly881Arg G/C polymorphism allelotrope and genotype frequency.
*Chromosome number (2n)
The genotype CC/CG of ACS smoker antagonism smoker contrast is to GG, odds ratio (OR)=2.1,95% confidence limits=0.662-6.6, χ
2(Mantel-Haenszel)=2.05, p=0.15,
CC/CG genotype=susceptibility
Table 29.ACS patient and resistance smoker's the 372T/C of tissue inhibitor of metalloproteinase 1 (TIMP1) polymorphism allelotrope and genotype frequency
Chromosome number (2n)
The genotype TT of ACS smoker antagonism smoker contrast is to CT/CC, odds ratio (OR)=0.27,95% confidence limit=0.13-0.54, χ
2(Mantel-Haenszel)=16.42, p=0.00005,
TT genotype=protectiveness
The genotype CC of ACS smoker antagonism smoker contrast is to CT/TT, odds ratio (OR)=1.4,95% confidence limits=1.0-2.1, χ
2(Mantel-Haenszel)=3.61, p=0.06,
CC genotype=susceptibility
The allelotrope T of ACS smoker antagonism smoker contrast is to C, odds ratio (OR)=0.61,95% confidence limit=0.45-0.81, χ
2(Mantel-Haenszel)=12.64, p=0.0004,
T allelotrope=protectiveness
Following table 30 has been summed up protectiveness and susceptibility SNP that this paper identifies.The susceptibility SNP that selects is accredited as S1 to S13, and the protectiveness SNP that selects is accredited as P1 to P16.The SNP that shows with boldface letter is comprised in hereinafter to discuss and is used for generating SNP fractional SNP group.
Table 30. is summed up for the protectiveness and the susceptibility SNP of acute coronary syndrome
Gene | rs | Polymorphism | Genotype | SNP# | Phenotype | OR | The P value |
CMA1 | 1800875 | -1903 A/G | GG | S1 | Susceptibility | 1.9 | 0.004 |
TGFB1 | 1800469 | -509 C/T | CC | S2 | Susceptibility | 1.5 | 0.05 |
MMP12 | 2276109 | -82 A/G | GG | S3 | Susceptibility | 3.2 | 0.05 |
FGF2 | 1449683 | Ser52Ser223 C/T | CT/FT (CC) | S4 | Susceptibility (protectiveness) | 1.5 | 0.08 |
IL4RA | 1801275 | Q576R A/G | GG AA | S5 | The susceptibility protectiveness | 2.7 0.47 | 0.02 0.05 |
LTA | 1041981 | Thr26Asn A/C | CC | P1 | Protectiveness | 0.66 | 0.04 |
HSP70 | 2227956 | Hom T2437C | CC/CT (TT) | P2 | Protectiveness (susceptibility) | 0.66 | 0.04 |
TLR4 | 4986790 | 1Asp299Gly A/G | AG/GG (AA) | P3 | Protectiveness (susceptibility) | 0.54 | 0.07 |
TLR4 | 4986791 | 2Thr399Ile C/T | CT/TT (CC) | P3.1 | Protectiveness (susceptibility) | 0.54 | 0.06 |
IFNG | 2430561 | 874 A/T | TT | P4 | Protectiveness | 0.57 | 0.03 |
NFKBIL1 | 2071592 | -63 T/A | AA | P11 | Protectiveness | 0.73 | 0.10 |
PDGFRA | - | -1630 I/D, (AACTT/Del) | I/Del, Del/Del (II) | P5 | Protectiveness (susceptibility) | 0.68 | 0.05 |
IL4 | 2243250 | -589 C/T | CT/TT (CC) | P6 | Protectiveness (susceptibility) | 0.68 | 0.11 |
MMP1 | 1799750 | -1607 1G/2G (Del/G) | Del.Del(ie 1G1G) | S6 | Susceptibility | 1.4 | 0.12 |
PDGFA | - | 12IN5 C/T | TT | S7 | Susceptibility | 1.4 | 0.14 |
GCLM | - | -588 C/T | CT/TT (CC) | S8 | Susceptibility (protectiveness) | 1.4 | 0.13 |
OR13G1 | 1151640 | Ile132Val A/G | AA | S9 | Susceptibility | 1.4 | 0.14 |
IL-10 | 1800896 | -1084 A/G(-1082) | GG | P12 | Protectiveness | 0.74 | 0.19 |
α 1-AT S-allele | 17580 | Glu288Val A/T (M/S) | AT/TT (MS/SS) | S10 | Susceptibility | 1.5 | 0.16 |
ICAM1 | 5498 | K469E A/G | AA | P7 | Protectiveness | 0.70 | 0.09 |
BAT1 | 2239527 | -23 C/G | GG | P8 | Protectiveness | 0.71 | 0.09 |
NOS3 | 1799983 | Glu298Asp G/T | GG | P9 | Protectiveness | 0.72 | 0.09 |
SOD3 | 1799895 | Arg213Gly C/G | CG/GG | P10 | Protectiveness | 0.23 | 0.13 |
PAI-1 | - | -668 4G/5G | 5G5G | P13 | Protectiveness | 0.72 | 0.19 |
MIP1A | 1719134 | +459 C/T Intron 1 | CT/TT | S11 | Susceptibility | 1.31 | 0.18 |
MMP7 | 17880821 | -181 A/G | GG | P14 | Protectiveness | 0.70 | 0.19 |
Cathepsin G | Asn 125Ser | AG/GG AA | P15 | Protectiveness (susceptibility) | 0.58 | 0.12 | |
CX3CR1 | 3732379 | 1249V | TT | S12 | Susceptibility | 1.5 | 0.15 |
NOD2 | 2066845 | Gly 881 Arg G/C | CC/CG | S13 | Susceptibility | 2.1 | 0.15 |
TIMP1 | 4898 | 372 T/C | TT CC | P16 | The protectiveness susceptibility | 0.27 1.4 | 0.00005 0.06 |
Discuss as this paper, S3 and S6 are in LD, and P1 and P11 are in LD, and P3 and P3.1 are in LD.Do not use these SNP when therefore deriving the SNP mark at same group.
Following table 31 has shown the distribution according to SNP mark ACS patient and smoking contrast.In conjunction with the analysis that 11 SNP that are made up of SNP S1-S5 and P1-P6 shown in table 30 organize, determine the SNP mark that each is individual.Each susceptibility SNP assignment is+1, and each protectiveness SNP assignment is-1.
Fig. 1 has shown this data in the graphic representation mode.
Table 31. is according to distribution-11SNP group of SNP mark ACS patient
Following table 32 has shown the distribution according to SNP fractional ACS object and smoking contrast, and wherein the SNP mark is measured with reference to bigger 15 SNP group.This 15 SNP group is made up of SNP S1-S5 and the P1-P10 shown in the table 30.Equally, each susceptibility SNP assignment is+1, and each protectiveness SNP assignment is-1.Fig. 2 has shown data shown in the table 32 in the graphic representation mode.
Table 32. is according to SNP fractional ACS patient's distribution-15 SNP group
Discuss
The above results discloses several polymorphisms and is associated with the rising or the reduction of the risk that ACS takes place.The association of individual polymorphism is worth although have to differentiate, and acceptable disease forecasting can not be provided.But, integrating, these polymorphic performances make a distinction the susceptible object with resistance object (smoker of ACS is for example taken place and have the smoker that similar smog exposes and have priming the pump).Polymorphism had both been represented promotor polymorphism, thereby it is considered to change genetic expression and changes protein synthesis, also represent the exon polymorphism, known its changed the aminoacid sequence (may express in addition and/or function) of the gene of a lot of coded proteins, and these protein play central role in comprising processes such as inflammation, matrix reconstruction and cytokine activity.
At not having in smoker's (though smoking but the risk of ACS takes place minimum) the comparison of ACS of ACS smoking object and coupling, the occurrence frequency that identifies several polymorphisms is more much higher or much lower than control group.Because ACS patient's formation is little, the polymorphism that therefore only shows difference trend (P=0.06-0.25) also is included into analysis, although only used the polymorphism with significant difference in Conjoint Analysis.
● when analyzing-1903 A/G polymorphisms of chyme enzyme 1 gene, discovery GG genotype is bigger in the ACS formation, and (OR=1.9 P=0.004), meets susceptibility effect (referring to table 1).Find also that in addition significantly (OR=1.4 p=0.01), meets susceptibility effect (table 1) greater than resistance smoking formation for the G allelotrope of ACS formation.
● in the analysis of-509 C/T of TGFB1 gene, find that (OR=1.5 p=0.05), meets susceptibility effect (referring to table 2) greater than resistance smoker formation for the CC genotype of ACS formation.Find also that in addition significantly (OR=1.4 p=0.05), meets susceptibility effect (table 2) greater than resistance smoker formation for the C allelotrope of ACS formation.
● the MMP12 gene-analysis of 82A/G in, find that (OR=3.2 p=0.05), meets susceptibility effect (referring to table 3) greater than resistance smoker formation for the GG genotype of ACS formation.
● in the Ser52Ser of FGF2 gene (223 C/T) polymorphism analysis, (OR=1.5 p=0.08), meets the two each tool susceptibility effect greater than resistance smoker formation for the CT of discovery ACS formation and TT genotype.(OR=1.5 p=0.07), meets the susceptibility effect to the T allelotrope of discovery ACS formation greater than resistance smoker formation.On the contrary, find CC genotype and its protective effect consistent (table 4).
● in the Q576R of IL4RA gene A/G polymorphism analysis, (OR=2.71 p=0.02), meets susceptibility effect (referring to table 5) to the GG genotype of discovery ACS formation greater than resistance smoker formation.Find also that in addition (OR=1.5 p=0.02), meets susceptibility effect (table 5) greater than resistance smoking formation for the G allelotrope of ACS formation.On the contrary, (OR=0.47 p=0.05), meets protective effect (referring to table 5) to the AA allelotrope of discovery resistance smoking formation greater than the ACS formation.
● in the Thr26Asn of LTA gene A/C polymorphism analysis, (OR=0.66 p=0.04), meets protective effect (referring to table 6) to the CC genotype of discovery resistance smoker formation greater than the ACS formation.
● in the HOM T2437C of HSP 70 genes C/T polymorphism analysis, (OR=0.66 p=0.04), meets the two each tool protective effect (referring to table 7) greater than the ACS formation for the CC of discovery resistance smoker formation and CT genotype.(OR=0.65 p=0.02), meets protective effect to the C allelotrope of discovery resistance smoker formation greater than the ACS formation.On the contrary, find TT genotype and its susceptibility effect consistent (referring to table 7).
● in the Asp299Gly of TLR4 gene A/G polymorphism analysis, (OR=0.54 p=0.07), meets the two each tool protective effect (referring to table 8a) greater than the ACS formation for the AG of discovery resistance smoker formation and GG genotype.On the contrary, find AA genotype consistent with the susceptibility effect (referring to table 8a).
● in the Thr399Ile of TLR4 gene C/T polymorphism analysis, (OR=0.54 p=0.06), meets protective effect (referring to table 8b) greater than the ACS formation for the CT of discovery resistance smoker formation and TT genotype.On the contrary, find CC genotype consistent with the susceptibility effect (table 8b).
● in the 874A/T of IFNG gene polymorphism analysis, (OR=0.57 p=0.03), meets protective effect (referring to table 9) to the TT genotype of discovery resistance smoker formation greater than the ACS formation.
● the NFKBIL1 gene-the 63T/A polymorphism analysis in, find that (OR=0.73 p=0.10), meets protective effect (referring to table 10) greater than the ACS formation for the AA genotype of resistance smoker formation.
● in-1630 Ins/Del (AACTT/Del) polymorphism analysis of PDGFRA gene, (OR=0.68 p=0.05), meets protective effect (table 11) greater than the ACS formation for the Ins Del of discovery resistance smoker formation and Del Del genotype.On the contrary, find Ins Ins genotype consistent with the susceptibility effect (referring to table 11).
● in-589 C/T polymorphism analysis of IL-4 gene, (OR=0.68 p=0.11), meets protective effect (referring to table 12) greater than the ACS formation for the CT of discovery resistance smoker formation and TT genotype.On the contrary, find CC genotype and susceptibility effect consistent (table 12).
● in-1607 1G/2G polymorphism analysis of MMP1 gene, (OR=1.4 p=0.12), meets susceptibility effect (referring to table 13) to the 1G1G genotype of discovery ACS formation greater than resistance smoker formation.
● in 12 IN of PDGFA gene, 5 C/T polymorphism analysis, (OR=1.4 p=0.14), meets susceptibility effect (referring to table 14) to the TT genotype of discovery ACS formation greater than resistance smoker formation.
● in-588 C/T polymorphism analysis of GCLM gene, (OR=1.4 p=0.13), meets susceptibility effect (referring to table 15) to the TT genotype of discovery ACS formation greater than resistance smoker formation.On the contrary, find CC genotype consistent with protective effect (referring to table 15).
● in the Ile132Val of OR13G1 gene A/G polymorphism analysis, (OR=1.4 p=0.14), meets susceptibility effect (table 16) to the AA genotype of discovery ACS formation greater than resistance smoker formation.
● in-1084 A/G polymorphism analysis of Il-10 gene, (OR=0.74 p=0.19), meets protective effect (referring to table 17) to the GG genotype of discovery resistance smoker formation greater than the ACS formation.
● in the Glu288Val A/T of α 1-AT gene (M/S) polymorphism analysis, (OR=1.5 p=0.16), meets susceptibility effect (referring to table 18) greater than resistance smoker formation for the AT of discovery ACS formation and TT genotype.
● in the K469E of ICAM1 gene A/G polymorphism analysis, (OR=0.70 p=0.09), meets protective effect (referring to table 19) to the AA genotype of discovery resistance smoker formation greater than the ACS formation.
● in-23 C/G polymorphism analysis of BAT1 gene, (OR=0.71 p=0.09), meets protective effect (referring to table 20) to the GG genotype of discovery resistance smoker formation greater than the ACS formation.
● in the Glu298Asp of nitricoxide synthase 3 genes (G/T) polymorphism analysis, (OR=0.72 p=0.09), meets protective effect (referring to table 21) to the GG genotype of discovery resistance smoker formation greater than the ACS formation.
● in the Arg213Gly of SOD3 gene C/G polymorphism analysis, (OR=0.23 p=0.13), meets protective effect (referring to table 22) greater than the ACS formation for the CG of discovery resistance smoker formation and GG genotype.
● in-668 Del/G (4G/5G) polymorphism analysis of PAI-1 gene, (OR=0.72 p=0.19), meets protective effect (referring to table 23) to the 5G5G genotype of discovery resistance smoker formation greater than the ACS formation.
● in the 459C/T of MIP1A gene polymorphism analysis, (OR=1.31 p=0.18), meets susceptibility effect (referring to table 24) greater than resistance smoker formation for the CT of discovery ACS formation and TT genotype.(OR=1.33 p=0.09), meets susceptibility effect (table 24) to the T allelotrope of discovery ACS formation greater than resistance smoking formation.
● in-181 A/G polymorphism analysis of MMP7 gene, (OR=0.70 p=0.19), meets protective effect (referring to table 25) to the GG genotype of discovery resistance smoker formation greater than the ACS formation.
● in the Asn125Ser of cathepsin G's gene A/G polymorphism analysis, (OR=0.58 p=0.12), meets the two each tool protective effect (referring to table 26) greater than the ACS formation for the AG of discovery resistance smoker formation and GG genotype.On the contrary, find AA genotype and susceptibility effect consistent (table 26).
● in the I249V of CX3CR1 gene C/T polymorphism analysis, (OR=1.5 p=0.15), meets susceptibility effect (table 27) to the TT genotype of discovery ACS formation greater than resistance smoker formation.
● in the Gly881Arg of NOD2 gene G/C polymorphism analysis, (OR=2.1 p=0.15), meets susceptibility effect (referring to table 28) greater than resistance smoker formation for the CC of discovery ACS formation and CG genotype.
● in 372 T/C polymorphism analysis of TIMP1 gene, (OR=0.27 p=0.00005), meets protective effect (referring to table 29) to the TT genotype of discovery resistance smoker formation greater than the ACS formation.Significantly (OR=0.61 p=0.0004), meets protective effect (table 29) to the T allelotrope of discovery resistance smoker formation greater than the ACS formation.On the contrary, (OR=1.4 p=0.06), meets susceptibility effect (referring to table 29) to the CC allelotrope of discovery ACS formation greater than resistance smoking formation.
People accept, and the ACS procatarxis is that idiogenetics is formed and the result of other factor joint effects, and wherein other factors comprise that it is throughout one's life to the exposure of the various air pollutant that contain tobacco smoke.Equally, people accept, and ACS comprises several vascular disease.This paper Notes of Key Data several gene pairss ACS plays a role.The transgenation that many actings in conjunction promote blood vessel injury or protection blood vessel to avoid damaging may participate in the rising to ACS resistivity or susceptibility.
Go out 20 susceptible gene types and 20 protective gene types from the Analysis and Identification of individual polymorphism, and analyze the frequency of these genotype in smoker's formation of forming by resistance smoker and the smoker who suffers from ACS.In a kind of predefined algorithm, wherein exist a kind of susceptible gene type must be divided into+1, exist a kind of protective gene type must be divided into-1, thereby generate the ACS SNP mark of every object.The ACS SNP mark that generates with reference to 11 SNP group is linear relevant with the frequency that ACS takes place.For example, the probability that ACS takes place is from having+58% the dropping to and have-4 or 5% (referring to table 31 and Fig. 1) of lower SNP fractional smoker of 2 SNP fractional smokers.In the analysis of 15 SNP that are made up of SNP S1-S5 and P1-P10 shown in another table 30 group, the probability that ACS takes place is from having 2 or 84% the reducing to and have-6 or 0% (referring to table 32 and Fig. 2) of lower SNP fractional smoker of higher SNP fractional smoker.
And, have the logarithm advantage of ACS and the SNP mark of ACS and be linear dependence---be that the SNP mark is high more, have the possibility big more (referring to Fig. 3) of acute coronary syndrome.Initial analysis according to C statistical value (be equivalent to and optimize test susceptibility and the following area of specific receiver operating curve), the C statistical value is as follows: SNP mark=0.65, SNP mark/age=0.74, SNP mark/BMI/ sex=0.78, SNP/ mark/BMI/ sex/age=0.93.
Therefore, the SNP mark independent association of ACS can be used inclusive NAND genetic risk factor to unite separately and make the risk that is used for assessing the risk of ACS and has the acute coronary incident in having ACS.
These discoveries show that the method for the invention was the ACS of measurable individuality before symptom occurs.
Therefore these find also to provide chance for therapeutic intervention discussed in this article and/or treatment plan.In brief, this class intervention or scheme can comprise providing to object carries out the power that mode of life changes, or comprises and be used to make abnormal gene expression or the normal methods of treatment of gene product functional rehabilitation.For example, as shown here ,-675 5G5G genotype of the promotor of PAI-1 gene reduce related with the risk that ACS takes place.It is reported that 5G allelotrope descends relevant in conjunction with increasing with genetic transcription with repressor.For having the genotypic individuality of-675 4G4G, suitable therapy can be to use the combination that can improve the repressor level and/or strengthen repressor, thereby promotes its downstream effect to transcribing.Another therapy can comprise gene therapy, for example introduces the gene of the coding repressor of at least one additional copies, and this repressor is attached to the avidity with the genotypic PAI-1 gene of-675 4G4G and raises.In another example shown in this article ,-82 A/GGG genotype of the promotor of coding MMP12 gene are associated with the ACS susceptibility.The inhibitor of known many matrix metalloproteinases, for example US 6,600, the inhibitor that 057 (integral body is incorporated this paper into) discussed, for example form the tissue inhibitor of metalloproteinase that comprises TIMP1, TIMP2, TIMP3 and TIMP4 (TIMP) of the mixture of non-activity with MMP, the conditioning agent of proteolytic enzyme more widely that stops MMP to play a role, activate the conditioning agent of MMP (comprising that film is in conjunction with MMP (the MT-MMP)) genetic expression of MMP secretion zymogen forms, for example 4, the compound of 5-dihydroxyanthraquinone-2-carboxylic acid (AQCA) and derivative thereof.Have-the genotypic object of 82A/G GG for known, suitable therapy can be to use the medicament of the genetic expression that can reduce coding MMP12, or use and to reduce the active medicament of MMP12, for example express or active medicament, or use and to reduce expression or the active medicament of one or more films in conjunction with MMP or other MMP12 activator by using one or more TIMP that to raise.For example, suitable therapy can be to use the MMP1 inhibitor to this class object, for example 4, and 5-dihydroxyanthraquinone-2-carboxylic acid (AQCA), anthraquinonyl-mercaptoethylamine, anthraquinonyl-L-Ala hydroxamic acid or their derivative.Equally, the 372T/C CC genotype of coding TIMP1 gene is relevant with the ACS susceptibility.Have a genotypic object of 372T/C CC for known, suitable therapy can be to use the medicament that can regulate and preferably increase the genetic expression of coding TIMP1.
In another example, with respect to the protective gene type, a certain susceptible gene type raises with genetic expression and is associated.For known object with susceptible gene type, suitable therapy is by for example using antisense or RNAi method to use the medicament that can reduce described genetic expression.Another suitable therapy can be to use the inhibitor of described gene product to this class object.In a further example, being present in the reduction that susceptible gene type and the combination of repressor in the gene promoter increase with genetic transcription is associated.Suitable therapy is to use can reduce the repressor level and/or prevent repressor bonded medicament, thereby alleviates its downward modulation effect to transcribing.Another therapy can comprise gene therapy, for example introduces the gene (gene copy that for example has the protective gene type) to the reduction of repressor binding affinity of at least one each additional copies.
The method and the medicament that are suitable for being applied in this class therapy are known in the art, and discuss in this article.
The evaluation of susceptibility described herein and protectiveness polymorphism also provides the screening candidate compound to assess the chance of its effect in preventing and/or treating.This class screening method relates to the candidate compound of the ability of the genotype of identifying a series of abilities with the genotype that reverses or offset the susceptibility polymorphism or phenotype effect or simulation or copy protection sexual polymorphism or phenotype effect.
In addition, the present invention also provides and has been used for the possible reactive method of evaluation object to existing prevention or methods of treatment.When existing treatment process related to physiologically active concentration with excessive or insufficient expressing gene product and returns to for age of object and sex in the normal scope, these class methods were particularly suitable for.In these cases, described method comprises whether exist, raise or down-regulation of gene expression if detecting the susceptibility polymorphism when it exists, make this excessive or insufficient state be the result, and the object that wherein has described polymorphism may be the respondent who handles.
Present embodiment has been described this paper has been identified that the SNP related with the risk that ACS takes place is substituted by the SNP that is in linkage disequilibrium with it, shows that this class SNP can obtain similar SNP mark.At this, when the SNP in being in LD is replaced by the concrete SNP that this paper put down in writing, can use substituting SNP to obtain the SNP mark.For this point is described, TLR4 Asp299Gly A/G SNP is replaced from the TLR4 Thr399Ile C/T SNP in the 11SNP group.It is reported that these two SNP are in linkage disequilibrium (it is reported the G allelotrope T allelotrope almost total and the Thr399Ile polymorphism of Asp299Gly polymorphism be divided into from).Table 33 hereinafter clearly illustrated this be divided into from, wherein there are 99% consistence (having got rid of genotyping " failure ") in Asp299Gly polymorphism genotype and Thr399Ile polymorphism genotype.
Consistence between table 33.TLR4 299 and 399 polymorphisms.
TLR4 299 genotype | TLR4 399 genotype | Consistence (%) | Summation | |
AA 534 | CC 524 TC 6 |
524/530 (99%) | 534 | |
AG 69 | TC 68 |
68/69 (99%) | 69 | |
|
|
2/2 | 2 |
(100%) | ||||
|
|
3 | ||
608 |
Table 34 has shown that when TLR4 Asp299Gly SNP is substituted by the TLR4 Thr399IleSNP of 11 SNP group ACS organizes and the SNP score distribution of control group.During derivation SNP mark, this means that mark with AG/GG genotype (protectiveness=+ 1) replaces with the mark of CT/TT genotype (protectiveness=+ 1) and calculates the latter's mark.But table 34 top shadow grid is represented and table 31 shown in comparative group between difference.Fig. 4 drawing illustrates the similar mark with Fig. 1 in the graphic representation mode.
Table 34. is according to the distribution-alternate 11SNP group of SNP mark ACS object
Therefore, replace the mark that has clinical meaning with derivation with this paper SNP that SNP that SNP fractional SNP is in LD can be in LD with it that is used to derive.
Table 35 has hereinafter provided the representative example that the polymorphism of indicating with table 30 is in linkage disequilibrium.Use public database can locate the example of this class polymorphism, for example
Www.hapmap.orgOn database.The polymorphism of indicating illustrates with bracket.The rs number that provides as those of skill in the art will recognize that is the unique identifier of each polymorphism.
These results show that the SNP that is put down in writing with this paper is in the SNP of the LD SNP of table 35 (for example from) and can be used in the SNP mark with similar clinical application.
Table 35. and the SNP that is in linkage disequilibrium with the related SNP of susceptibility or protectiveness phenotype.
CMA1
rs7150627 | rs2007323 | rs11844710 | rs7151943 | rs7148705 |
rs1885107 | rs9806075 | rs4982956 | rs1956920 | rs7146705 |
rs12434912 | rs1956921 | rs2208447 | rs927281 | rs1800875(-1903 A/G) |
rs7400965 | rs761988 | rs1800876 | rs6573850 | rs1956916 |
rs3759635 | rs8007723 | rs1956917 | rs1956922 | rs927278 |
rs1956918 | rs1956923 | rs2007316 | rs1956919 |
TGFB1
rs1529717 | rs13447341 | rs1046909 | rs2241712 |
rs2241714 | rs1982072 | rs2317130 | rs4803457 |
rs1800469(-509 C/T) | rs1982073 | rs1800471 |
MMP12
rs17368890 | rs11225444 | rs608194 | rs12793969 | rs1277718 |
rs4323842 | rs17099726 | rs7931510 | rs12786343 | rs7934568 |
rs17099720 | rs4420231 | rs7934710 | rs3814766 | rs4393288 |
rs621170 | rs2276109(-82 A/G) | rs11225443 | rs11225445 | rs10895367 |
rs17368659 | rs636648 | rs495914 | rs7126998 | rs17368814 |
rs610341 | rs1799750(MMP1-1607 G/GG) | rs501371 | rs610338 |
FGF2
rs13434728 | rs308395 | rs12509901 | rs308405 | rs13434738 |
rs308396 | rs177814 | rs308404 | rs308447 | rs308397 |
rs308412 | rs10470916 | rs13435470 | rs308398 | rs1563704 |
rs308403 | rs10003693 | rs308399 | rs10049563 | rs308402 |
rs11940812 | rs308400 | rs308411 | rs308401 | rs13137174 |
rs1449683(Ser52Ser) | rs308410 | rs10028307 | rs2922979 | rs416124 |
rs7668232 | rs3804144 | rs374880 | rs13349352 | rs2922980 |
rs308409 | rs11940156 | rs12650248 | rs4574429 | rs308391 |
rs1992980 | rs308408 | rs12507250 | rs2922981 | rs367344 |
rs308392 | rs1984971 | rs367331 | rs11098673 | rs366192 |
rs308407 | rs6828763 | rs411027 | rs968346 | rs6829351 |
rs421184 | rs4254785 | rs308393 | rs2926173 | rs728694 |
rs6830094 | rs11934448 | rs13119363 | rs308394 | rs4146526 |
rs308406 |
IL4RA
rs3024672 | rs1805012 | rs3024696 | rs2234899 | rs3024673 |
rs2234923 | rs3024674 | rs2234900 | rs3024675 | rs1805013 |
rs3024676 | rs1805015 | rs2234897 | rs1801275(Q576R) | rs6413500 |
rs3024677 | rs1805011 | rs3024678 | rs2234898 | rs1805016 |
LTA
rs2857708 | rs3093540 | rs4645834 | rs4947326 | rs2516312 |
rs3093547 | rs4947327 | rs2844482 | rs3093545 | rs2844486 |
rs2071590 | rs4248157 | rs2857601 | rs1800683 | rs9282875 |
rs2844485 | rs2239704 | rs1799964 | rs3131637 | rs3093546 |
rs4647198 | rs7449641 | rs909253 | rs9282876 | rs12174951 |
rs4986978 | rs2507961 | rs3135048 | rs746868 | rs1800630 |
rs2844484 | rs4647193 | rs2844483 | rs4647194 | rs9267499 |
rs2857713 | rs2857706 | rs3093542 | rs2009658 | rs3093543 |
rs3093539 | rs2071589 | rs736160 | rs1041981(Thr26Asn) | rs915654 |
rs4647195 | rs4647191 | rs4647196 | rs4647192 | rs3093544 |
HSP70
rs547828 | rs11557921 | rs2075800 | rs1061581 |
rs2227956(T2437C) | rs506770 | rs1008438 | rs541340 |
rs1043618 | rs508603 | rs11557923 | rs508633 |
rs1043620 | rs562047 | rs12190359 | rs11557924 |
TLR4
rs2149356 | rs5030714 | rs5030727 | rs4986790(Asp299Gly) | rs5030728 |
rs2770145 | rs5030729 | rs2770144 | rs100001066 | rs5031050 |
rs5030710 | rs11536884 | rs5030711 | rs4986791(Thr399Ile) | rs5030712 |
rs16906079 | rs5030713 |
IFNG
rs2069705 | rs2069713 | rs2069719 | rs2069724 | rs2069731 |
rs1861494 | rs9282708 | rs2069725 | rs2069706 | rs2234685 |
rs2069720 | rs4394909 | rs2069707 | rs1861493 | rs1042274 |
rs2069726 | rs3814242 | rs2069714 | rs2069721 | rs2069727 |
rs2069709 | rs2069715 | rs2069734 | rs2069710 | rs2069716 |
rs2069722 | rs2069711 | rs2069717 | rs2234687 | rs2069712 |
rs2069718 | rs7957366 | rs2430561(874 A/T) | rs3087272 | rs2069723 |
NFKBIL1
rs2071592(-63 T/A) | rs2844492 | rs12181589 | rs3869143 | rs2857710 |
rs2516386 | rs2523500 | rs11756780 | rs4081553 | rs3131641 |
rs2516385 | rs2523499 | rs2857606 | rs4947324 | rs2844490 |
rs11962114 | rs9267491 | rs2516395 | rs4947325 | rs2844489 |
rs2239708 | rs2516383 | rs9267493 | rs2516479 | rs2857709 |
rs2071591 | rs7749930 | rs12526552 | rs13215091 | rs2844488 |
rs9380262 | rs6916921 | rs12200955 | rs2516392 | rs2844487 |
rs3219183 | rs9378162 | rs3130061 | rs2516391 | rs2857602 |
rs9267489 | rs7754479 | rs13220163 | rs2857603 | rs2857708 |
rs3219182 | rs11752951 | rs13220165 | rs2516390 | rs4947326 |
rs3219181 | rs11752976 | rs2857605 | rs9501149 | rs4947327 |
rs3219180 | rs2255798 | rs2857604 | rs9267494 | rs2844486 |
rs2857607 | rs9267492 | rs3093949 | rs6903106 | rs2857601 |
rs9267490 | rs3094594 | rs2239707 | rs928815 | rs2844485 |
rs9394075 | rs2516397 | rs3219179 | rs7762619 | rs3131637 |
rs2516384 | rs2516396 | rs2230365 | rs12663590 | rs7449641 |
rs13190709 | rs2255899 | rs3130062 | rs7746486 | rs12174951 |
rs2523501 | rs9394076 | rs13192469 | rs3135043 | rs3135048 |
rs7738380 | rs12661769 | rs9469024 | rs3135042 | rs2844484 |
rs11751074 | rs6929796 | rs4288225 | rs2523514 |
PDGFRA
rs7682912 | rs17084062 | rs890203 | rs2412555 | rs4484359 |
rs17084065 | rs4864861 | rs11941325 | rs12649484 | rs2114039 |
rs4864504 | rs11942406 | rs7683707 | rs13140747 | rs4608869 |
rs11944066 | rs12506783 | rs13114391 | rs4368668 | rs4422471 |
rs17084050(-1630I/D) | rs17084067 | rs4635872 | rs10029499 | rs17084051 |
rs6850748 | rs4637467 | rs7673597 | rs1800809 | rs4864862 |
rs7677751 | rs7673625 | rs6554162 | rs4864505 | rs7673984 |
rs1800810 | rs4864863 | rs4352534 | rs1800813 | rs4864844 |
rs4394060 | rs1135534 | rs7678144 | rs4508953 | rs1800812 |
rs6554163 | rs4864857 | rs7690503 | rs6836215 | rs4864858 |
rs7673027 | rs6554164 | rs4864859 | rs7668190 | rs11727127 |
rs4864860 | rs7689569 | rs11937644 | rs7698425 | rs12644271 |
rs13435164 | rs7681399 | rs7673853 | rs6554165 | rs6839108 |
rs7679903 | rs6842432 |
IL4
rs2243250(-589C/T) | rs2243261 | rs2243280 | rs10066662 | rs4986963 |
rs2227282 | rs2243281 | rs6885996 | rs17772853 | rs2243263 |
rs6879348 | rs13181331 | rs2070874 | rs2243264 | rs2243282 |
rs13161530 | rs2243251 | rs2243265 | rs2243283 | rs4426908 |
rs4986964 | rs2243266 | rs2243284 | rs7731792 | rs2243252 |
rs2243267 | rs2243285 | rs11749544 | rs2079102 | rs2243268 |
rs7703922 | rs6897429 | rs734244 | rs9282745 | rs12521281 |
rs2406539 | rs2243253 | rs9282746 | rs2243286 | rs11747814 |
rs4996002 | rs2243270 | rs2243287 | rs10043403 | rs9327636 |
rs2243308 | rs2243309 | rs11242122 | rs9327637 | rs2243271 |
rs2243288 | rs11242123 | rs2243254 | rs2243272 | rs2243289 |
rs11242124 | rs2243255 | rs2243273 | rs2243290 | rs11242125 |
rs2243257 | rs2243274 | rs2243291 | rs6879672 | rs2243258 |
rs2243275 | rs2243292 | rs1859139 | rs2243259 | rs2243276 |
rs7379604 | rs1859138 | rs2227284 | rs2243277 | rs7379607 |
rs10068370 | rs2243260 | rs2243279 | rs10066660 | rs11949166 |
MMP1
rs498186 | rs509332 | rs570662 | rs575727 | rs473509 |
rs534191 | rs7125865 | rs7102189 | rs2075847 | rs1155764 |
rs2000609 | rs573764 | rs470146 | rs7107224 | rs2839969 |
rs574939 | rs1799750(-16071G/2G) | rs685265 | rs12283571 | rs542603 |
rs470211 | rs12279710 | rs519806 | rs12280880 | rs533621 |
rs2408490 | rs12285331 | rs526215 | rs470206 | rs470307 |
rs12286876 | rs504875 | rs2105581 | rs484915 | rs634607 |
rs12283759 | rs11225427 | rs552306 |
PDGFA
rs1800815 C-26IN3T | No rs His69His | rs1800814(C+12IN5T) |
GCLM
rs3170633 | rs2234730 | rs12094906 | rs2273407 | rs10489605 |
rs6703130 | rs7515991 | rs2273406 | rs12094966 | rs11165031 |
rs12057371 | rs12401915 | rs7549683 | rs6667121 | rs12068345 |
rs743119 | rs7513671 | rs1803636 | rs11165033 | rs736762 |
rs1087480g | rs11165032 | rs7527855 | no rs number(-588C/T) | rs7552401 |
rs12062047 | rs3827715 | rs6700112 | rs11589165 | rs17376966 |
rs12040570 | rs11587480 | rs2234729 | rs12090038 | rs12062214 |
rs6680315 | rs4598495 | rs12062216 | rs6541405 | rs12090230 |
rs12760946 | rs12730517 | rs6692306 | rs12089163 | rs7541690 |
rs6702045 | rs12140446 | rs718873 | rs6702064 | rs7522297 |
rs718874 | rs2391323 | rs7517826 | rs718875 | rs2064764 |
rs7515191 | rs12741834 | rs12143416 | rs1803635 | rs12410324 |
rs12064127 | rs12068168 | rs2301022 | rs769211 | rs7515813 |
rs3789453 |
OR13G1
rs1151640Ile132Val | The SNP that does not have other genotypings |
IL10
rs3024498 | rs3024508 | rs1518110 | rs3024489 | rs3024510 |
rs1878672 | rs3021094 | rs3024488 | rs3024497 | rs3024493 |
rs3024491 | rs1800872 | rs3024496 | rs3024507 | rs3021093 |
rs1800895 | rs5743628 | rs3024492 | rs3790622 | rs1800871 |
rs3024495 | rs2352792 | rs3024490 | rs1800894 | rs5743627 |
rs1554286 | rs2222202 | rs1800896(IL10-1082A/G) | rs3024509 | rs5743626 |
rs3021098 | rs3024494 | rs1518111 | rs3001099 | rs9282740 |
rs3024506 | rs5743625 |
AAT;SERPINA1
rs17824597 | rs1243166 | rs11846959 | rs20546 | rs17090693 |
rs1051052 | rs17090719 | rs11558261 | rs1243168 | rs1243165 |
rs2070709 | rs709932 | rs1884549 | rs7142803 | rs2753938 |
rs17751614 | rs7144409 | rs1243162 | rs1243167 | rs1243164 |
rs2749547 | rs1884548 | rs2073333 | rs2753937 | rs1885065 |
rs1243163 | rs2854258 | rs1884547 | rs1802960 | Rs17580 (S-allele) |
rs1884546 | rs1303 | rs1049800 | rs9944117 | rs13170 |
rs2230075 | rs875989 | rs12233 | rs8350 | rs877084 |
rs12077 | rs6647 | rs877083 | rs1050520 | rs11558264 |
rs877082 | rs1050469 | rs7141735 | rs877081 | rs1802961 |
rs7145047 | rs11568814 | rs1802959 | rs2239652 | rs9944155 |
rs2753939 | rs7145770 | rs11832 | rs2749521 | rs2239651 |
rs11628917 | rs1802962 | rs11558263 |
ICAM1
rs1799969 | rs5030383 | rs2735439 | rs2569705 | rs5493 |
rs281436 | rs2569697 | rs10402760 | rs5030381 | rs923366 |
rs2075742 | rs2569706 | rs5494 | rs281437 | rs2569698 |
rs2569707 | rs3093033 | rs3093030 | rs11669397 | rs2735441 |
rs5495 | rs5030384 | rs901886 | rs2436545 | rs1801714 |
rs5030385 | rs885742 | rs2436546 | rs13306429 | rs3810159 |
rs2569699 | rs2916060 | rs2071441 | rs281438 | rs1056538 |
rs2916059 | rs5496 | rs3093029 | rs11549918 | rs2916058 |
rs5497 | rs2735442 | rs2569700 | rs2569708 | rs13306430 |
rs2569693 | rs2228615 | rs12972990 | rs5498(K469E) | rs281439 |
rs2569701 | rs735747 | rs5030400 | rs281440 | rs2569702 |
rs885743 | rs2071440 | rs2569694 | rs2735440 | rs5499 |
rs11575073 | rs2569703 | rs3093032 | rs2569695 | rs10418913 |
rs1057981 | rs2075741 | rs1056536 | rs5500 | rs11575074 |
rs2569704 | rs5501 | rs2569696 | rs11673661 |
BAT1
rs10456058 | rs3219190 | rs3130057 | rs2523507 | rs2516485 |
rs1048885 | rs1266079 | rs2239525 | rs2734572 | rs11264 |
rs2844504 | rs2239526 | rs3093984 | rs9267480 | rs9267483 |
rs16899756 | rs3130051 | rs3093978 | rs13211189 | rs2239527(-23G/C) |
rs2734580 | rs11543322 | rs2734583 | rs2523506 | rs3130052 |
rs2516478 | rs2516338 | rs2523505 | rs3130053 | rs3130056 |
rs9267484 | rs2239528 | rs2734579 | rs2734585 | rs9380261 |
rs16899760 | rs2734578 | rs2516477 | rs9267485 | rs2523504 |
rs2734577 | rs3853601 | rs3130058 | rs2844509 | rs3130633 |
rs3093977 | rs2516394 | rs3130630 | rs2907768 | rs2734584 |
rs3093975 | rs3130629 | rs2516484 | rs9267481 | rs3093974 |
rs12662306 | rs9267478 | rs11796 | rs1129640 | rs9267487 |
rs2734588 | rs3093948 | rs933208 | rs2251824 | rs2516483 |
rs1055385 | rs2071596 | rs12215563 | rs2516482 | rs1055384 |
rs2516393 | rs2071594 | rs2516481 | rs1055388 | rs2523512 |
rs2071593 | rs3130054 | rs3131629 | rs2523511 | rs2239705 |
rs9394074 | rs6915692 | rs3219187 | rs2523503 | rs2516480 |
rs3131628 | rs2071595 | rs2523502 | rs2259435 | rs6915573 |
rs2239709 | rs3093983 | rs3093976 | rs2516473 | rs2286712 |
rs7753431 | rs9501148 | rs13206927 | rs2516475 | rs2523510 |
rs2734587 | rs2516474 | rs2269476 | rs3093982 | rs2471826 |
rs12665489 | rs2734586 | rs2734582 | rs11757236 | rs3130055 |
rs929138 | rs12665501 | rs3093981 | rs2075581 | rs12178599 |
rs3093980 | rs2734581 | rs2079170 | rs2075582 | rs2075580 |
rs2523508 | rs3093979 | rs9267482 | rs7738430 | rs3115537 |
rs10456396 | rs3130059 |
rs2373962 | rs2566519 | rs2853797 | rs2373961 | rs3918157 |
rs13311166 | rs6951150 | rs3918158 | rs13310774 | rs13238512 |
rs3918159 | rs2853798 | rs10247107 | rs2566516 | rs11974098 |
rs10276930 | rs3918225 | rs3918166 | rs10277237 | rs3918160 |
rs3730001 | rs12703107 | rs1800779 | rs3918167 | rs6946340 |
rs2243311 | rs3918168 | rs6946091 | rs3918161 | rs3918169 |
rs6946415 | rs10952298 | rs3918170 | rs10952296 | rs2070744 |
rs3793342 | rs13309715 | rs3918226 | rs3793341 | rs10952297 |
rs3918162 | rs1549758 | rs7784943 | rs3918163 | rs1007311 |
rs11771443 | rs3918164 | rs9282803 | rs2243310 | rs3918165 |
rs9282804 | rs1800783 | rs1800781 | rs1799983(Asp298Glu) | rs3918155 |
rs13310854 | rs3918156 | rs13310763 |
SOD3
rs1799895;Arg213Gly | Be positioned at the recombination hotspot district |
PAI-1
rs6972498 | rs7788533 | rs2227707 | rs12536798 | rs6975620 |
rs2227631 | rs6959121 | rs6956010 | rs1799768(-675/-668 4G/5G) | rs17135252 |
rs12534508 | rs4729662 | rs4729664 | rs11770439 | rs2527316 |
rs4727479 | rs2854235 | rs4729663 | rs10228765 | rs6950982 |
rs2854225 | rs6465787 | rs2854226 |
MIP1A
rs8075808 | rs1719126 | rs4995343 | rs17616714 | rs5023530 |
rs4995344 | rs7214787 | rs5023529 | rs4995345 | rs9903603 |
rs5023528 | rs4995346 | rs1634486 | rs5023527 | rs9972917 |
rs7213813 | rs1396785 | rs1634497 | rs8075709 | rs2522124 |
rs7406518 | rs1634488 | rs2522125 | rs1634498 | rs1634489 |
rs764871 | rs8076279 | rs3859285 | rs764872 | rs1634499 |
rs3859286 | rs2376461 | rs17679109 | rs3859287 | rs2011959 |
rs9972960 | rs1634490 | rs1719127 | rs1634500 | rs17616756 |
rs3169944 | rs1634501 | rs5022560 | rs1049203 | rs17617023 |
rs2136430 | rs8951 | rs1634502 | rs4319819 | rs1049200 |
rs17617047 | rs6505505 | rs16971943 | rs8068313 | rs1620728 |
rs1049199 | rs12602397 | rs4302099 | rs3210166 | rs1634503 |
rs4319820 | rs1063340 | rs2687498 | rs1634491 | rs1049195 |
rs16971970 | rs4506953 | rs1049191 | rs12452083 | rs1634492 |
rs16971944 | rs5011009 | rs1634493 | rs8070375 | rs4636955 |
rs4309452 | rs1049188 | rs1626203 | rs5015795 | rs16971946 |
rs9900984 | rs1851503 | rs5029406 | rs12937093 | rs1719209 |
rs5029407 | rs12937627 | rs16971936 | rs1049131 | rs1719135 |
rs16971937 | rs1049121 | rs1719136 | rs1634494 | rs1049114 |
rs1634504 | rs9893539 | rs5029408 | rs1634505 | rs12601899 |
rs5029409 | rs11658357 | rs9916016 | rs5029410 | rs1634506 |
rs1719123 | rs1719130 | rs16971972 | rs16971938 | rs6505506 |
rs9913910 | rs1879917 | rs6505507 | rs1634507 | rs1719124 |
rs1719131 | rs17679271 | rs7406217 | rs1130371 | rs8072326 |
rs7406596 | rs16971957 | rs2072091 | rs7406597 | rs1851501 |
rs1634508 | rs7502900 | rs1719133 | rs7220510 | rs7222527 |
rs1634495 | rs1719134(+459C/T) | rs2188973 | rs16971960 | rs2188974 |
rs4995339 | rs7222850 | rs4995340 | rs7222217 | rs4995341 |
rs1719125 | rs4995342 |
MMP7
rs14983 | rs11225305 | rs12289943 | rs2847530 | rs12419959 |
rs12788028 | rs7926218 | rs12419977 | rs10895308 | rs2187364 |
rs11225306 | rs2408391 | rs2156528 | rs11225307 | rs11820758 |
rs17098292 | rs10502001 | rs880197 | rs17352054 | rs12289049 |
rs1943778 | rs11225303 | rs10750646 | rs11827824 | rs12288254 |
rs10502002 | rs1943779 | rs7933135 | rs11225308 | rs7926470 |
rs12575975 | rs11225304 | rs11225309 | rs17098295 | rs17098317 |
rs6590970 | rs10895306 | rs1996352 | rs10895307 | rs12418158 |
rs2408390 | rs2701982 | rs17881472 | rs12419636 | rs17880821(-181A/G) |
rs17098306 | rs4543946 | rs12285347 | rs17098318 |
Cathepsin G
rs9671740 | rs34792401 | rs12588201 | rs10148261 | rs6573865 | rs8007970 |
rs11848310 | rs35614744 | rs35345293 | rs4537944 | rs2332397 | rs8012655 |
rs12889110 | rs10311660 | rs4981537 | rs36079901 | rs2332398 | rs1956907 |
rs12587099 | rs12147842 | rs4981538 | rs9989246 | rs3891906 | rs1956906 |
rs12879629 | rs9671474 | rs4981539 | rs9989184 | rs3891905 | rs35316440 |
rs35776728 | rs1756602 | rs4981540 | rs34712519 | rs11851298 | rs28778409 |
rs35270658 | rs11157885 | rs34432073 | rs12100969 | rs3861508 | rs8008954 |
rs34377408 | rs10143176 | rs35884608 | rs10144984 | rs7142675 | rs2093256 |
rs34310125 | rs12436232 | rs4981541 | rs10145731 | rs11301449 | rs11158781 |
rs35426278 | rs5007574 | rs9646161 | rs28806511 | rs28441642 | rs7157694 |
rs2216900 | rs28878775 | rs4982959 | rs10145286 | rs2011607 | rs8005739 |
rs12435455 | rs35112976 | rs11158761 | rs28803584 | rs11158778 | rs7143951 |
rs10138356 | rs34065379 | rs4632067 | rs9652365 | rs11845858 | rs7144090 |
rs4644778 | rs12433770 | rs34318040 | rs12888328 | rs2224426 | rs7144096 |
rs11850630 | rs11159232 | rs8010555 | rs12887710 | rs4982968 | rs7144104 |
rs34841597 | rs12882370 | rs10148816 | rs8006887 | rs35704637 | rs34651242 |
rs12879894 | rs36126615 | rs10133351 | rs8007599 | rs1951132 | rs10136912 |
rs4375584 | rs9672023 | rs12890682 | rs9652294 | rs1951131 | rs9323523 |
rs800849 | rs9944068 | rs4553550 | rs7155992 | rs1951130 | rs28722668 |
rs34042254 | rs9944069 | rs4537943 | rs12888151 | rs1951129 | rs35959655 |
rs34545435 | rs1956918 | rs12433996 | rs34436261 | rs3079309 | rs34997518 |
rs12885502 | rs1956917 | rs34092671 | rs36100678 | rs34634241 | rs17257069 |
rs12885756 | rs1956916 | rs8005125 | rs35239717 | rs11849152 | rs6573871 |
rs12885748 | rs761988 | rs35584604 | rs12587746 | rs1956911 | rs17105013 |
rs12885747 | rs927281 | rs1956915 | rs34035545 | rs12888496 | rs28479407 |
rs12885233 | rs12434912 | rs10873216 | rs4420452 | rs1956910 | rs12100907 |
rs34449575 | rs28656464 | rs34656084 | rs721134 | rs1956909 | rs11158791 |
rs34780137 | rs35275136 | rs34416904 | rs10130107 | rs12588702 | rs1956912 |
rs12886566 | rs4982956 | rs28496049 | rs3901388 | rs2332399 | rs1956908 |
rs11850400 | rs7148705 | rs12589666 | rs35220969 | rs1951128 | rs1304909 |
rs12882368 | rs2007323 | rs7151899 | rs3861506 | rs2332400 | rs8021299 |
rs12882089 | rs2007316 | rs7149913 | rs3861507 | rs28768164 | rs7155452 |
rs12896244 | rs927278 | rs7149925 | rs3905107 | rs10144882 | rs2332401 |
rs35106724 | rs8007723 | rs7156977 | rs1956914 | rs1951127 | rs8007285 |
rs35193389 | rs6573850 | rs4982960 | rs1956913 | rs8022028 | rs11849224 |
rs12432795 | rs34858090 | rs7141080 | rs987630 | rs10131084 | rs6573874 |
rs12432796 | rs3079301 | rs33993912 | rs987629 | rs10139948 | rs12587351 |
rs34281648 | rs35839512 | rs4982961 | rs987628 | rs10139332 | rs12587425 |
rs800850 | rs34614283 | rs12878586 | rs11158770 | rs1951125 | rs4982969 |
rs34013113 | rs4982957 | rs8004636 | rs932617 | rs33995132 | rs12587539 |
rs11851718 | rs2208447 | rs10130100 | rs932616 | rs1951124 | rs10601342 |
rs12433789 | rs7146705 | rs11849539 | rs1885106 | rs8007117 | rs35533698 |
rs13379195 | rs9806075 | rs35778376 | rs8008866 | rs8006658 | rs10601343 |
rs13379433 | rs34657109 | rs8008632 | rs4982964 | rs34042582 | rs4592564 |
rs4287482 | rs7151943 | rs11520369 | rs4982965 | rs34002761 | rs8019787 |
rs34264349 | rs7150627 | rs34079088 | rs4982966 | rs8007445 | rs1885597 |
rs4417480 | rs4981536 | rs4982962 | rs10134629 | rs34071722 | Asn 125Ser |
rs2792215 | rs4982958 | rs4981542 | rs8003038 | rs12890487 | rs17105289 |
rs10313155 | rs11351813 | rs4982963 | rs8017569 | rs12890488 | rs34281853 |
rs34640640 | rs10712328 | rs36074365 | rs10137473 | rs12890064 | rs2070697 |
CX3CR1
rs4234139 | rs11707528 | rs17038647 | rs2669850 | rs4676621 | rs34570795 |
rs11129819 | rs17793056 | rs4676622 | rs34841495 | rs11129820 | rs2669851 |
rs12491311 | rs6599018 | rs9826296 | rs2853714 | rs34980214 | rs11709600 |
rs17038663 | rs36040453 | rs35840437 | rs34991361 | rs7636125 | rs34864276 |
rs35425914 | rs9847920 | rs11710546 | rs13088991 | rs13078589 | rs17038640 |
rs17038674 | rs13099085 | rs9869871 | rs1050592 | rs34681148 | rs10695501 |
rs3732378 | rs35007101 | rs35540291 | rs3732379(I249V) | rs6790767 | rs4016736 |
rs4986872 | rs9882352 | rs11711922 | rs17038679 | rs938206 | rs4676623 |
rs3732380 | rs938207 | rs34481570 | rs7645269 | rs11706384 | rs4676487 |
rs4271863 | rs11711391 | rs35291973 | rs35502141 | rs7649301 | rs1877563 |
rs34743375 | rs17038638 | rs11713282 | rs12634272 | rs13315491 | rs17038645 |
rs34139145 |
NOD2
rs6596 | rs34430742 | rs1078327 | rs8061960 | rs12929234 | rs17314544 |
rs35435054 | rs4785224 | rs5743274 | rs34192073 | rs34552113 | rs17223195 |
rs35581802 | rs5743261 | rs35422070 | rs2066847 | rs35899583 | rs13337656 |
rs8054275 | rs5743262 | rs1861759 | rs5743293 | rs12324931 | rs13338860 |
rs13339019 | rs5743263 | rs5743275 | rs5743294 | rs3135501 | rs12599914 |
rs35973532 | rs8046608 | rs5743276 | rs34829738 | rs3135502 | rs35234675 |
rs1131716 | rs35378728 | rs2066844 | rs2357791 | rs3135503 | rs16948819 |
rs17846633 | rs5743264 | rs5743277 | rs7359452 | rs34683241 | rs7200370 |
rs34428900 | rs5743265 | rs35285618 | rs7203344 | rs11861521 | rs4785226 |
rs2302723 | rs5743266 | rs5743278 | rs5743295 | rs4785450 | rs11646600 |
rs7195707 | rs2076752 | rs6413461 | rs5743296 | rs11862710 | rs17223257 |
rs9888893 | rs5743267 | rs3813758 | rs35980453 | rs11862720 | rs11865799 |
rs7191692 | rs8061316 | rs5743279 | rs3135499 | rs1990752 | rs35072258 |
rs10600956 | rs8061636 | rs5743280 | rs5743297 | rs11864090 | rs11866167 |
rs35509283 | rs34456998 | rs5743281 | rs5743298 | rs34464167 | rs10451132 |
rs12448380 | rs16948754 | rs5743282 | rs5743299 | rs34620046 | rs3064638 |
rs12445637 | rs34627107 | rs4785225 | rs3135500 | rs8062105 | rs2066852 |
rs7202124 | rs35085911 | rs16948773 | rs5743300 | rs34321598 | rs2302759 |
rs2270369 | rs34281847 | rs9931711 | rs8056611 | rs16948792 | rs7194167 |
rs2270368 | rs7206340 | rs17313265 | rs35111385 | rs34741614 | rs34233862 |
rs35929558 | rs36034720 | rs34912053 | rs2357792 | rs11859047 | rs12444259 |
rs34828195 | rs35701609 | rs35263569 | rs12600253 | rs11863594 | rs28705891 |
rs2287195 | rs2076753 | rs10680678 | rs12598306 | rs11864698 | rs28654666 |
rs2066848 | rs34936594 | rs35322998 | rs7205423 | rs1477176 | rs11382774 |
rs36094725 | rs35095295 | rs11646168 | rs718226 | rs35967774 | rs34593836 |
rs11336436 | rs34684955 | rs35431588 | rs34963149 | rs2066851 | rs2160683 |
rs10709169 | rs2067085 | rs9925315 | rs11646242 | rs1592639 | rs3743781 |
rs4785223 | rs16948755 | rs5743284 | rs35151581 | rs9925070 | rs9646285 |
rs9926569 | rs34939799 | rs5743285 | rs7498888 | rs11863544 | rs16948829 |
rs9939349 | rs2111235 | rs751271 | rs5816718 | rs3064635 | rs34088926 |
rs28651300 | rs35617724 | rs748855 | rs11323644 | rs12933741 | rs16948836 |
rs8062727 | rs2111234 | rs1861758 | rs8060765 | rs12933742 | rs17314948 |
rs8044354 | rs7190413 | rs13332952 | rs16948789 | rs11863916 | rs34262697 |
rs8043770 | rs7206582 | rs7198979 | rs17313747 | rs5816721 | rs7184210 |
rs10459815 | rs8045009 | rs1861757 | rs5816719 | rs11859674 | rs34917190 |
rs9302752 | rs6500328 | rs7203691 | rs35360138 | rs1420873 | rs34015619 |
rs13331872 | rs7500036 | rs5743286 | rs5816720 | rs8053457 | rs34678551 |
rs1420685 | rs8057341 | rs5743287 | rs34562455 | rs6500329 | rs35812259 |
rs5816713 | rs35863026 | rs11319364 | rs3064634 | rs7500289 | rs6500333 |
rs33925268 | rs12918060 | rs34103974 | rs751919 | rs12924216 | rs17223592 |
rs4027240 | rs7204911 | rs10521209 | rs3743782 | rs1548989 | rs11866769 |
rs35554928 | rs7500826 | rs2066845 Gly881 Arg G/C) | rs11353661 | rs16948808 | rs1861762 |
rs2004804 | rs4785449 | rs5743288 | rs7199842 | rs4283227 | rs7187386 |
rs12448915 | rs12922299 | rs5743289 | rs1362698 | rs1420872 | rs8051573 |
rs5816714 | rs11649521 | rs8063130 | rs2216313 | rs4785451 | rs35224296 |
rs5816715 | rs13339578 | rs2076756 | rs11364818 | rs6500331 | rs3922267 |
rs34609432 | rs17221417 | rs12920425 | rs10655305 | rs11644525 | rs3087557 |
rs11297087 | rs13331327 | rs12920040 | rs35620436 | rs35189427 | rs1054987 |
rs34919724 | rs11642482 | rs12920558 | rs11451496 | rs16948810 | rs9635531 |
rs34746653 | rs11642646 | rs11326665 | rs1548990 | rs16948811 | rs11374168 |
rs34550909 | rs17312836 | rs11292073 | rs7195766 | rs16948813 | rs33995398 |
rs5816716 | rs5743268 | rs11423748 | rs9940175 | rs6500332 | rs4785452 |
rs34235838 | rs5743269 | rs12919099 | rs8060598 | rs17222902 | rs4785453 |
rs3064632 | rs5743270 | rs12920721 | rs7198188 | rs1420871 | rs4785227 |
rs1981760 | rs12925051 | rs2076755 | rs7187352 | rs2302760 | rs4785454 |
rs8063362 | rs12929565 | rs5743290 | rs34564491 | rs7192397 | rs4785455 |
rs9933594 | rs13380733 | rs5743291 | rs12599808 | rs17314341 | rs3064640 |
rs1362632 | rs13380741 | rs11642651 | rs11271535 | rs12597446 | rs13332720 |
rs12926429 | rs11647841 | rs1861756 | rs7200535 | rs3785141 | rs16948850 |
rs35831008 | rs34409335 | rs749910 | rs13336419 | rs13333006 | rs6500334 |
rs4785448 | rs34133110 | rs34333043 | rs3785142 | rs3785140 | rs5816722 |
rs11647143 | rs10451131 | rs2066846 | rs7342808 | rs9938976 | rs3064642 |
rs34981889 | rs2066842 | rs5816717 | rs7342715 | rs8061821 | rs6500335 |
rs7194886 | rs35090774 | rs4990643 | rs28454013 | rs8062540 | rs16948851 |
rs34231814 | rs5743271 | rs1077861 | rs7197362 | rs16948817 | rs3135504 |
rs11645448 | rs7498256 | rs34810706 | rs12934597 | rs8047910 | rs7189846 |
rs35832802 | rs5743272 | rs5743292 | rs12930153 | rs4027241 | rs7205760 |
rs5743259 | rs5743273 | rs9921146 | rs12934724 | rs34145774 | rs8049077 |
rs5743260 | rs2076754 | rs11645386 | rs12934730 | rs35896215 | rs1861761 |
rs2066850 | rs2066843 | rs7187857 | rs12929222 | rs2111435 | rs12925755 |
TIMP1
rs2858769 | rs13440654 | rs2097423 | rs35754459 | rs34026683 | rs5952438 |
rs35510014 | rs17147652 | rs5906436 | rs2854412 | rs1984392 | rs7064051 |
rs34644595 | rs3211164 | rs4824621 | rs34987183 | rs35777532 | rs12010140 |
rs10701204 | rs35895268 | rs4824622 | rs34465989 | rs28764016 | rs12559303 |
rs35338820 | rs28764017 | rs34324592 | rs1050151 | rs1043428 | rs5953061 |
rs34865437 | rs5953060 | rs5953062 | rs35946819 | rs4898(372T/C) | rs13441207 |
rs34663452 | rs35209437 | rs5953063 | rs1050175 | rs6609533 | rs5906437 |
rs10066 | rs34220495 | rs3921110 | rs35136843 | rs1803571 | rs34949562 |
rs2855135 | rs11551797 | rs6520281 | rs2854414 | rs17850165 | rs34910886 |
rs2855136 | rs1062849 | rs5953065 | rs2854415 | rs2070584 | rs9887335 |
rs2854416 | rs6609534 | rs34207832 | rs2854417 | rs34478552 | rs35891328 |
rs723556 | rs5906434 | rs12007301 | rs12394306 | rs6520278 | rs6609539 |
rs35093912 | rs6520279 | rs5953066 | rs5953059 | rs7886171 | rs6608733 |
rs34576985 | rs12556415 | rs4824424 | rs6609532 | rs5905614 | rs4824623 |
rs4282692 | rs5905615 | rs6608734 | rs13440825 | rs5906435 |
Industrial application
The present invention relates to be used for the method that the risk of ACS takes place evaluation object.Described method comprises analyzing and raises with the risk that ACS takes place shown in this paper or reduce related polymorphism, or analysis derives from the result of this alanysis.The present invention also provides to use shown in this paper and has been used for the risk of evaluation object with the polymorphism that risk raises or reduction is associated of generation ACS, and the nucleotide probe and primer, test kit and the microarray that are suitable for described assessment.The present invention also provides treatment to have the method for the object of polymorphism described herein.The present invention also provides the method that is used to screen the compound that can regulate the genetic expression that is associated with polymorphism described herein.
***
This paper with reference to or all patents, publication, scientific paper and other documents mentioned and the material level that all shows one of ordinary skill in the art of the present invention, each described reference and material are incorporated in this method by reference, and its incorporated extent is identical with the degree that the independent integral body of its method is by reference incorporated into or the listed integral body of this paper is incorporated into.But the present patent application people keeps the right that will physically incorporate this specification sheets into from any and all material and the information of any described patent, publication, scientific paper, website, electronics acquired information and other materials of quoting or document.
Concrete grammar as herein described has been represented numerous embodiments or preferred implementation, and only as exemplary application, is not used in to limit the scope of the invention.Those skilled in the art can expect other purposes, aspect, embodiment and embodiment after thinking deeply this specification sheets, and they include in the spirit of the present invention that is limited by the claim scope.Can carry out various replacements and change to the present invention disclosed herein and do not depart from scope and spirit of the present invention, this is conspicuous for those skilled in the art.Illustrative ground can suitably lack under any factor or the restriction in the present invention that this paper is described to be implemented, and this point is not open especially as necessary item in this article.Therefore, for example, under the various situations of this paper, in embodiments of the present invention or embodiment, " comprise ", " substantially by ... form " and " by ... form " in any term can be by any the substituting in other two terms in this specification sheets, and so show that additional embodiment of the present invention, the present invention have different scopes and various substituting embodiment of the present invention.Equally, term " comprises ", " comprising ", " containing " etc. should wide in range understandings and the restriction that do not have.The described method of the exemplary description of this paper can different steps in order be implemented, and they might not be confined to the order of steps shown in this paper or in claims.Use as this paper and appended claims, unless context clearlys show other implications, " a kind of (a) " of singulative, " a kind of (an) " and " being somebody's turn to do " comprise plural reference.Therefore for example mentioning " a kind of host cell " comprises multiple this class host cell (for example culture or colony), or the like.This patent all cannot be interpreted as being confined to this paper concrete disclosed specific embodiment of institute or embodiment or method in any case.This patent all may not be interpreted as being subjected to the restriction of any statement that any auditor of patent and trademark office or any other official or employee make in any case, unless this statement is concrete and adopt in the present patent application people's written reply undoubtedly, and indefinite conditioned disjunction reserve.
Term that has used and expression are used as exemplary term and non-limiting term; Equivalent or these terms and the Equivalent of expressing part not getting rid of these terms when using these terms and expression and express shown and the characteristics of description, but will be appreciated that the various changes in the scope of the invention of asking for protection are fine.Therefore, be understood that, although the present invention has obtained concrete disclosing by preferred implementation and optional feature, those skilled in the art can take the change and the variation of described notion disclosed herein, and described change and variation are considered to be in the scope of the present invention.
Sequence table
<110〉Synergenz Bioscience Ltd.
<120〉be used to assess the method and composition of cardiovascular function and obstacle
<130>550282
<150>NZ 543520
<151>2005-11-10
<150>NZ 543985
<151>2005-12-06
<150>NZ 549951
<151>2005-09-15
<160>124
<170>PatentIn version 3.2
<210>1
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>1
acgttggatg aaggctctga agacctgttc 30
<210>2
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>2
acgttggatg atccggatta tcgggaagag 30
<210>3
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>3
acgttggatg cttggtgatg atatcgtggg 30
<210>4
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>4
acgttggatg tcttcttcct gcctgatgag 30
<210>5
<211>29
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>5
acgttggatg aaacggtcgc ttcgacgtg 29
<210>6
<211>28
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>6
acgttggatg gggcagaagg aagagttc 28
<210>7
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>7
acgttggatg tacaggtgtc tgcctcctga 30
<210>8
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>8
acgttggatg aagagggtct gtcaacatgg 30
<210>9
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>9
acgttggatg atagccatga ccatgctgag 30
<210>10
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>10
acgttggatg ggccatttgt ttccctcttc 30
<210>11
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>11
acgttggatg ttgagataga tcaagggatg 30
<210>12
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>12
acgttggatg gtccgggttc tgtgaatatg 30
<210>13
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>13
acgttggatg agcatactta gactactacc 30
<210>14
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>14
acgttggatg cacactcacc agggaaaatg 30
<210>15
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>15
acgttggatg attccatgga ggctggatag 30
<210>16
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>16
acgttggatg gacaacacta ctaaggcttc 30
<210>17
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>17
acgttggatg actcacagag cacattcacg 30
<210>18
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>18
acgttggatg tgtcactcga gatcttgagg 30
<210>19
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>19
acgttggatg aggcggcgtc cgcggagaca 30
<210>20
<211>29
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>20
acgttggatg ctcggccgct cttctgtcc 29
<210>21
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>21
acgttggatg ttacctaaac agggagagcg 30
<210>22
<211>29
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>22
acgttggatg aagcctgcaa ccggaagtg 29
<210>23
<211>29
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>23
acgttggatg ctcaggcggc cttgcactc 29
<210>24
<211>29
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>24
acgttggatg aggcgcggga gcactcaga 29
<210>25
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>25
acgttggatg gctccacagc atcaagattc 30
<210>26
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>26
acgttggatg ttccatttcc tcaccctcag 30
<210>27
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>27
acgttggatg ggttcaagaa gtcatacccc 30
<210>28
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>28
acgttggatg agctctgtcc cttggatgtc 30
<210>29
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>29
acgttggatg cgacctgtcc ttctcaaaac 30
<210>30
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>30
acgttggatg gaataacagg cagactctcc 30
<210>31
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>31
acgttggatg gaaatgtcct ccagcatggg 30
<210>32
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>32
acgttggatg accctgctcc accgcatgta 30
<210>33
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>33
acgttggatg tgatcttgtt caccttgccg 30
<210>34
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>34
acgttggatg cgaggtgacg tttgacattg 30
<210>35
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>35
acgttggatg cttcagtata tcttggattg 30
<210>36
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>36
acgttggatg gttatgccac ttagatgagg 30
<210>37
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>37
acgttggatg ggagtcaatt tatgcagcag 30
<210>38
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>38
acgttggatg catcgttatt ggcaggaagc 30
<210>39
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>39
acgttggatg agcccaagaa gtttgaactc 30
<210>40
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>40
acgttggatg aggttgctgt tctcaaagtg 30
<210>41
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>41
acgttggatg gaggtcaggt ggatgtttac 30
<210>42
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>42
acgttggatg accccaagat gcatcttgcc 30
<210>43
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>43
acgttggatg ggcaactagc ctaaaaaccc 30
<210>44
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>44
acgttggatg cagagtgcgg aataaaaggc 30
<210>45
<211>29
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>45
acgttggatg tgaggtagac accgcctcc 29
<210>46
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>46
acgttggatg aagagacgtg taggaagccc 30
<210>47
<211>29
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>47
acgttggatg cagacattca caattgatt 29
<210>48
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>48
acgttggatg gatagttcca aacatgtgcg 30
<210>49
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>49
acgttggatg taacgcccct cacagttcac 30
<210>50
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>50
acgttggatg actccaggct ggaggaaatg 30
<210>51
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>51
acgttggatg cacagagaga gtctggacac 30
<210>52
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>52
acgttggatg tcttggtctt tccctcatcc 30
<210>53
<211>17
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>53
tcacgatgcc gacgaag 17
<210>54
<211>18
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>54
tcacgatgcc gacgaaga 18
<210>55
<211>19
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>55
ggcgtgggtg agttcattt 19
<210>56
<211>20
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>56
<210>57
<211>20
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>57
<210>58
<211>21
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>58
gtgctgcagg ccccagatga g 21
<210>59
<211>22
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>59
cggcctcctg acccttccat cc 22
<210>60
<211>23
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>60
cggcctcctg acccttccat ccc 23
<210>61
<211>22
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>61
ccacacatat ggtggttcat aa 22
<210>62
<211>23
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>62
ccacacatat ggtggttcat aac 23
<210>63
<211>23
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>63
tagatcaagg gatgatatca act 23
<210>64
<211>24
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>64
tagatcaagg gatgatatca acta 24
<210>65
<211>24
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>65
catacttaga ctactacctc gatg 24
<210>66
<211>25
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>66
catacttaga ctactacctc gatga 25
<210>67
<211>28
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>67
ctttcctctt acctatccct acttcccc 28
<210>68
<211>29
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>68
ctttcctctt acctatccct acttccccc 29
<210>69
<211>16
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>69
<210>70
<211>17
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>70
acattcacgg tcacctc 17
<210>71
<211>16
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>71
cgcggagaca cccatc 16
<210>72
<211>17
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>72
cgcggagaca cccatcc 17
<210>73
<211>17
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>73
cgacgaagga gggaaat 17
<210>74
<211>18
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>74
cgacgaagga gggaaatc 18
<210>75
<211>19
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>75
tcctcgctct cgcgccgcc 19
<210>76
<211>20
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>76
<210>77
<211>19
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>77
ccaagactta agttttgct 19
<210>78
<211>20
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>78
ccaagactta agttttgctc 20
<210>79
<211>19
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>79
ggaccccaac ccaagagaa 19
<210>80
<211>20
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>80
<210>81
<211>20
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>81
<210>82
<211>21
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>82
gaaacttggg agaacattgt c 21
<210>83
<211>23
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>83
ttcttccccc accagtggct atc 23
<210>84
<211>24
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>84
ttcttccccc accagtggct atca 24
<210>85
<211>23
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>85
acaacttgcc ggtgctcttg tcc 23
<210>86
<211>24
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>86
acaacttgcc ggtgctcttg tcca 24
<210>87
<211>24
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>87
gattgatttg agataagtca tatc 24
<210>88
<211>25
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>88
gattgatttg agataagtca tatcc 25
<210>89
<211>25
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>89
cagaaaaaaa aatcctttga aagac 25
<210>90
<211>26
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>90
cagaaaaaaa aatcctttga aagaca 26
<210>91
<211>26
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>91
ggtgcagatc taaatacttt aggctg 26
<210>92
<211>27
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>92
ggtgcagatc taaatacttt aggctga 27
<210>93
<211>17
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>93
gagcagcagg tttgagg 17
<210>94
<211>18
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>94
gagcagcagg tttgaggg 18
<210>95
<211>19
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>95
taaaaacccg gttctcaac 19
<210>96
<211>20
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>96
<210>97
<211>21
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>97
ctccgcctgg tgaggtctcc c 21
<210>98
<211>22
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>98
ctccgcctgg tgaggtctcc ca 22
<210>99
<211>23
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>99
ttcttacaac acaaaatcaa atc 23
<210>100
<211>24
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>100
ttcttacaac acaaaatcaa atca 24
<210>101
<211>16
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>101
<210>102
<211>17
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>102
acttccgtcc tccacca 17
<210>103
<211>17
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>103
agtctggaca cgtgggg 17
<210>104
<211>18
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>104
agtctggaca cgtgggga 18
<210>105
<211>29
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>105
acgttggatg gtctgttgac tcttttggc 29
<210>106
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>106
acgttggatg tggtgatcac ccaaggcttc 30
<210>107
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>107
acgttggatg catagagctt aagcgtctcc 30
<210>108
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>108
acgttggatg tgatccttct ggtggtcatc 30
<210>109
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>109
acgttggatg tcagtccctc ctgggctcta 30
<210>110
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>110
acgttggatg agaagagtca gacggaatcg 30
<210>111
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>111
acgttggatg gactcttgca catcactacc 30
<210>112
<211>30
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>112
acgttggatg agtgtaggtc ttggtgaagc 30
<210>113
<211>19
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>113
tggccttttc agattctgg 19
<210>114
<211>20
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>114
tggccttttc agattctggc 20
<210>115
<211>23
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>115
aagcgtctcc aggaaaatca taa 23
<210>116
<211>24
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>116
aagcgtctcc aggaaaatca taac 24
<210>117
<211>24
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>117
tgggatctag gcagagccac tggg 24
<210>118
<211>25
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>118
tgggatctag gcagagccac tgggc 25
<210>119
<211>20
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>119
<210>120
<211>21
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>120
cccatcacta cctgcagttt c 21
<210>121
<211>20
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>121
tggccttttc agattctggg 20
<210>122
<211>24
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>122
aagcgtctcc aggaaaatca taat 24
<210>123
<211>25
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>123
tgggatctag gcagagccac tgggt 25
<210>124
<211>21
<212>DNA
<213>Artificial
<220>
<223>Synthetic
<400>124
cccatcacta cctgcagttt t 21
Claims (50)
1. the method for the risk of ACS takes place in a determination object, and it comprises whether analysis exists one or more to be selected from following group polymorphism from the sample of described object:
The gene of coding chyme enzyme 1 (CMA1)-1903A/G;
The gene of coding matrix metalloproteinase 12 (MMP12)-82A/G;
Be encoded into the Ser52Ser (223C/T) of the gene of fibroblast growth factor 2 (FGF2);
The Q576R A/G of the gene of coding interleukin-4 acceptor α (IL4RA);
The HOM T2437C of the gene of coding heat shock protein 70 (HSP70);
The 874A/T of the gene of the plain γ of coded interference (IFNG);
The gene of coding interleukin-4 (IL-4)-589C/T;
The gene of coding interleukin 10 (IL-10)-1084A/G (1082);
The Arg213Gly C/G of the gene of encoding superoxide dismutase 3 (SOD3);
The 459C/T Intron I of the gene of coding macrophage inflammatory protein 1 α (MIP1A);
Asn 125 SerA/G of the gene of coding cathepsin G;
The I249V C/T of the gene of coding chemokine (CX3C motif) acceptor 1 (CX3CR1);
The Gly 881 Arg G/C of the gene of coding Caspase (NOD2); Or
The 372T/C of the gene of coding tissue inhibitor of metalloproteinase 1 (TIMP1);
Or be in one or more polymorphisms of linkage disequilibrium with any or multiple described polymorphism;
Wherein whether the existence of one or more described polymorphisms is the indication that the risk of ACS takes place object.
2. the method for claim 1, wherein one or more existence that are selected from following group polymorphism are that the indication that the risk of ACS reduces takes place:
Ser52Ser (223 C/T) the CC genotype of the gene of coding FGF2;
The Q576R A/G AA genotype of the gene of coding IL4RA;
The Hom T2437C CC or the CT genotype of the gene of coding HSP70;
874 A/T TT genotype of the gene of coding IFNG;
The gene of coding IL-4-589C/T CT or TT genotype;
-1084 A/G GG genotype of the gene of coding IL-10;
The Arg213Gly C/G CG or the GG genotype of the gene of coding SOD3;
The Asn 125 Ser AG or the GG genotype of the gene of coding cathepsin G; Or
372 T/C TT genotype of the gene of coding TIMP1.
3. the method for claim 1, wherein one or more existence that are selected from following group polymorphism are that the indication that the risk of ACS raises takes place:
-1903 A/G GG genotype of the gene of coding CMA1;
-82 A/G GG genotype of the gene of coding MMP12;
The gene of coding MIP1A+459 C/T Intron 1CT or TT genotype;
The Asn 125 Ser AA genotype of the gene of coding cathepsin G;
The I249V TT genotype of the gene of coding CX3CR1;
The Gly 881 Arg G/C CC or the CG genotype of the gene of coding NOD2; Or
372 T/C CC genotype of the gene of coding TIMP1.
4. the method for claim 1, wherein said method comprise whether analyze described sample exists one or more to be selected from other polymorphisms of following group:
The gene of coding transforminggrowthfactor-(TGFB1)-509C/T;
The Thr26Asn A/C of the gene of coding lymphotoxin α (LTA);
The Asp299Gly A/G of the gene of coding Toll sample acceptor 4 (TLR4);
The Thr399Ile C/T of the gene of coding TLR4;
The gene of the inhibitor-like 1 (NFKBIL1) of the nf of coding B cell κ light chain polypeptide genetic enhancer-63T/A;
The gene of coding platelet derived growth factor receptor α (PDGFRA)-1630Ins/Del (AACTT/Del);
-1607 1G/2G (Del/G) of the gene of coding matrix metalloproteinase 1 (MMP1);
12 IN 5C/T of the gene of coding Thr6 PDGF BB α (PDGFA);
The gene of coding L-glutamic acid-halfcystine ligase enzyme modification subunit (GCLM)-588C/T;
The Ile132Val A/G of the gene of coding olfactory receptor analogue OR13G1 (OR13G1);
The Glu288Val A/T (M/S) of the gene of coding alpha1-antitrypsin (α 1-AT);
The K469E A/G of the gene of coding intercellular adhesion molecule 1 (ICAM1);
The gene of the coding related transcript 1 of HLA-B (BAT1)-23C/G;
The Glu298Asp G/T of the gene of coding nitricoxide synthase 3 (NOS3);
The gene of coding Type 1 plasminogen activator inhibitor 1 (PAI-1)-6684G/5G;
The gene of coding matrix metalloproteinase 7 (MMP7)-181A/G; Or
Be in one or more polymorphisms of linkage disequilibrium with one or more described polymorphisms.
5. method as claimed in claim 4, wherein one or more existence that are selected from following group polymorphism are that the indication that the risk of ACS reduces takes place:
Ser52Ser (223 C/T) the CC genotype of the gene of coding FGF2;
The Q576R A/G AA genotype of the gene of coding IL4RA;
The Thr26Asn A/C CC genotype of the gene of coding LTA;
The Hom T2437C CC or the CT genotype of the gene of coding HSP70;
The Asp299Gly A/G AG or the GG genotype of the gene of coding TLR4;
The Thr399Ile C/T CT or the TT genotype of the gene of coding TLR4;
The 874A/T TT genotype of the gene of coding IFNG;
The gene of coding NFKBIL1-63T/A AA genotype;
The gene of coding PDGFRA-1630Ins/Del (AACTT/Del) Ins/Del or Del/Del genotype;
-589 C/T CT or the TT genotype of the gene of coding IL-4;
-588 C/T CC genotype of the gene of coding GCLM;
-1084 A/G GG genotype of the gene of coding IL-10;
The K469E A/G AA genotype of the gene of coding ICAM1;
-23 C/G GG genotype of the gene of coding BAT1;
The Glu298Asp G/T GG genotype of the gene of coding NOS3;
The Arg213Gly C/G CG or the GG genotype of the gene of coding SOD3;
-668 4G/5G 5G5G genotype of the gene of coding PAI-1;
-181 A/G GG genotype of the gene of coding MMP7;
The Asn 125 Ser AG or the GG genotype of the gene of coding cathepsin G; Or
372 T/C TT genotype of the gene of coding TIMP1.
6. as claim 4 or 5 described methods, wherein one or more existence that are selected from following group polymorphism are that the indication that the risk of ACS raises takes place:
-1903 A/G GG genotype of the gene of coding CMA1;
-509 C/T CC genotype of the gene of coding TGFB1;
-82 A/G GG genotype of the gene of coding MMP12;
Ser52Ser (223 C/T) CT or TT genotype in the coding FGF2 gene;
The Q576R A/G GG genotype of the gene of coding IL4RA;
The Hom T2437C TT genotype of the gene of coding HSP70;
Asp299GlyA/GAA genotype in the coding TLR4 gene;
The Thr399Ile C/T CC genotype of the gene of coding TLR4;
The gene of coding PDGFRA-1630Ins/Del (AACTT/Del) Ins Ins (AACTTAACTT) genotype;
-589 C/T CC genotype of the gene of coding IL4;
-1607 1G/2G (Del/G) Del Del (1G 1G) genotype of the gene of coding MMP1;
12 IN5 C/T TT genotype of the gene of coding PDGFA;
-588 C/T CT or the TT genotype of the gene of coding GCLM;
The Ile132Val A/G AA genotype of the gene of coding OR13G1;
Glu288Val A/T (M/S) AT of the gene of coding for alpha 1-AT or TT (MS or SS) genotype;
The gene of coding MIP1A+459 C/T Intron 1CT or TT genotype;
The Asn 125 Ser AA genotype of the gene of coding cathepsin G;
The I249V TT genotype of the gene of coding CX3CR1;
The Gly 881 Arg G/C CC or the CG genotype of the gene of coding NOD2; Or
The 372T/C CC genotype of the gene of coding TIMP1.
7. the method for ACS risk takes place in an evaluation object, and described method comprises the following steps:
(i) whether the existence of at least a protectiveness polymorphism that mensuration is relevant with the risk reduction that ACS takes place to be, and
(ii) do not exist under at least a protection polymorphism situation, whether the existence of at least a susceptibility polymorphism that mensuration is relevant with the risk rising that ACS takes place;
Wherein the existence of one or more described protectiveness polymorphisms is that the indication that the risk of ACS reduces takes place, and not having at least a protectiveness polymorphism and having at least a susceptibility polymorphism then is the indication that the risk rising of ACS takes place.
8. method as claimed in claim 7, wherein said at least a protectiveness polymorphism is selected from:
Ser52Ser (223C/T) the CC genotype of the gene of coding FGF2;
The Q576R A/G AA genotype of the gene of coding IL4RA;
The Thr26Asn A/C CC genotype of the gene of coding LTA;
The Hom T2437C CC or the CT genotype of the gene of coding HSP70;
The Asp299Gly A/G AG or the GG genotype of the gene of coding TLR4;
The Thr399Ile C/T CT or the TT genotype of the gene of coding TLR4;
874 A/T TT genotype of the gene of coding IFNG;
The gene of coding NFKBIL1-the 63T/AAA genotype;
The gene of coding PDGFRA-1630Ins/Del (AACTT/Del) Ins/Del or Del/Del genotype;
-589 C/T CT or the TT genotype of the gene of coding IL-4;
-588 C/T CC genotype of the gene of coding GCLM;
-1084 A/G GG genotype of the gene of coding IL-10;
The K469E A/G AA genotype of the gene of coding ICAM1;
-23 C/G GG genotype of the gene of coding BAT1;
The G1u298Asp G/T GG genotype of the gene of coding NOS3;
The Arg213Gly C/G CG or the GG genotype of the gene of coding SOD3;
-668 4G/5G 5G5G genotype of the gene of coding PAI-1;
-181 A/G GG genotype of the gene of coding MMP7;
Asn 125 SerAG or the GG genotype of the gene of coding cathepsin G; Or
372 T/C TT genotype of the gene of coding TIMP1.
9. as claim 7 or 8 described methods, wherein said at least a susceptibility polymorphism is to be selected from following group genotype;
-1903 A/G GG genotype of the gene of coding CMA1;
-509 C/T CC genotype of the gene of coding TGFB1;
-82 A/G GG genotype of the gene of coding MMP12;
Ser52Ser (223 C/T) CT or the TT genotype of the gene of coding FGF2;
The Q576R A/G GG genotype of the gene of coding IL4RA;
The Hom T2437C TT genotype of the gene of coding HSP70;
The Asp299Gly A/G AA genotype of the gene of coding TLR4;
The Thr399Ile C/T CC genotype of the gene of coding TLR4;
The gene of coding PDGFRA-1630Ins/Del (AACTT/Del) Ins Ins (AACTTAACTT) genotype;
-589 C/T CC genotype of the gene of coding IL4;
-1607 1G/2G (Del/G) Del Del (1G 1G) genotype of the gene of coding MMP1;
The 12IN5 C/T TT genotype of the gene of coding PDGFA;
-588 C/T CT or the TT genotype of the gene of coding GCLM;
The Ile132Val A/G AA genotype of the gene of coding OR13G1;
Glu288Val A/T (M/S) AT of the gene of coding for alpha 1-AT or TT (MS or SS) genotype;
The gene of coding MIP1A+459C/T Intron 1CT or TT genotype;
The Asn 125 Ser AA genotype of the gene of coding cathepsin G;
The I249V TT genotype of the gene of coding CX3CR1;
The Gly 881Arg G/C CC or the CG genotype of the gene of coding NOD2; Or
The 372T/C CC genotype of the gene of coding TIMP1.
10. as each described method of claim 7 to 9, wherein no matter whether have one or more susceptibility polymorphisms, the existence of two or more protectiveness polymorphisms is that the indication that the risk of ACS reduces takes place.
11. as each described method of claim 7 to 9, wherein when the protectiveness polymorphism did not exist, the existence of one or more susceptibility polymorphisms was that the indication that the risk of ACS raises takes place.
12. as each described method of claim 7 to 9, wherein the existence of two or more susceptibility polymorphisms is that the indication that the risk of ACS raises takes place.
13. the method for the risk of ACS takes place a determination object, it comprises whether analysis exists two or more to be selected from following group polymorphism from the sample of described object:
The gene of coding chyme enzyme 1 (CMA1)-1903A/G;
The gene of coding matrix metalloproteinase 12 (MMP12)-82A/G;
Be encoded into the Ser52Ser (223C/T) of the gene of fibroblast growth factor 2 (FGF2);
The Q576R A/G of the gene of coding interleukin-4 acceptor α (IL4RA);
The HOM T2437C of the gene of coding heat shock protein 70 (HSP70);
The 874A/T of the gene of the plain γ of coded interference (IFNG);
The gene of coding interleukin-4 (IL-4)-589C/T;
The gene of coding interleukin 10 (IL-10)-1084A/G (1082);
The Arg213Gly C/G of the gene of encoding superoxide dismutase 3 (SOD3);
The 459C/T Intron I of the gene of coding macrophage inflammatory protein 1 α (MIP1A);
The Asn 125 Ser A/G of the gene of coding cathepsin G;
The I249V C/T of the gene of coding chemokine (CX3C motif) acceptor 1 (CX3CR1);
The Gly 881 Arg G/C of the gene of coding Caspase (NOD2); Or
The 372T/C of the gene of coding tissue inhibitor of metalloproteinase 1 (TIMP1);
The gene of coding transforminggrowthfactor-(TGFB1)-509C/T;
The Thr26Asn A/C of the gene of coding lymphotoxin α (LTA);
The Asp299Gly A/G of the gene of coding Toll sample acceptor 4 (TLR4);
The Thr399Ile C/T of the gene of coding TLR4;
The gene of the inhibitor-like 1 (NFKBIL1) of the nf of coding B cell κ light chain polypeptide genetic enhancer-63T/A;
The gene of coding platelet derived growth factor receptor α (PDGFRA)-1630Ins/Del (AACTT/Del);
-1607 1G/2G (Del/G) of the gene of coding matrix metalloproteinase 1 (MMP1);
12 IN 5C/T of the gene of coding Thr6 PDGF BB α (PDGFA);
The gene of coding L-glutamic acid-halfcystine ligase enzyme modification subunit (GCLM)-588C/T;
The Ile132Val A/G of the gene of coding olfactory receptor analogue OR13G1 (OR13G1);
The Glu288Val A/T (M/S) of the gene of coding alpha1-antitrypsin (α 1-AT);
The K469E A/G of the gene of coding intercellular adhesion molecule 1 (ICAM1);
The gene of the coding related transcript 1 of HLA-B (BAT1)-23C/G;
The Glu298Asp G/T of the gene of coding nitricoxide synthase 3 (NOS3);
-668 4G/5G of the gene of coding Type 1 plasminogen activator inhibitor 1 (PAI-1);
The gene of coding matrix metalloproteinase 7 (MMP7)-181A/G;
Or be in one or more polymorphisms of linkage disequilibrium with any or multiple described polymorphism.
14. as each described method of claim 1 to 13, wherein said method comprises analyzes one or more epidemiology risks and assumptions.
15. the method for the risk of ACS takes place determination object, described method comprises the following steps:
(i) acquisition is from results of one or more heredity tests of the sample of described object; And (ii) analyze described result, judge whether to exist one or more to be selected from following group polymorphism:
The gene of coding chyme enzyme 1 (CMA1)-1903A/G;
The gene of coding matrix metalloproteinase 12 (MMP12)-82A/G;
Be encoded into the Ser52Ser (223C/T) of the gene of fibroblast growth factor 2 (FGF2);
The Q576R A/G of the gene of coding interleukin-4 acceptor α (IL4RA);
The HOM T2437C of the gene of coding heat shock protein 70 (HSP70);
The 874A/T of the gene of the plain γ of coded interference (IFNG);
The gene of coding interleukin-4 (IL-4)-589C/T;
The gene of coding interleukin 10 (IL-10)-1084A/G (1082);
The Arg213Gly C/G of the gene of encoding superoxide dismutase 3 (SOD3);
The 459C/T Intron I of the gene of coding macrophage inflammatory protein 1 α (MIP1A);
The Asn 125 Ser A/G of the gene of coding cathepsin G;
The I249V C/T of the gene of coding chemokine (CX3C motif) acceptor 1 (CX3CR1);
The Gly 881 Arg G/C of the gene of coding Caspase (NOD2); Or
The 372T/C of the gene of coding tissue inhibitor of metalloproteinase 1 (TIMP1);
Or be in one or more polymorphisms of linkage disequilibrium with any or multiple described polymorphism;
Show that wherein the result whether one or more described polymorphisms exist is the indication that the risk of ACS takes place object.
16. method as claimed in claim 15 shows that wherein the result whether one or more polymorphisms that are selected from following group exist is the indication that the risk reduction of ACS takes place object:
Ser52Ser (223C/T) the CC genotype of the gene of coding FGF2;
The Q576RA/GAA genotype of the gene of coding IL4RA;
The Hom T2437C CC or the CT genotype of the gene of coding HSP70;
The 874A/T TT genotype of the gene of coding IFNG;
-589 C/T CT or the TT genotype of the gene of coding IL-4;
-1084 A/G GG genotype of the gene of coding IL-10;
The Arg213Gly C/G CG or the GG genotype of the gene of coding SOD3;
The Asn 125 Ser AG or the GG genotype of the gene of coding cathepsin G; Or
372 T/C TT genotype of the gene of coding TIMP1.
17. method as claimed in claim 15 shows that wherein the result whether one or more polymorphisms that are selected from following group exist is the indication that the risk rising of ACS takes place object:
-1903 A/G GG genotype of the gene of coding CMA1;
-82 A/G GG genotype of the gene of coding MMP12;
The gene of coding MIP1A+459 C/T Intron 1CT or TT genotype;
The Asn 125 Ser AA genotype of the gene of coding cathepsin G;
The I249V TT genotype of the gene of coding CX3CR1;
The Gly 881 Arg G/C CC or the CG genotype of the gene of coding NOD2; Or
372 T/C CC genotype of the gene of coding TIMP1.
18. be used for one or more nucleotide probes and/or primer as claim 1 to 17 method as described in each, wherein said one or more nucleotide probes and/or primer are crossed over or be can be used in the polymorphic regions of crossing over described gene, and there is described polymorphism to be analyzed in wherein said gene.
19. one or more nucleotide probes as claimed in claim 18 and/or primer, it comprises among the SEQ.ID.NO.1 to SEQ.ID.NO.124 arbitrary sequence.
20. a nucleic acid microarray, it comprises the base material of presenting nucleotide sequence, and wherein said nucleotide sequence can be hybridized with nucleotide sequence or its complementary sequence that coding is selected from one or more polymorphisms of defined group of claim 1.
21. the purposes of at least a polymorphism in the risk of evaluation object generation ACS, wherein said at least a polymorphism is selected from following group:
The gene of coding chyme enzyme 1 (CMA1)-1903A/G;
The gene of coding matrix metalloproteinase 12 (MMP12)-82A/G;
Be encoded into the Ser52Ser (223C/T) of the gene of fibroblast growth factor 2 (FGF2);
The Q576RA/G of the gene of coding interleukin-4 acceptor α (IL4RA);
HOM T2437C in coding heat shock protein 70 (HSP70) gene;
The 874A/T of the gene of the plain γ of coded interference (IFNG);
The gene of coding interleukin-4 (IL-4)-589C/T;
The gene of coding interleukin 10 (IL-10)-1084A/G (1082);
The Arg213Gly C/G of the gene of encoding superoxide dismutase 3 (SOD3);
The 459C/T Intron I of the gene of coding macrophage inflammatory protein 1 α (MIP1A);
The Asn 125 Ser A/G of the gene of coding cathepsin G;
The I249V C/T of the gene of coding chemokine (CX3C motif) acceptor 1 (CX3CR1);
The Gly 881 Arg G/C of the gene of coding Caspase (NOD2); Or
The 372T/C of the gene of coding tissue inhibitor of metalloproteinase 1 (TIMP1);
Or be in one or more polymorphisms of linkage disequilibrium with any or multiple described polymorphism.
22. purposes as claimed in claim 21, wherein said purposes can be used at least a other polymorphisms that are selected from following group:
The gene of coding transforminggrowthfactor-(TGFB1)-509C/T;
The Thr26Asn A/C of the gene of coding lymphotoxin α (LTA);
The Asp299Gly A/G of the gene of coding Toll sample acceptor 4 (TLR4);
The Thr399Ile C/T of the gene of coding TLR4;
The gene of the inhibitor-like 1 (NFKBIL1) of the nf of coding B cell κ light chain polypeptide genetic enhancer-63T/A;
The gene of coding platelet derived growth factor receptor α (PDGFRA)-1630Ins/Del (AACTT/Del);
-1607 1G/2G (Del/G) of the gene of coding matrix metalloproteinase 1 (MMP1);
The 12IN 5C/T of the gene of coding Thr6 PDGF BB α (PDGFA);
The gene of coding L-glutamic acid-halfcystine ligase enzyme modification subunit (GCLM)-588C/T;
The Ile132Val A/G of the gene of coding olfactory receptor analogue OR13G1 (OR13G1);
The Glu288Val A/T (M/S) of the gene of coding alpha1-antitrypsin (α 1-AT);
The K469E A/G of the gene of coding intercellular adhesion molecule 1 (ICAM1);
The gene of the coding related transcript 1 of HLA-B (BAT1)-23C/G;
The Glu298Asp G/T of the gene of coding nitricoxide synthase 3 (NOS3);
-668 4G/5G of the gene of coding Type 1 plasminogen activator inhibitor 1 (PAI-1);
The gene of coding matrix metalloproteinase 7 (MMP7)-181A/G;
Or be in one or more polymorphisms of linkage disequilibrium with any or multiple described polymorphism.
23. a method for the treatment of the object that risk that ACS takes place raises, it comprises from genotype or phenocopy and is selected from the described object existence and/or functional effect as the protectiveness polymorphism of defined group of claim 8.
24. method for the treatment of the risk rising object that ACS takes place, described object has the detected susceptibility polymorphism that is selected from defined group of claim 9, the expression of described polymorphism or rise or down-regulated gene, make the physiologically active concentration of expressed genes product not in the age and the normal range for the sex of described object, described method comprises that the physiologically active concentration with described gene expression product returns to normal range for described object age and sex with interior step.
25. the method for ACS risk takes place a determination object, it comprises that analyzing two or more is selected from following group genotype:
The gene of coding chyme enzyme 1 (CMA1)-1903A/G;
The gene of coding matrix metalloproteinase 12 (MMP12)-82A/G;
Be encoded into the Ser52Ser (223C/T) of the gene of fibroblast growth factor 2 (FGF2);
The Q576R A/G of the gene of coding interleukin-4 acceptor α (IL4RA);
The HOM T2437C of the gene of coding heat shock protein 70 (HSP70);
The 874A/T of the gene of the plain γ of coded interference (IFNG);
The gene of coding interleukin-4 (IL-4)-589C/T;
The gene of coding interleukin 10 (IL-10)-1084A/G (1082);
The Arg213Gly C/G of the gene of encoding superoxide dismutase 3 (SOD3);
The 459C/T Intron I of the gene of coding macrophage inflammatory protein 1 α (MIP1A);
The Asn 125SerA/G of the gene of coding cathepsin G;
The I249V C/T of the gene of coding chemokine (CX3C motif) acceptor 1 (CX3CR1);
The Gly 881Arg G/C of the gene of coding Caspase (NOD2); Or
The 372T/C of the gene of coding tissue inhibitor of metalloproteinase 1 (TIMP1);
The gene of coding transforminggrowthfactor-(TGFB1)-509C/T;
The Thr26Asn A/C of the gene of coding lymphotoxin α (LTA);
The Asp299Gly A/G of the gene of coding Toll sample acceptor 4 (TLR4);
The Thr399Ile C/T of the gene of coding TLR4;
The gene of the inhibitor-like 1 (NFKBIL1) of the nf of coding B cell κ light chain polypeptide genetic enhancer-63T/A;
The gene of coding platelet derived growth factor receptor α (PDGFRA)-1630Ins/Del (AACTT/Del);
The gene of coding matrix metalloproteinase 1 (MMP1)-16071G/2G (Del/G);
The 12IN 5C/T of the gene of coding Thr6 PDGF BB α (PDGFA);
The gene of coding L-glutamic acid-halfcystine ligase enzyme modification subunit (GCLM)-588C/T;
Ile132Val A/G in coding olfactory receptor analogue OR13G1 (OR13G1) gene;
The Glu288Val A/T (M/S) of the gene of coding alpha1-antitrypsin (α 1-AT);
The K469E A/G of the gene of coding intercellular adhesion molecule 1 (ICAM1);
The gene of the coding related transcript 1 of HLA-B (BAT1)-23C/G;
The Glu298Asp G/T of the gene of coding nitricoxide synthase 3 (NOS3);
-668 4G/5G of the gene of coding Type 1 plasminogen activator inhibitor 1 (PAI-1);
The gene of coding matrix metalloproteinase 7 (MMP7)-181A/G; Or
Be in one or more polymorphisms of linkage disequilibrium with any or multiple described polymorphism.
26. one kind is used for as the antibody microarray in the method as described in claim 1 to 17 each or the claim 25; described microarray comprises presents the base material that can be attached to the antibody on the gene expression product; when wherein this gene and claim 2 or the defined susceptibility of claim 3 or protectiveness polymorphism are associated, its up-regulated or downward modulation.
27. one kind is used to screen, and regulatory gene is expressed and/or the method for active compound; wherein said gene is when being selected from defined susceptibility of claim 2 or claim 3 or protectiveness polymorphism and being associated; its expression is raised or is reduced, and described method comprises the following steps:
Candidate compound is raised with genetic expression or the susceptibility that downward modulation is relevant or the cells contacting of protectiveness polymorphism with containing to be determined; And
Use described candidate compound contact back to measure described expression of gene,
Wherein with before the contact procedure compare, the variation of the gene expression dose after the contact procedure represents that described compound regulates described expression of gene and/or active ability.
28. method as claimed in claim 27, wherein said cell is for confirming to exist people's vascular cell of described polymorphism through prescreen.
29. method as claimed in claim 27, wherein said cell is for confirming to exist people's blood vessel epithelial cell of described polymorphism through prescreen.
30. as each described method of claim 27 to 29, wherein said cell comprises and the relevant susceptibility polymorphism of described genetic expression rise that described screening is used to select to reduce the candidate compound of described genetic expression.
31. as each described method of claim 27 to 29, wherein said cell comprises the susceptibility polymorphism relevant with described down regulation of gene expression, described screening is used to select to raise the candidate compound of described genetic expression.
32. as each described method of claim 27 to 29, wherein said cell comprises and the relevant protectiveness polymorphism of described genetic expression rise that described screening is used to select further to raise the candidate compound of described genetic expression.
33. as each described method of claim 27 to 29, wherein said cell comprises the protectiveness polymorphism relevant with described down regulation of gene expression, described screening is used to select further reduce the candidate compound of described genetic expression.
34. one kind is used to screen, and regulatory gene is expressed and/or the method for active compound; wherein said gene is when being selected from defined susceptibility of claim 2 or claim 3 or protectiveness polymorphism and being associated; its up-regulated or downward modulation, described method comprises the following steps:
With candidate compound with contain the cells contacting of gene, its expression was upward or downward when described gene was associated with susceptibility or protectiveness polymorphism, did not cut but neither raise also in expression of gene described in the described cell; And
Use described candidate compound contact back to measure described expression of gene,
Wherein with before the contact procedure compare, the variation of the gene expression dose after the contact procedure represents that described compound regulates described expression of gene and/or active ability.
35. method as claimed in claim 34, wherein said cell is for confirming to exist people's vascular cell of described gene and described gene baseline expression level through prescreen.
36. method as claimed in claim 34, wherein said cell is for confirming to exist people's blood vessel epithelial cell of described gene and described gene baseline expression level through prescreen.
37. as each described method of claim 34 to 36, its down-regulated expression when wherein said gene is related with the susceptibility polymorphism, and described screening is used for being chosen in the candidate compound that described cell raises described genetic expression.
38. as each described method of claim 34 to 36, its up-regulated when wherein said gene is related with the susceptibility polymorphism, and described screening is used for being chosen in the candidate compound of the described genetic expression of described cell downward modulation.
39. as each described method of claim 34 to 36, its up-regulated when wherein said gene is related with the protectiveness polymorphism, and described screening is used for being chosen in the candidate compound that described cell raises described genetic expression.
40. as each described method of claim 34 to 36, its down-regulated expression when wherein said gene is related with the protectiveness polymorphism, and described screening is used for being chosen in the candidate compound of the described genetic expression of described cell downward modulation.
41. possible reactive method that object that ASC or diagnosis suffer from ASC is handled prevention or treatment is tended in an assessment, described processing comprises that the physiologically active concentration with gene expression product returned in the age and the normal range for the sex of described object, described method comprises whether detect the susceptibility polymorphism that is selected from defined group of claim 3 in the described object exists, when described susceptibility polymorphism exists or rise or reduce described expression of gene, make the physiologically active concentration of described expressing gene product exceed beyond the described normal range, the existence that wherein detects described polymorphism represents that described object may respond described processing.
42. one kind is used for the test kit that the risk of ACS takes place evaluation object, described test kit comprises whether analysis exists one or more to be selected from the device of following group polymorphism from the sample of described object:
The gene of coding chyme enzyme 1 (CMA1)-1903A/G;
The gene of coding matrix metalloproteinase 12 (MMP12)-82A/G;
Be encoded into the Ser52Ser (223C/T) of the gene of fibroblast growth factor 2 (FGF2);
Q576R A/G in coding interleukin-4 acceptor α (IL4RA) gene;
The HOM T2437C of the gene of coding heat shock protein 70 (HSP70);
The 874A/T of the gene of the plain γ of coded interference (IFNG);
The gene of coding interleukin-4 (IL-4)-589C/T;
-1084 A/G (1082) of the gene of coding interleukin 10 (IL-10);
The Arg213Gly C/G of the gene of encoding superoxide dismutase 3 (SOD3);
The 459C/T Intron I of the gene of coding macrophage inflammatory protein 1 α (MIP1A);
The Asn 125 Ser A/G of the gene of coding cathepsin G;
The I249V C/T of the gene of coding chemokine (CX3C motif) acceptor 1 (CX3CR1);
The Gly 881 Arg G/C of the gene of coding Caspase (NOD2); Or
The 372T/C of the gene of coding tissue inhibitor of metalloproteinase 1 (TIMP1);
Or be in one or more polymorphisms of linkage disequilibrium with any or multiple described polymorphism.
43. method for the treatment of the object of the risk rising that ACS takes place, determined the GG genotype of existence-82A/G polymorphism in the gene promoter of coding MMP12 for described object, described method comprises using to described object can regulate the active medicament of MMP12 in the described subject.
44. method as claimed in claim 43, wherein said medicament are can improve one or more tissue inhibitor of metalloproteinase (TIMP) to express or active medicament.
45. method as claimed in claim 44, wherein said tissue inhibitor of metalloproteinase is selected from TIMP1, TIMP2, TIMP3 or TIMP4.
46. method as claimed in claim 43, wherein said medicament are can reduce one or more films to express or active medicament in conjunction with MMP.
47. method as claimed in claim 46, wherein said medicament are the MMP inhibitor.
48. method as claimed in claim 47, wherein said MMP inhibitor is selected from 4,5-dihydroxyanthraquinone-2-carboxylic acid (AQCA), anthraquinonyl-mercaptoethylamine, anthraquinonyl-L-Ala hydroxamic acid or their derivative.
49. method for the treatment of the object of the risk rising that ACS takes place, determined in the gene promoter of coding TIMP1, to exist the CC genotype at 372T/C polymorphism place, described method to comprise to use for described object and can regulate the active medicament of TIMP1 in the described subject to described object.
50. being a kind of TIMP1 that can increase, method as claimed in claim 49, wherein said medicament express or active medicament.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ54352005 | 2005-11-10 | ||
NZ543520 | 2005-11-10 | ||
NZ543985 | 2005-12-06 | ||
NZ549951 | 2006-09-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101356287A true CN101356287A (en) | 2009-01-28 |
Family
ID=40308455
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2006800507772A Pending CN101356287A (en) | 2005-11-10 | 2006-11-10 | Methods and compositions for the assessment of cardiovascular function and disorders |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN101356287A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103276078A (en) * | 2013-05-28 | 2013-09-04 | 中国人民解放军第三军医大学第三附属医院 | Cytokine gene SNP genetic marker detection kit and using method thereof |
CN108359718A (en) * | 2018-02-09 | 2018-08-03 | 苏州百源基因技术有限公司 | A method of detection TLR4 gene SNP site rs2149356 genotype |
CN108929906A (en) * | 2018-08-24 | 2018-12-04 | 山东德诺生物科技有限公司 | For detecting the primed probe group and its application of rs1799889 |
-
2006
- 2006-11-10 CN CNA2006800507772A patent/CN101356287A/en active Pending
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103276078A (en) * | 2013-05-28 | 2013-09-04 | 中国人民解放军第三军医大学第三附属医院 | Cytokine gene SNP genetic marker detection kit and using method thereof |
CN108359718A (en) * | 2018-02-09 | 2018-08-03 | 苏州百源基因技术有限公司 | A method of detection TLR4 gene SNP site rs2149356 genotype |
CN108929906A (en) * | 2018-08-24 | 2018-12-04 | 山东德诺生物科技有限公司 | For detecting the primed probe group and its application of rs1799889 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7933722B2 (en) | Methods of analysis of polymorphisms and uses thereof | |
US8076065B2 (en) | Methods and compositions for assessment of pulmonary function and disorders | |
JP2010506588A (en) | Methods and compositions for assessment of lung function and disorders | |
KR20080084806A (en) | Methods and compositions for the assessment of cardiovascular function and disorders | |
CA2608142A1 (en) | Methods and compositions for assessment of pulmonary function and disorders | |
US20100009368A1 (en) | Methods and compositions for the assessment of cardiovascular function and disorders | |
US20160076104A1 (en) | Methods and compositions for assessment of pulmonary function and disorders | |
US20220162710A1 (en) | Composition for diagnosis or prognosis prediction of glioma, and method for providing information related thereto | |
CN101356287A (en) | Methods and compositions for the assessment of cardiovascular function and disorders | |
CN116574801A (en) | PAI-1 gene promoter 4G/5G polymorphism detection kit, composition and application thereof | |
JP2008545389A (en) | Methods and compositions for assessment of lung function and lung injury | |
US20130281319A1 (en) | Methods and compositions for assessment of pulmonary function and disorders | |
CN101218357A (en) | Method for examining pulmonary function and abnormality and composition therefor | |
EP1960543B1 (en) | Method for the diagnosis and treatment of cardiovascular diseases | |
EP1554399A1 (en) | Detecting the risk of cardiovascular diseases by detecting mutations in genes, including genes encoding a2b-adrenoceptor and apolipoprotein b | |
CN101180409A (en) | Methods and compositions for assessment of pulmonary function and disorders | |
JP6788879B2 (en) | Peripheral artery disease test method and test reagent | |
JP4825956B2 (en) | Determination of the risk of airway mucosal inflammatory disease | |
JP5791171B2 (en) | Method for examining arrhythmia based on single nucleotide polymorphism of first long arm 24 region, NEURL gene, or CUX2 gene | |
MX2007013926A (en) | Methods and compositions for assessment of pulmonary function and disorders. | |
WO2006111749A2 (en) | Pulmonary disease marker |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20090128 |