WO2020060170A1 - Composition de marqueur pour le diagnostic de dermatite atopique et procédé, utilisant celle-ci, pour la prédiction ou le diagnostic de dermatite atopique - Google Patents

Composition de marqueur pour le diagnostic de dermatite atopique et procédé, utilisant celle-ci, pour la prédiction ou le diagnostic de dermatite atopique Download PDF

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WO2020060170A1
WO2020060170A1 PCT/KR2019/012031 KR2019012031W WO2020060170A1 WO 2020060170 A1 WO2020060170 A1 WO 2020060170A1 KR 2019012031 W KR2019012031 W KR 2019012031W WO 2020060170 A1 WO2020060170 A1 WO 2020060170A1
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base
atopic dermatitis
gene
ptgr2
snp
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Korean (ko)
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홍수종
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울산대학교 산학협력단
재단법인 아산사회복지재단
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention relates to a marker composition for diagnosing atopic dermatitis in the PTGR2 gene and a method for predicting or diagnosing atopic dermatitis using the same, more specifically, by confirming that the PTGR2 polymorphism is associated with atopic dermatitis, its It can be used for diagnostic purposes.
  • Atopic dermatitis is a chronic inflammatory skin disease that chronically inflames the skin by showing hypersensitivity of the skin to triggers that are not harmful to normal people.
  • Atopic dermatitis is known to be caused by hypersensitivity of the immune system to infections caused by bacteria, viruses, fungi, etc., certain substances such as pollen, food, artificial compounds, etc., but the exact cause has not been clearly identified.
  • atopic dermatitis is the most common skin disease worldwide, and it is estimated that 20% of children and 3% of adults are suffering worldwide, and the incidence is gradually increasing.
  • Atopic dermatitis patients are generally classified into two groups: exogenous atopic dermatitis and endogenous atopic dermatitis.
  • Patients with extrinsic atopic dermatitis (EAD) have increased levels of total immunoglobulin E (IgE) and allergen-specific IgE in serum.
  • Patients with total IgE levels in normal serum without allergen-specific IgE are called intrinsic atopic dermatitis (ADD) or atopic dermatitis.
  • IgE immunoglobulin E
  • ADD intrinsic atopic dermatitis
  • Patent Document 1 galectin-10 in blood
  • ECP eosinophil cationic protein
  • IL interleukin
  • New biomarkers such as IL-18, IL-31, thymus and activation-regulated chemokine (TARC / CCL17), and lactate dehydrogenase (LDH) track the severity of atopic dermatitis It has been reported to be possible. However, they do not properly reflect the diversity of pathophysiology, and require a lot of time to effectively diagnose atopic dermatitis, or there is a problem of poor accuracy or reliability.
  • Patent Document 0001 Patent Document 1. Republic of Korea Patent Registration No. 10-1512121
  • the present inventors made great efforts to discover PTGR2 polymorphism useful for the development of a new method for diagnosing atopic dermatitis.
  • a strategy was devised to analyze that the PTGR2 gene's single-base polymorphism or Haeplough type is associated with atopic dermatitis, and the present invention was completed by predicting or diagnosing atopic dermatitis using this.
  • an object of the present invention is to provide a marker composition for diagnosing atopic dermatitis composed of a single nucleotide polymorphism or a heflotype of the PTGR2 gene and a method for predicting or diagnosing atopic dermatitis using the same.
  • Another object of the present invention is to provide a diagnostic composition or a kit comprising the same, which includes an agent capable of detecting or amplifying a monobasic polymorphism or a haploid type of the PTGR2 gene.
  • the present invention provides a marker composition composed of a single nucleotide polymerphism (SNP) and a haplotype capable of predicting or diagnosing atopic dermatitis.
  • SNP single nucleotide polymerphism
  • the present inventors have tried to discover new markers that can predict or diagnose atopic dermatitis from the intestinal microbes, which are related to immune development and immune response and play an important role in the invention of allergic diseases. Using regression analysis between the patient and the normal control group, it was confirmed that the polymorphism of the PTGR2 gene and the Haflow type had a significant association with atopic dermatitis.
  • PTGR2 is a potential risk factor for atopic dermatitis
  • the sequence in the PTGR2 gene was analyzed, and atopic dermatitis phenotype in Korean atopic dermatitis patients and normal controls And PTGR2 were analyzed.
  • genotyping was confirmed through direct analysis of 17 monobasic polymorphisms.
  • the association with PTGR2 polymorphisms was analyzed using logistic and linear regression while adjusting age and gender, and as a result, it was detected that there was a significant association between genetic polymorphisms in the PTGR2 gene.
  • the two SNPs rs1968105 # G or rs9646165 # A
  • ht2 Haflotype 2 #
  • the rs9646165 SNP and the haplotype ht2 had a significant effect on the SCORAD value. That is, through the strong association between the polymorphism of the PTGR2 gene and atopic dermatitis, it can be usefully used to accurately predict or diagnose atopic dermatitis disease by analyzing genetic epidemiology from an individual.
  • the marker composition may be all or part of the polynucleotide comprising the SNP of the PTGR2 gene, more preferably all or part of the polynucleotide consisting of SEQ ID NO: 1, and most preferably of the polynucleotide.
  • the base sequence of the PTGR2 gene of 1, consisting of 20 to 100 contiguous DNA sequences comprising a single nucleotide polymorphism (SNP) of rs9646165 # A, rs1962795 # A, rs1968105 # G, rs17782239 # T or rs8005140 # A It may be a marker composition for diagnosing atopic dermatitis.
  • nucleotide is a deoxyribonucleotide or ribonucleotide present in single-stranded or double-stranded form, and includes analogs of natural nucleotides unless specifically stated otherwise (Scheit, Nucleotide Analogs, John Wiley, New York (1980); Uhlman and Peyman, Chemical Reviews, 90: 543-584 (1990)).
  • the present invention relates to the use as a marker for predicting or diagnosing atopic dermatitis using the polymorphism of the PTGR2 gene, and it was first identified that a specific SNP of the PTGR2 gene is associated with atopic dermatitis.
  • DNA consisting of the nucleic acid sequence of SEQ ID NO: 1, including the 73862202 th G base (rs1968105), or the 73858104 th G base (major base of minor A indicated in the present invention) (rs9646165) 20 ⁇ 100
  • It may be a polynucleotide composed of a sequence of dogs, a marker composition capable of diagnosing atopic dermatitis.
  • the nucleic acid sequence of SEQ ID NO: 1 of the present invention is a sequence from 73849831 to 73885465 for chr14 of hg38_ncbiRefSeqCurated_NM_001146154.1 in the Homo sapiens prostaglandin reductase 2 (PTGR2) sequence, and the position in the nucleic acid sequence of SEQ ID NO: 1 in the present invention This is shown as a reference.
  • the PTGR2 gene is prostaglandin reductase 2 and is an enzyme involved in catalysis of prostaglandins.
  • the base sequence of the PTGR2 gene can be obtained from public databases such as NCBI's GenBank and UCSC's Genome Browser.
  • GenBank Accession No. It may be a gene represented by NM_001146154.1, and preferably may include the polynucleotide of SEQ ID NO: 1.
  • the marker composition may not only provide information for predicting or diagnosing atopic dermatitis in each of the SNPs, but may also serve as a better marker by combining the haplotype of the SNP.
  • Gene polymorphism refers to a case in which two or more alleles exist in one locus, and a gene mutation occurs at a frequency of at least 1% or more in a population.
  • SNP single nucleotide polymorphism
  • polymorphism refers to the arrangement in the sequence of genes that change within a population. Polymorphism consists of different "alleles”. The placement of this polymorphism can be confirmed by its position in the gene and the different amino acids or bases found therein. This amino acid variation is the result of two different alleles, two possible variant bases, C and T. Since the genotype consists of two different distinct alleles, any of several possible variants can be observed in either individual (eg, CC, CT or TT in this example).
  • Single nucleotide polymorphism is a diversity of DNA sequences that occurs when a single base (A, T, C or G) in the genome differs between members of a species or between pairs of chromosomes of an individual (individual). Means For example, if it contains a difference in a single base, such as three DNA fragments of different individuals (eg AAGT [A / A] AG, AAGT [A / G] AG, AAGT [G / G] AG), Called two alleles (C or T), and generally all SNPs have two alleles. Within a population, SNPs can be assigned to the minor allele frequency (MAF; lowest allele frequency in the locus found in a particular population). A single base can be altered (replaced), removed (deleted) or added (inserted) to a polynucleotide sequence. SNP can cause a change in the translation frame.
  • a single base can be altered (replaced), removed (deleted) or added (inserted) to
  • gene refers to a specific allele of a particular gene in a cell or tissue sample.
  • Allele refers to one or more alternative forms of a gene occupying the same chromosomal locus. Alleles are also used to indicate polymorphism, for example, SNPs have two types of alleles.
  • Allele frequency refers to the frequency (percentage or percentage) in which an allele is present in an individual, within a lineage, or within a population of lineages. The allele frequency within a lineage or population can be estimated by averaging the allele frequency of a sample of individuals from the lineage or population.
  • Diagnosis means identifying the presence or characteristics of a pathological condition. Among them, the present invention is particularly useful for diagnosing atopic dermatitis (AD).
  • the present invention includes a method for predicting or determining the relationship between atopic dermatitis progression, onset, and SCORAD association. Accordingly, an index capable of accurately predicting the progression and development of atopic dermatitis is very important, and a factor capable of predicting the response of treatment while supplementing the clinical indicator is necessary. Since SNP of PTGR2 of the present invention functions as such an indicator, diagnosis of atopic dermatitis Can be used as an argument. That is, measuring the polymorphic properties of these genes can be used as an index (diagnostic marker) useful for predicting or diagnosing atopic dermatitis.
  • Diagnostic markers or diagnostic markers are substances that can differentiate cells with atopic dermatitis from normal cells and diagnose them.
  • Polypeptides or nucleic acids that show an increase in cells with atopic dermatitis compared to normal cells eg mRNA, etc.
  • lipids eg mRNA, etc.
  • glycolipids e.g. glycolipids
  • glycoproteins e.g., glycoproteins
  • sugars monosaccharides, disaccharides, polysaccharides, etc.
  • Atopic dermatitis predictive marker means a marker having a polymorphism capable of predicting the risk of developing atopic dermatitis, whether the onset of atopic dermatitis is cured, or the course thereof, and preferably the nucleotide described above.
  • the patient means a patient for determining the risk of developing atopic dermatitis or a patient with atopic dermatitis on the family history.
  • “Risk” refers to a statistically high incidence of disease or condition in an individual with a particular polymorphic allele, compared to the incidence of disease or condition in a member of an individual without a specific polymorphic allele.
  • Subject or “patient” means any single individual in need of treatment, including humans, cattle, dogs, guinea pigs, rabbits, chickens, reptiles, fish, amphibians, insects, and the like.
  • the subject includes any subject who participated in a clinical study trial that did not show any disease clinical manifestations, or a subject who participated in epidemiological studies or a control group.
  • tissue or cell sample means a collection of similar cells obtained from a subject or patient's tissue.
  • Sources of tissue or cell samples may include fresh, frozen and / or preserved organ or tissue samples or solid tissue from biopsies or aspirates; Blood or any blood component; It can be a cell at any time in the subject's pregnancy or development.
  • the tissue sample can also be primary or cultured cells or cell lines.
  • Nucleic acid is meant to include any DNA or RNA, eg, chromosomal, mitochondrial, viral and / or bacterial nucleic acids present in a tissue sample. Includes one or both strands of a double-stranded nucleic acid molecule, and any fragment or portion of an intact nucleic acid molecule.
  • Gene means any nucleic acid sequence or portion thereof that has a functional role in protein coding or transcription or in the regulation of other gene expression.
  • the gene may consist of all nucleic acids encoding functional proteins or only a portion of nucleic acids encoding or expressing proteins.
  • Nucleic acid sequences can include gene abnormalities in exons, introns, initiation or termination regions, promoter sequences, other regulatory sequences, or unique sequences adjacent to genes.
  • the present invention developed a marker for diagnosing atopic dermatitis in relation to the PTGR2 gene, and according to one embodiment, it was confirmed that the marker composition according to the present invention is closely related to atopic dermatitis.
  • the genotype of the marker composition of the present invention is detected or a primer capable of detecting the genotype is used, it is expected to accurately predict or diagnose atopic dermatitis from individuals who have or are expected to have atopic dermatitis.
  • SNPs confirmed to be related to the atopic dermatitis and clinical indicators were first identified by the present inventors.
  • SNP single base polymorphism
  • an agent capable of detecting or amplifying an SNP marker means a composition capable of determining atopic dermatitis by confirming a single nucleotide polymorphism (SNP) region of the gene as described above, preferably Means a primer capable of specifically amplifying the polynucleotide of the SNP marker.
  • the primers used for the amplification of the SNP markers are template-directed DNA under appropriate conditions in a suitable buffer (e.g., four different nucleoside triphosphates and a polymerizing agent such as DNA, RNA polymerase or reverse transcriptase) and appropriate temperature.
  • primer sequence may be a single-stranded oligonucleotide that can serve as a starting point for template-directed DNA synthesis.
  • the appropriate length of the primer may vary depending on the purpose of use, but is usually 15 to 30 nucleotides. Short primer molecules generally require lower temperatures to form a stable hybrid with the template.
  • the primer sequence need not be completely complementary to the SNP marker, but must be sufficiently complementary to hybridize with the SNP marker.
  • primer of the present invention is a base sequence having a short free 3 'hydroxyl group, which can form a complementary template and a base pair and start for template strand copying. A short sequence that functions as a point.
  • Primers can initiate DNA synthesis in the presence of reagents for polymerization (i.e., DNA polymerase or reverse transcriptase) at appropriate buffers and temperatures and four different nucleoside triphosphates. PCR amplification can be used to predict atopic dermatitis through the production of a desired product. PCR conditions, sense and antisense primer lengths can be modified based on those known in the art.
  • Primers of the present invention can be chemically synthesized using a phosphoramidite solid support method, or other well-known method.
  • Such nucleic acid sequences can also be modified using many means known in the art. Non-limiting examples of such modifications include methylation, "capping", substitution with one or more homologs of natural nucleotides, and modifications between nucleotides, such as uncharged linkages (eg methyl phosphonate, phosphotriester, Phosphoroamidate, carbamate, etc.) or a modified linker (eg, phosphorothioate, phosphorodithioate, etc.).
  • uncharged linkages eg methyl phosphonate, phosphotriester, Phosphoroamidate, carbamate, etc.
  • a modified linker eg, phosphorothioate, phosphorodithioate, etc.
  • nucleotide sequence of the PTGR2 gene of SEQ ID NO: 1 single base polymorphism (SNP) of rs9646165 # A, rs1962795 # A, rs1968105 # G, rs17782239 # T or rs8005140 # A is detected or It relates to a kit for predicting or diagnosing atopic dermatitis comprising an amplifiable agent.
  • SNP single base polymorphism
  • the kit of the present invention is to make it possible to predict or diagnose atopic dermatitis by confirming the SNP of the PTGR2 gene capable of diagnosing atopic dermatitis through amplification or by confirming the expression level of the SNP marker.
  • the target to use the kit is more preferably targeted to Koreans, Japanese or Chinese, but is not limited thereto.
  • the diagnostic kit includes a primer capable of amplifying the SNP (rs1968105 # G or rs9646165 # A) of the PTGR2 gene of the present invention, as well as reagents required for a polymerization reaction, such as dNTP, various polymerases, and colorants You can.
  • the "amplifiable primer” is a template-directed DNA synthesis under appropriate conditions (e.g., four different nucleoside triphosphates and a polymerizing agent such as DNA, RNA polymerase or reverse transcriptase) in a suitable buffer and a suitable temperature. It refers to a single-stranded oligonucleotide that can act as a starting point.
  • the appropriate length of the primer may vary depending on the purpose of use, but is usually 15 to 30 nucleotides. Short primer molecules generally require lower temperatures to form a stable hybrid with the template.
  • the primer sequence need not be completely complementary to the template, but must be sufficiently complementary to hybridize with the template.
  • a kit for measuring the mRNA expression level of a composition for predicting or diagnosing atopic dermatitis may be a kit including essential elements necessary for performing RT-PCR.
  • RT-PCR kits in addition to each primer pair specific for the gene of the SNP marker, RT-PCR kits include test tubes or other suitable containers, reaction buffers (pH and magnesium concentrations vary), deoxynucleotides (dNTPs), Enzymes such as taq-polymerase and reverse transcriptase, DNase, RNAse inhibitor, DEPC-water (DEPCwater), sterile water, and the like.
  • it may include a primer pair specific to the gene used as a quantitative control.
  • the kit of the present invention may be a kit for predicting or diagnosing atopic dermatitis, which includes essential elements necessary to perform a DNA chip.
  • the DNA chip kit is a flat solid support plate, typically a nucleic acid species attached to a glass surface that is not larger than a microscope slide, in a gridded array, in which nucleic acids are regularly arranged on the chip surface, and the DNA chip is It is a tool that enables multi-parallel analysis by generating multiple hybridization reactions between the nucleic acid on the phase and the complementary nucleic acid contained in the solution treated on the chip surface.
  • a genotyping method of the gene PTGR2 for atopic dermatitis comprising the step of amplifying the single base polymorphism (SNP) of A.
  • a sample isolated in vitro from a subject was obtained, and in the sample, in the base sequence of the PTGR2 gene of SEQ ID NO: 1, single bases of rs9646165 # A, rs1962795 # A, rs1968105 # G, rs17782239 # T or rs8005140 # A
  • SNP polymorphism
  • the sample separated from the subject from the body outside the body is not particularly limited, and may be, for example, hair, urine, saliva, various body fluids, muscles, epidermis, blood, bones, organs, and preferably muscle or blood. have.
  • DNA can be extracted from the isolated sample. Separation of gDNA can be carried out according to conventional methods known in the art (Rogers & Bendich (1994)), and when the starting material is mRNA, it can be synthesized into cDNA using reverse transcriptase.
  • amplify the single nucleotide polymorphism (SNP) region of rs9646165 # A, rs1962795 # A, rs1968105 # G, rs17782239 # T or rs8005140 # A in the base sequence of the PTGR2 gene of SEQ ID NO: 1 or with a probe It can be hybridized, and any method known to those skilled in the art can be used. For example, it can be obtained by amplifying and purifying the target nucleic acid through PCR.
  • LCR ligase chain reactions
  • genotype from the product it may be characterized in that to provide a method for genotyping the gene PTGR2 for atopic dermatitis.
  • Any method known to those skilled in the art can be used to analyze the genotype from the product, for example, sequencing, hybridization by microarray, allele specific PCR, dynamic allele-specific Dynamic allele-specific hybridization (DASH), PCR extension analysis, PCRSSCP (Polymerase Chain Reaction-Single Strand Conformation Polymorphism, polymerase chain reaction-single-strand polymorphism), PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) , Polymerase chain reaction-restriction fragment length polymorphism analysis or TaqMan technique, SNPlex platform (Applied Biosystems), mass spectrometry (e.g.
  • Sequenom's MassARRAY system mini-sequencing method, Bio-Plex System (BioRad), CEQ and SNPstream system (Beckman), Molecular Inversion Probe array technology (e.g. Affymetrix GeneChip), Fludigm system And Bead Array Technologies one (e. G., Illumina GoldenGate and Infinium assays), and the like.
  • One or more alleles in a polymorphic marker can be identified, including microsatellite, SNP, or other types of polymorphic markers, by the above methods or other methods available to those skilled in the art to which this invention pertains. . Determining the base of such a polymorphic site can preferably be performed through an SNP chip.
  • allele-specific PCR refers to a PCR method for amplifying a DNA fragment in which the SNP is located with a primer set including a primer designed with the base in which the SNP is located at the 3 'end.
  • the principle of the method is, for example, when a specific base is substituted with C or A, a PCR reaction is designed by designing a primer containing the unsubstituted original sequence and a reverse primer capable of amplifying a DNA fragment of a suitable size.
  • the amplification reaction When performing, when the base of the SNP position is not substituted, the amplification reaction is normally performed to observe the band of the desired position, and when the base is substituted with C or A, the primer can complementarily bind to the template DNA. However, the amplification reaction is not properly performed because the 3 'end does not have a complementary bond. DASH can be performed by a conventional method, preferably by a method such as Prince.
  • PCR extension analysis first amplifies a DNA fragment containing a base in which a single-base polymorphism is located with a primer pair, and then deactivates all nucleotides added to the reaction by dephosphorylation, and therein, an SNP specific extension primer, This is accomplished by adding a dNTP mixture, didioxynucleotide, reaction buffer and DNA polymerase to perform primer extension reaction.
  • the extension primer is a 5 'direction of the base in which the SNP is located, and a 3' end is immediately adjacent to the dNTP mixture, and a nucleic acid having the same base as the didioxynucleotide is excluded, and the didioxynucleotide represents SNP.
  • It is selected from one of the base types. For example, when there is a substitution from A to G, when a mixture of dGTP, dCTP and TTP and ddATP are added to the reaction, the primer at the base where the substitution occurs is extended by DNA polymerase, and after several bases, A The primer extension reaction is terminated by ddATP at the position where the base first appears. If the substitution has not occurred, the extension reaction is terminated at that position, and thus the length of the extended primer can be compared to determine the type of base representing SNP.
  • the SNP is detected by detecting fluorescence using a gene analyzer (eg, Model 3700 from ABI) used for general sequencing.
  • a gene analyzer eg, Model 3700 from ABI
  • the molecular weight of the SNP is measured by measuring a molecular weight using a matrix assisted laser desorption ionization-time of flight (MALDI-TOF) technique.
  • MALDI-TOF matrix assisted laser desorption ionization-time of flight
  • the genotype of the PTGR2 gene of SEQ ID NO: 1 includes any one or more of rs9646165 # A, rs1962795 # A, rs1968105 # G, rs17782239 # T, and rs8005140 # A, or both. Can be predicted or diagnosed as having atopic dermatitis.
  • the 73849885 th base is C
  • the 73850297 th base is C
  • the 73851433 th base is T
  • the 73851970 th base is G
  • the 73854619 th base Is G
  • the 73858104 th base is G
  • the 73858548 th base is G
  • the 73862199 th base is G
  • the 73862202 th base is G
  • the 73871846 th base is T
  • the 73874094 th base is A
  • the 73874421 th base is G
  • 73875453 th base is C
  • 73880710 th base is A
  • 73880736 th base is C
  • 73882116 th base is A
  • 73882524 th base is G to 20 to 100 for amplifying SNPs It relates to a marker composition for diagnosing atopic derma
  • the PTGR2 gene is prostaglandin reductase 2 and is an enzyme involved in catalysis of prostaglandins.
  • the base sequence of the PTGR2 gene can be obtained from public databases such as NCBI's GenBank and UCSC's Genome Browser.
  • GenBank Accession No. It may be a gene represented by NM_001146154.1, and preferably may include the polynucleotide of SEQ ID NO: 1.
  • the Haflow type is a combination of SNPs in PTGR2, and can provide information for predicting or diagnosing atopic dermatitis with higher accuracy, because it constitutes linkage disequilibrium between SNPs.
  • the linkage disequilibrium refers to a non-random association of alleles at two or more loci that are not necessarily on the same chromosome in population genetics.
  • ht2 has a significant correlation with the development of atopic dermatitis (Table 3). Moreover, it was confirmed in the analysis of the relationship between atopic dermatitis and SCORAD. According to the number of subjects, the statistical significance was preserved between 0.02 and 0.06. Through the above results, it will be suggested that Haplotype 2 (ht2), a SNP combination of PTGR2 gene, is strongly associated with atopic dermatitis.
  • the present inventors genotyping PTGR2 gene polymorphism, and confirmed the type of these genes related to atopic dermatitis in atopic dermatitis patients. As a result, it was confirmed that the ht2 haflow type of the present invention became more prominent, which would be very useful in presenting a new method for diagnosing atopic dermatitis.
  • the genotype of the marker composition of the present invention is detected or a primer capable of detecting the genotype is used, it is expected to accurately predict or diagnose atopic dermatitis from individuals who have or are expected to have atopic dermatitis.
  • the SNP was first identified by the present inventors.
  • the 73849885 th base is C
  • the 73850297 th base is C
  • the 73851433 th base is T
  • the 73851970 th base is G
  • the 73854619 th base is G
  • 73858104 th base is G
  • 73858548 th base is G
  • 73862199 th base is G
  • 73862202 th base is G
  • 73871846 th base is T
  • 73874094 th base is A
  • 73874421 th base is G
  • 73875453 th base is C
  • 73880710 th base is A
  • 73880736 th base is C
  • 73882116 th base is A
  • 73882524 th base is G. It relates to a composition for predicting or diagnosing atopic dermatitis comprising an agent capable of detecting or amplifying
  • the SNP region of Korean genotype based on the Haploid type 2 substituted with minor allele in the present invention is 73858104 It is preferred that the first base is G (rs9646165), the 73874094 th base is A (rs11159042), the 73874421 th base is G (rs45559033), and the 73882116 th base is A (rs6574151).
  • the minor may be considered to be the same as the reference base of SEQ ID NO: 1, but in the three cases, there is no Asian frequency in the NCBI DB or because the minor allele is different due to racial differences.
  • the composition for predicting or diagnosing atopic dermatitis comprising an agent capable of detecting or amplifying 20 to 100 consecutive DNA sequences for amplifying SNPs constituting the above-described haploid type.
  • an agent capable of detecting or amplifying an SNP marker means a composition capable of determining atopic dermatitis by confirming a single nucleotide polymorphism (SNP) region of the gene as described above, preferably Means a primer capable of specifically amplifying the polynucleotide of the SNP marker.
  • the primers used for the amplification of the SNP markers are template-directed DNA under appropriate conditions in a suitable buffer (e.g., four different nucleoside triphosphates and a polymerizing agent such as DNA, RNA polymerase or reverse transcriptase) and appropriate temperature. It may be a single-stranded oligonucleotide that can act as a starting point for synthesis.
  • the appropriate length of the primer may vary depending on the purpose of use, but is usually 15 to 30 nucleotides. Short primer molecules generally require lower temperatures to form a stable hybrid with the template.
  • the primer sequence need not be completely complementary to the SNP marker, but must be sufficiently complementary to hybridize with the SNP marker.
  • primer of the present invention is a base sequence having a short free 3 'hydroxyl group, which can form a complementary template and a base pair and start for template strand copying. A short sequence that functions as a point.
  • Primers can initiate DNA synthesis in the presence of reagents for polymerization (i.e., DNA polymerase or reverse transcriptase) at appropriate buffers and temperatures and four different nucleoside triphosphates. PCR amplification can be used to predict atopic dermatitis through the production of a desired product. PCR conditions, sense and antisense primer lengths can be modified based on those known in the art.
  • the primers of the present invention can be chemically synthesized using a phosphoramidite solid support method, or other well-known method.
  • Such nucleic acid sequences can also be modified using many means known in the art. Non-limiting examples of such modifications include methylation, "capping", substitution with one or more homologs of natural nucleotides, and modifications between nucleotides, such as uncharged linkages (eg methyl phosphonate, phosphotriester, Phosphoroamidate, carbamate, etc.) or a modified linker (eg, phosphorothioate, phosphorodithioate, etc.).
  • uncharged linkages eg methyl phosphonate, phosphotriester, Phosphoroamidate, carbamate, etc.
  • a modified linker eg, phosphorothioate, phosphorodithioate, etc.
  • the 73849885 th base is C
  • the 73850297 th base is C
  • the 73851433 th base is T
  • the 73851970 th base is G
  • 73854619 The first base is G
  • the 73858104 th base is G
  • the 73858548 th base is G
  • the 73862199 th base is G
  • the 73862202 th base is G
  • the 73871846 th base is T
  • the 73874094 th base is A
  • the 73874421 th 20 for SNP amplification constituting the Haflow type with base G, 73875453 th base C, 73880710 th base A, 73880736 th base C, 73882116 th base A, and 73882524 th base G It relates to a kit for predicting or diagnosing atopic dermatiti
  • the kit of the present invention is to make it possible to predict or diagnose atopic dermatitis by confirming the SNP of the PTGR2 gene capable of diagnosing atopic dermatitis through amplification or by confirming the expression level of the SNP marker.
  • the target to use the kit is preferably targeted to East Asians, more preferably targeted to Koreans, Japanese or Chinese, but is not limited thereto.
  • the diagnostic kit includes a primer capable of amplifying the SNP (rs9646165 # A, rs1962795 # A, rs1968105 # G, rs17782239 # T or rs8005140 # A) of the PTGR2 gene of the present invention, as well as reagents required for polymerization reaction, for example dNTP, and various polymerases and colorants.
  • a primer capable of amplifying the SNP (rs9646165 # A, rs1962795 # A, rs1968105 # G, rs17782239 # T or rs8005140 # A) of the PTGR2 gene of the present invention, as well as reagents required for polymerization reaction, for example dNTP, and various polymerases and colorants.
  • the "amplifiable primer” is a template-directed DNA synthesis under appropriate conditions (e.g., four different nucleoside triphosphates and a polymerizing agent such as DNA, RNA polymerase or reverse transcriptase) in a suitable buffer and a suitable temperature. It refers to a single-stranded oligonucleotide that can act as a starting point.
  • the appropriate length of the primer may vary depending on the purpose of use, but is usually 15 to 30 nucleotides. Short primer molecules generally require lower temperatures to form a stable hybrid with the template.
  • the primer sequence need not be completely complementary to the template, but must be sufficiently complementary to hybridize with the template.
  • a kit for measuring the mRNA expression level of a composition for predicting or diagnosing atopic dermatitis may be a kit including essential elements necessary for performing RT-PCR.
  • RT-PCR kits in addition to each primer pair specific for the gene of the SNP marker, RT-PCR kits include test tubes or other suitable containers, reaction buffers (pH and magnesium concentrations vary), deoxynucleotides (dNTPs), Enzymes such as taq-polymerase and reverse transcriptase, DNase, RNAse inhibitor, DEPC-water (DEPCwater), sterile water, and the like.
  • it may include a primer pair specific to the gene used as a quantitative control.
  • the kit of the present invention may be a kit for predicting or diagnosing atopic dermatitis, which includes essential elements necessary to perform a DNA chip.
  • the DNA chip kit is a flat solid support plate, typically a nucleic acid species attached to a glass surface not larger than a microscope slide in a gridded array, in which nucleic acids are regularly arranged on the chip surface to form a DNA chip. It is a tool that enables multi-parallel analysis by generating multiple hybridization reactions between the nucleic acid on the phase and the complementary nucleic acid contained in the solution treated on the chip surface.
  • the 73849885 th base is C
  • the 73850297 th base is C
  • the 73851433 th base is T
  • 73851970 th base is G
  • 73854619 th base is G
  • 73858104 th base is G
  • 73858548 th base is G
  • 73862199 th base is G
  • 73862202 th base is G
  • 73871846 th base is T
  • 73874094 th base is A
  • 73874421 th base is G
  • 73875453 th base is C
  • 73880710 th base is A
  • 73880736 th base is C
  • 73882116 th base is A
  • 73882524 th base is G Amplifying the half-flow type; relates to a genotyping method of the gene PT
  • a sample isolated in vitro from a subject is obtained, and in the sample, in the base sequence of the PTGR2 gene of SEQ ID NO: 1, the 73849885 th base is C, the 73850297 th base is C, the 73851433 th base is T, and 73851970
  • the first base is G
  • the 73854619 th base is G
  • the 73858104 th base is G
  • the 73858548 th base is G
  • the 73862199 th base is G
  • the 73862202 th base is G
  • the 73871846 th base is T
  • the base is A, the 73874421 th base is G, the 73875453 th base is C, the 73880710 th base is A, the 73880736 th base is C, the 73882116 th base is A, and the 73882524 th base is G
  • the sample separated from the subject from the body outside the body is not particularly limited, and may be, for example, hair, urine, saliva, various body fluids, muscles, epidermis, blood, bones, organs, and preferably muscle or blood. have.
  • DNA can be extracted from the isolated sample. Separation of gDNA can be carried out according to conventional methods known in the art (Rogers & Bendich (1994)), and when the starting material is mRNA, it can be synthesized into cDNA using reverse transcriptase.
  • the 73849885 th base is C
  • the 73850297 th base is C
  • the 73851433 th base is T
  • the 73851970 th base is G
  • the 73854619 th base Is G
  • the 73858104 th base is G
  • the 73858548 th base is G
  • the 73862199 th base is G
  • the 73862202 th base is G
  • the 73871846 th base is T
  • the 73874094 th base is A
  • the 73874421 th base is G
  • 73875453 th base is C
  • 73880710 th base is A
  • 73880736 th base is C
  • 73882116 th base is A
  • 73882524 th base is G.
  • NASBA nucleic acid based sequence amplification
  • genotype from the product it may be characterized in that to provide a method for genotyping the gene PTGR2 for atopic dermatitis.
  • Any method known to those skilled in the art can be used to analyze the genotype from the product, for example, sequence analysis, hybridization by microarray, allele specific PCR, dynamic allele hybridization technique ( dynamic allelespecifichybridization (DASH), PCR extension analysis, PCR-SSCP, PCRRFLP analysis or TaqMan technique, SNPlex platform (Applied Biosystems), mass spectrometry (e.g.
  • Sequenom's MassARRAY system mini-sequencing method, Bio-Plex system (BioRad), CEQ and SNPstream system (Beckman), Molecular Inversion Probe array technology (e.g. Affymetrix GeneChip), Fludigm system and BeadArray Technologies (e.g. Illumina GoldenGate and Infinium analysis), It is not limited to this.
  • One or more alleles in a polymorphic marker including microsatellites, SNPs or other types of polymorphic markers, can be identified by these methods or other methods available to those skilled in the art to which this invention pertains. Determining the base of such a polymorphic site can preferably be performed through an SNP chip.
  • allele-specific PCR refers to a PCR method for amplifying a DNA fragment in which the SNP is located with a primer set including a primer designed with the base in which the SNP is located at the 3 'end.
  • the principle of the method is, for example, when a specific base is substituted with C or A, a PCR reaction is designed by designing a primer containing the unsubstituted original sequence and a reverse primer capable of amplifying a DNA fragment of a suitable size.
  • the amplification reaction When performing, when the base of the SNP is not substituted, the amplification reaction is normally performed to observe the band of the desired location, and when the base is substituted with C or A, the primer may complementarily bind to the template DNA, However, the 3 'end side does not perform complementary binding, so the amplification reaction is not properly performed.
  • DASH can be performed by a conventional method, preferably by a method such as Prince.
  • PCR extension analysis first amplifies a DNA fragment containing a base in which a single-base polymorphism is located with a primer pair, and then deactivates all nucleotides added to the reaction by dephosphorylation, and therein, an SNP specific extension primer, This is accomplished by adding a dNTP mixture, didioxynucleotide, reaction buffer and DNA polymerase to perform primer extension reaction.
  • the extension primer is a 5 'direction of the base in which the SNP is located, and a 3' end is immediately adjacent to the dNTP mixture, and a nucleic acid having the same base as the didioxynucleotide is excluded, and the didioxynucleotide represents SNP.
  • It is selected from one of the base types. For example, when there is a substitution from A to G, when a mixture of dGTP, dCTP and TTP and ddATP are added to the reaction, the primer at the base where the substitution occurs is extended by DNA polymerase, and after several bases, A The primer extension reaction is terminated by ddATP at the position where the base first appears. If the substitution has not occurred, the extension reaction is terminated at that position, and thus the length of the extended primer can be compared to determine the type of base representing SNP.
  • the SNP is detected by detecting fluorescence using a gene analyzer (eg, Model 3700 from ABI) used for general sequencing.
  • a gene analyzer eg, Model 3700 from ABI
  • the SNP can be detected by measuring the molecular weight using a matrix assisted laser desorption ionization-time of flight (MALDI-TOF) technique.
  • MALDI-TOF matrix assisted laser desorption ionization-time of flight
  • the 73849885 th base is C
  • the 73850297 th base is C
  • the 73851433 th base is T
  • the 73851970 th base is G
  • the 73854619 th base Is G
  • the 73858104 th base is G
  • the 73858548 th base is G
  • the 73862199 th base is G
  • the 73862202 th base is G
  • the 73871846 th base is T
  • the 73874094 th base is A
  • the 73874421 th base is If G, the 73875453 th base is C, the 73880710 th base is A, the 73880736 th base is C, the 73882116 th base is A, and the 73882524 th base contains a G-flow type, the subject Can be predicted or diagnosed as having atopic dermatitis
  • rs9646165 # A in the nucleotide sequence of the PTGR2 gene of SEQ ID NO: 1 among DNA sequences extracted from tissue or cell samples isolated from a subject, rs9646165 # A, rs1962795 # A, rs1968105 # G, rs17782239 # T or rs8005140 It relates to a method for diagnosing atopic dermatitis comprising the step of detecting or amplifying a single base polymorphism (SNP) of #A.
  • SNP single base polymorphism
  • the 73849885 th base is C
  • the 73850297 th base is C
  • the 73851433 th The base is T
  • the 73851970 th base is G
  • the 73854619 th base is G
  • the 73858104 th base is G
  • the 73858548 th base is G
  • the 73862199 th base is G
  • the 73862202 th base is G
  • the 73871846 th base Is T
  • 73874094 th base is A
  • 73874421 th base is G
  • 73875453 th base is C
  • 73880710 th base is A
  • 73880736 th base is C
  • 73882116 th base is A
  • 73882524 th base is It relates to a method for diagnosing atopic dermatitis
  • the "diagnosis” or “diagnosis method” of the present invention is a method for predicting or determining whether atopic dermatitis disease occurs, whether the disease is likely to occur, and SCORAD association, wherein the method for diagnosing atopic dermatitis of the present invention amplifies SNP of PTGR2 gene By confirming or confirming the expression level of the SNP marker, it is possible to predict or diagnose atopic dermatitis.
  • the method for diagnosing atopic dermatitis of the present invention includes the above-described gene analysis and single-basic polymorphism analysis method, and the specific method is as described above.
  • the present invention is a marker for diagnosing atopic dermatitis comprising a continuous DNA sequence comprising single base polymorphism (SNP) of rs9646165 # A, rs1962795 # A, rs1968105 # G, rs17782239 # T or rs8005140 # A in the PTGR2 gene.
  • SNP single base polymorphism
  • the present invention also provides a haflow type marker composition through linkage disequilibrium analysis in the PTGR2 gene.
  • the present invention confirmed genetic characteristics through association analysis of genes related to atopic dermatitis caused by various causes, and the marker composition discovered through this shows the ability to accurately distinguish atopic dermatitis, and utilizes this function Therefore, it can be usefully used as a predictive or diagnostic composition for atopic dermatitis.
  • Figure 1 shows the physical map of the PTGR2 gene, Haflow type and Linkage Disequilibrium (LD).
  • Figure 1A shows the physical map of the PTGR2 gene and the location of the SNPs identified in this study, showing the polymorphisms identified in PTGR2 on chromosome 14q24.3 (reference genomic sequence NM_001146154.1).
  • ⁇ is an encoded exon, and ⁇ means 5'-UTR (5'-untranslated region) and 3'-UTR (3'-untranslated region).
  • 1B shows the haploid type of the PTGR2 gene.
  • 1C is an LD plot of the PTRG2 gene, the SNP investigated in this experiment constitutes one LD block, and the block number represents the numerical value of the LD coefficient
  • AD atopic dermatitis
  • food allergies e.g., food allergies, allergic rhinitis, asthma, Alzheimer's, no history of atopic dermatitis, and negative skin rash test results.
  • Total serum IgE levels were measured from peripheral blood for all subjects, and the total serum IgE levels were measured using a fluorescence enzyme immunoassay (ImmunoCAP system; Phadia AB, Uppsala, Sweden).
  • the subject measured sensitivity through skin terminal tests for 16 allergens (Dermatophagoides pteronyssinus, large leg mite (Dermatophagoides farina), dog epithelium, cat epithelium, Cockroach, grass, pollen mixtures of several trees 1 and 2, Alternaria, Aspergillus, ragweed, wormwood, milk, egg white, peanuts and beans ).
  • Table 1 summarizes the clinical characteristics of the subjects. As discussed above, a cohort of 420 atopic dermatitis patients and 444 normal controls was recruited, and the average age of atopic dermatitis patients was lower than that of the normal control group (7.0 ⁇ 3.7 year vs. 11.9 ⁇ 2.1 year, P ⁇ 0.01). Total serum IgE levels were significantly higher in patients with atopic dermatitis than normal controls (660.8 ⁇ 1040.1 IU / ml vs. 119.9 ⁇ 225.1 IU / ml, P ⁇ 0.01).
  • Data are means ⁇ standard deviation.
  • the P value is a figure for the difference between atopic dermatitis patients and normal controls.
  • PTGR2 the gene with the most significant association in GWAS, was selected.
  • MAF minor allele frequency
  • LD linkage disequilibrium
  • 17 PTGR2 gene SNPs were selected from the gene in the range of 2 kb anterior and 1 kb anterior.
  • MAF minor allele frequency
  • LD linkage disequilibrium
  • 17 SNPs were selected from the 1000 Genomes Project (http://browser.1000genomes.org/index.html) with an MAF of 0.05 or more, and considering LD from Asian race data (including China and Japan).
  • DNA was isolated from peripheral blood using WizPrepTM gDNA Mini Kit (Wizbio solutions, Seongnam, Korea).
  • the genotype of the blood sample was analyzed using a high-throughput Fluidigm EP1 system (Fluidigm, South San Francisco, CA) equipped with a Fluidigm SNP TypeTM analysis platform. It was performed according to the manual and the copy number of the target genomic region was increased using a Qiagen 2X Multiplex PCR Master Mix (Qiagen, Hilden, Germany) using a specific target amplification reaction. The amplification reaction was performed in a dynamic array Integrated Fluidic Circuits (IFC), and fluorescence intensity was measured with an EP1 reader.
  • the genotype was analyzed using the Fluidigm SNP Genotyping Analysis program. Determination of the SNP was performed through visual inspection, and SNPs having a call rate of 95% or more among all samples were selected.
  • LD Linkage disequilibrium
  • Haploview v4.2 software obtained from Broad Institute (http://www.broadinstitute.org/mpg/haploview). Lewontin's D '(
  • Figure 1 shows the physical map of the PTGR2 gene, Haflow type and LD.
  • 1A shows the physical map of the PTGR2 gene and the SNP genotype identified in this study.
  • ⁇ is an encrypted exon, and ⁇ means 5'-UTR (5'-untranslated region) and 3'-UTR.
  • 1B shows the haploid type of the PTGR2 gene.
  • 1C is an LD plot of the PTRG2 gene, the SNP investigated in this experiment constitutes one LD block, and the block number represents the numerical value of the LD coefficient
  • a total of 17 SNPs (single nucleotide polymorphism) of PTGR2 (NM_001146154.1) on chromosome 14q24.3 ( ⁇ 35 kb) were identified and selected according to the method described above, and 864 subjects were successfully selected. It was confirmed that the genotype was determined as a target.
  • one LD block was identified through pair-wise comparison of base sequences, and four halftone types (ht1, ht2, ht3, ht4) were identified using PHASE software.
  • Example 3 PTGR2 clinical genotype (clincal phenotypes) and atopic dermatitis association analysis (Association analysis)
  • Table 2 shows the results of the analysis of the relationship between atopic dermatitis and SNP.
  • Table 3 shows the results of the analysis of the relationship between atopic dermatitis and Haflow type.
  • the P value of the linear regression analysis was calculated using a co-dominant-recessive genotype model with age and gender adjustments as covariates.
  • M / M, M / m, and m / m represent the homozygote for the common allele, the homozygote, and the homozygote for the rare allele, respectively. Shows.
  • Bold values indicate statistical significance of P ⁇ 0.05, a.a is amino acid and n is the number of subjects.
  • Table 4 shows the results of a linear regression analysis adjusted for age and sex as a covariate for SCORAD in patients with atopic dermatitis. According to this, it can be used as a significant guideline for evaluating atopic dermatitis in patients with atopic dermatitis.
  • the P value of the linear regression analysis was calculated using a co-dominant-recessive genotype model with age and gender adjustments as covariates.
  • M / M, M / m, and m / m represent the homozygote for the common allele, the homozygote, and the homozygote for the rare allele, respectively. Shows.
  • Bold values indicate statistical significance of P ⁇ 0.05, a.a is amino acid and n is the number of subjects.

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Abstract

La présente invention concerne une composition de marqueur pour le diagnostic de dermatite atopique et pour le SCORAD, la composition comprenant une séquence d'ADN consécutive ayant le polymorphisme mononucléotidique (SNP) de rs9646165#A, rs1962795#A, rs1968105#G, rs17782239#T ou rs8005140#A sur le gène PTGR2. Dans la présente invention, des caractéristiques génétiques de dermatite atopique dans l'apparition de laquelle diverses causes sont impliquées sont identifiées par l'analyse d'une corrélation entre des polymorphismes mononucléotidiques et des haplotypes de gènes associés au SCORAD. La composition de marqueur développée sur la base des caractères génétiques identifiés présente la fonction capable de distinguer la dermatite atopique et le SCORAD. En utilisant la fonction, la composition de marqueur peut être avantageusement utilisée en tant que composition pour la prédiction ou le diagnostic de dermatite atopique et de SCORAD.
PCT/KR2019/012031 2018-09-18 2019-09-18 Composition de marqueur pour le diagnostic de dermatite atopique et procédé, utilisant celle-ci, pour la prédiction ou le diagnostic de dermatite atopique WO2020060170A1 (fr)

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