SNPs for diagnosing drug hypersensitivity reactions and diagnostic methods using the same

Abstract

The present invention relates to SNPs for diagnosing drug hypersensitivity reactions and diagnostic methods using the same. The present inventors analyzed protein coding sites in genomic DNA of patients with drug hypersensitivity reactions and found that specific SNPs including rs35372932 are closely related to the onset of drug hypersensitivity reactions. The SNPs can be used to develop genetic diagnostic reagents for diagnosing or predicting the onset of drug hypersensitivity reactions.

Description

Technical Field

[0001] The present invention relates to SNPs for diagnosing drug hypersensitivity reactions and diagnostic methods using the same.

[0002] This application claims priority based on Korean Patent Application No. 10-2021-0107164 filed on August 13, 2021, and all the contents disclosed in the specification and drawings of the said application are incorporated herein by reference.

Background Art

[0003] Medically, drug allergy is a reaction mediated by an immunological mechanism in patients sensitized to drugs, which has a different meaning from what the general public or patients mean when they say they have drug side effects or drug allergies. Generally, what is commonly referred to as drug side effects or drug allergies often means adverse drug reactions. However, adverse drug reactions include most of the harmful reactions caused by drugs. The WHO defines it as a harmful reaction that appears in the human body unintentionally other than the therapeutic effect when a drug of the usual dose is administered by an appropriate administration route for prevention, diagnosis, and treatment. Adverse drug reactions can be broadly classified into predictable type A reactions that appear in relation to the dose of the drug and unpredictable type B reactions that appear regardless of the dose of the drug. Predictable type A adverse drug reactions account for about 80% of all adverse drug reactions and are mainly caused by the inherent pharmacological effects of the drug, so they are drug poisoning, side effects, indirect effects, drug interactions, etc. in a dose-dependent manner. Unpredictable type B adverse drug reactions account for the remaining about 15 - 20% and include hypersensitivity reactions, idiosyncrasies, intolerances, pseudoallergic reactions, etc. caused by drugs.

[0004] The World Allergy Organization (WAO) recommends classifying drug allergies into immediate (within 1 hour) and delayed (more than 1 hour) types based on the time it takes for symptoms to appear after drug exposure. According to the Gell & Coombs classification, hypersensitivity reactions caused not only by drugs but also by other environmental factors are divided into four types, of which those related to drug allergies are mainly type I, which involves IgE, and type IV, which involves T-cells.

[0005] Type I is an immediate-type humoral immune response mediated by IgE, mast cells, basophils, etc., and includes anaphylaxis, angioedema, bronchospasm, urticaria (hives), etc. Representative drugs that cause this type of reaction include β-antibiotics (penicillins and cephalosporins), quinolone myocardial blockade agents, platinum compounds such as carboplatin and oxaliplatin n, and monoclonal antibodies such as cetuximab and rituximab.

[0006] Types II to IV are delayed-type reactions. Type II refers to humoral cytotoxic reactions mediated by IgM or IgG antibodies and complement, including hemolytic anemia, thrombocytopenia, and neutropenia. Representative drugs include β-lactam antibiotics (penicillins and cephalosporins), NSAIDs (non-steroidal antiinflammatory drugs), quinine / quinidine, vancomycin, carbamazepine, propylthiouracil, and flecainide.

[0007] Thus, drug hypersensitivity reactions are the most serious form of allergic reactions and are considered a medical emergency; therefore, predicting the occurrence of drug hypersensitivity reactions in advance is extremely important.

[0008] Based on this, the inventors conducted GWAS analysis to predict and diagnose drug hypersensitivity reactions in advance, and as a result confirmed SNPs that have a significant association with drug hypersensitivity reactions, thus completing the present invention. [Overview of the project] [Problems that the invention aims to solve]

[0009] Therefore, the object of the present invention is the dbSNP database rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73 The objective is to provide a composition for diagnosing or predicting the onset of drug hypersensitivity reactions, comprising a detection formulation for one or more SNPs selected from the group consisting of 202933, rs72622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999.

[0010] Another object of the present invention is to provide a diagnostic kit for drug hypersensitivity reactions comprising the above composition.

[0011] Another object of the present invention is to input the nucleotide sequence of SNP sites in a sample obtained from a subject into the dbSNP database. rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562 , rs3924164, rs11206477, rs62225078, rs73202933, rs72622187, rs1391411 The objective is to provide a method for providing information necessary for diagnosing drug hypersensitivity reactions, including the step of determining that a subject has developed a drug hypersensitivity reaction if one or more single nucleotide polymorphisms selected from the group consisting of 04, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 are present.

[0012] A further object of the present invention is to provide a method for providing information necessary for predicting the onset of drug hypersensitivity reactions, which includes the step of determining that a subject is at high risk of developing a drug hypersensitivity reaction if one or more single nucleotide polymorphisms selected from the group consisting of dbSNP database rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 are present in the base sequence of an SNP site in a sample obtained from a subject.

[0013] Another object of the present invention is to use the dbSNP database to sequence SNP sites in samples obtained from patients with drug hypersensitivity reactions. rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114, r s143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73202933, rs72622187, rs13914110 The objective is to provide a method for providing information necessary for diagnosing delayed-type drug hypersensitivity reactions, which includes the step of determining that a subject has a delayed-type drug hypersensitivity reaction if one or more single nucleotide polymorphisms selected from the group consisting of rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 are present.

[0014] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other problems not mentioned can be clearly understood by an ordinary person skilled in the art from the following description. [Means for solving the problem]

[0015] To solve the above-mentioned problems, the present invention relates to the dbSNP databases rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078 The present invention provides a composition for diagnosing or predicting the onset of drug hypersensitivity reactions, comprising a detection formulation for one or more SNPs selected from the group consisting of rs73202933, rs72622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999.

[0016] In one embodiment of the present invention, the drug hypersensitivity reaction may be an immediate-type drug hypersensitivity reaction or a delayed-type drug hypersensitivity reaction, but is not limited thereto.

[0017] In another embodiment of the present invention, if the SNP is one or more selected from the group consisting of 1) rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, and rs206887084, the composition is for diagnosing or predicting the onset of drug hypersensitivity reactions in healthy individuals.

[0018] If the SNP is one or more selected from the group consisting of rs9557291, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, and rs3924164, then the composition is for diagnosing or predicting the onset of immediate-type drug hypersensitivity reactions in healthy individuals.

[0019] If the SNP is one or more selected from the group consisting of rs11206477, rs62225078, rs73202933, rs72622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, and rs144130219, then the composition is for diagnosing or predicting the onset of delayed-type drug hypersensitivity reactions in healthy individuals.

[0020] If the SNP is one or more selected from the group consisting of 4)rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999, the composition may, but is not limited to, distinguish between immediate-type and delayed-type drug hypersensitivity reactions.

[0021] In yet another embodiment of the present invention, the SNP may be, but is not limited to, rs35372932 or rs139141104.

[0022] In yet another embodiment of the present invention, the drug hypersensitivity reaction may occur in a Korean person, but is not limited thereto.

[0023] In yet another embodiment of the present invention, the detection formulation may be, but is not limited to, a probe capable of detecting the SNP.

[0024] In still other embodiments of the present invention, the detection agent may be a primer capable of detecting the SNP, but is not limited thereto.

[0025] The present invention also provides a kit for diagnosing drug hypersensitivity reactions, which comprises the above composition.

[0026] In one embodiment of the present invention, the kit may be a RT-PCR kit or a microarray chip kit, but is not limited thereto.

[0027] The present invention also provides a method for providing information necessary for diagnosing drug hypersensitivity reactions, which includes the step of determining that the subject has developed a drug hypersensitivity reaction when one or more single nucleotide polymorphisms selected from the group consisting of dbSNP database rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73202933, rs72622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 exist in the base sequence of the SNP site in the sample obtained from the subject.

[0028] Furthermore, the present invention relates to the dbSNP database, which records the base sequence of SNP sites in a sample obtained from a subject. rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114, r s143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73202933, rs72622187, rs139141104 The present invention provides a method for providing information necessary for predicting the onset of drug hypersensitivity reactions, including a step of determining that a subject is at high risk of developing a drug hypersensitivity reaction if one or more single nucleotide polymorphisms selected from the group consisting of rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 are present.

[0029] Furthermore, the present invention provides a method for providing information necessary for diagnosing delayed-type drug hypersensitivity reactions, which includes the step of determining that a subject has a delayed-type drug hypersensitivity reaction if one or more single nucleotide polymorphisms selected from the group consisting of dbSNP database rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 are present in the base sequence of an SNP site in a sample obtained from a patient with a drug hypersensitivity reaction.

[0030] Furthermore, the present invention relates to the dbSNP database, which records the base sequence of SNP sites in a sample obtained from a subject. rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058 114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73202933, rs72622187, r The present invention provides a diagnostic method for drug hypersensitivity reactions, which includes the step of determining that a subject has developed a drug hypersensitivity reaction if one or more single nucleotide polymorphisms selected from the group consisting of s139141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 are present.

[0031] Furthermore, the present invention relates to the dbSNP database, which records the base sequence of SNP sites in a sample obtained from a subject. rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs805811 4, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73202933, rs72622187, rs139 The present invention provides a method for predicting the onset of drug hypersensitivity reactions, which includes a step of determining that a subject is at high risk of developing a drug hypersensitivity reaction if one or more single nucleotide polymorphisms selected from the group consisting of 141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 are present.

[0032] In one embodiment of the present invention, the method may be performed by one or more methods selected from the group consisting of sequencing, exome sequencing, microarray hybridization, allele-specific PCR, dynamic allele-specific hybridization, PCR extension analysis, and the Taqman method, but is not limited thereto.

[0033] Furthermore, the present invention relates to the dbSNP database rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73202933, The present invention provides a composition comprising a detection formulation for one or more SNPs selected from the group consisting of rs72622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 for use in diagnosing drug hypersensitivity reactions.

[0034] Furthermore, the present invention relates to the dbSNP database rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73202933, r This invention provides a composition containing a detection formulation for one or more SNPs selected from the group consisting of s72622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999, for use in predicting the onset of drug hypersensitivity reactions.

[0035] Furthermore, the present invention relates to the dbSNP database rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs7 The present invention provides applications for one or more SNP detection formulations selected from the group consisting of 3202933, rs72622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999. [Effects of the Invention]

[0036] The inventors analyzed the protein coding sites of genomic DNA in patients with drug hypersensitivity reactions and found that single nucleotide polymorphism (SNP) sites are located in the dbSNP database. rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs80581 14, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73202933, rs72622187, rs1 The genes 39141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 have been identified as being closely associated with the onset of drug hypersensitivity reactions, and can be used to develop genetic diagnostic reagents for the diagnosis or prediction of drug hypersensitivity reactions. [Brief explanation of the drawing]

[0037] [Figure 1a-1b] Figures 1a and 1b are diagrams summarizing the quality control (QC) process flow according to one embodiment of the present invention, where Figure 1a is a quality control process flow diagram for discovery analysis, and Figure 1b is a quality control process flow diagram for replication analysis. [Figure 2] Figure 2 shows a multidimensional scaling (MDS) plot of the discovery data for the 1000G dataset, where blue, yellow, and gray represent the control group, cases (DHR, immediate + delayed), and the 1000G population, respectively. [Figure 3a-3c]Figures 3a and 3c show quantile (QQ) plots of the analysis data. Figure 3a shows the analysis results for the control group versus DHR, Figure 3b shows the analysis results for the control group versus immediate-type reactions, and Figure 3c shows the analysis results for the control group versus delayed-type reactions. [Figure 4] Figure 4 shows the Manhattan plot of the control group versus DHR (immediate + delayed) based on discovery analysis, with the red line indicating the significance level of Bonferroni correction. [Figures 5a-5b] Figures 5a and 5b show region plots; Figure 5a shows the results of logistic regression analysis for the control group versus DHR, and Figure 5b shows a generalized multinomial logit model for the control group versus delayed response. [Figure 6] Figure 6 shows the Miami plot obtained from discovery analysis. The upper panel shows the comparison between immediate-type responses and the control group, and the lower panel shows the comparison between delayed-type responses and the control group. The dotted line indicates the significance level of the Bonferroni correction. [Figure 7] Figure 7 shows the proportion of phenotypic variations explained by genotypic SNPs at different prevalence rates. The proportion of phenotypic variations explained by genotypic SNPs and hSNP2 was calculated using GCTA. [Best Mode for Carrying Out the Invention]

[0038] This invention relates to the dbSNP database rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73202933, rs72 The present invention relates to a composition for diagnosing or predicting the onset of drug hypersensitivity reactions, comprising a detection formulation for one or more SNPs selected from the group consisting of 622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999.

[0039] The present invention will be described in detail below.

[0040] In this specification, “polynucleotide” or “nucleic acid” refers to deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), which are single-stranded or double-stranded. Unless otherwise limited, this also includes known analogs of natural nucleotides that hybridize to nucleic acids in a manner similar to naturally occurring nucleotides. Generally, DNA is composed of four bases: adenine (A), guanine (G), cytosine (C), and thymine (T), while RNA has uracil (U) instead of thymine. In a double-stranded nucleic acid, A forms a hydrogen bond with T or U, and C forms a hydrogen bond with G; such a relationship between bases is called “complementary.”

[0041] In this specification, when gene mutations are indicated, "c." means a mutation in a protein coding site, and "(base position)(single base letter)(symbol>)(single base letter)" means that the base indicated first at that base position is replaced by the base indicated second.

[0042] In this specification, “polymorphism” means the occurrence of two or more alternative sequences or alleles (or alleles) within a genetically determined population, and “single nucleotide polymorphism (SNP)” means a polymorphism of a single base. Specifically, it refers to the diversity of DNA sequences in which a single base (A, T, C, or G) occurs between members of a species or between pairs of chromosomes in an individual. For example, if there is a difference at one base, such as three DNA fragments from different individuals (e.g., AAGT[A / A]AG, AAGT[A / G]AG, AAGT[G / G]AG), these are called two alleles (A or G), and generally almost all SNPs have two alleles. Furthermore, if an SNP is genetically closely associated with a particular disease, it may mean that a mutation has occurred at a specific base location compared to a confirmed normal or wild-type (WT) individual or allele.

[0043] mRNA (messenger RNA) is an RNA molecule that transmits the genetic information of a specific gene's base sequence to ribosomes during the protein synthesis process, acting as a blueprint for polypeptide synthesis (protein translation). Single-stranded mRNA is synthesized through the transcription process using a gene as a template.

[0044] In this specification, “protein” is used interchangeably with “polypeptide” or “peptide” and refers to a polymer of amino acid residues, for example, as is commonly found in proteins in their natural state.

[0045] The single (or three) letters of amino acid abbreviations used herein refer to the following amino acids according to standard abbreviation rules in the field of biochemistry: A (Ala): Alanine; C (Cys): Cysteine; D (Asp): Aspartic acid; E (Glu): Glutamic acid; F (Phe): Phenylalanine; G (Gly): Glycine; H (His): Histidine; I (IIe): Isoleucine; K (Lys): Lysine; L (Leu): Leucine; M (Met): Methionine; N (Asn): Asparagine; O (Ply): Pyrrolicine; P (Pro): Proline; Q (Gln): Glutamine; R (Arg): Arginine; S (Ser): Serine; T (Thr): Threonine; U (Sec): Selenocysteine; V (Val): Valine; W (Trp): Tryptophan; Y (Tyr): Tyrosine.

[0046] In this specification, "(1 amino acid letter)(amino acid position)(1 amino acid letter)" means that the amino acid preceding the one indicated at that amino acid position in the wild-type protein is replaced by the amino acid following the one indicated.

[0047] As used herein, the term "complementary" means that under given hybridization or annealing conditions, specifically under physiological conditions (intracellular), the intracellular targeting moisture of the nucleic acid molecule is sufficiently complementary to selectively hybridize with the target (e.g., the SNP of the present invention), and may have one or more mismatched base sequences. It encompasses substantially complementary and perfectly complementary sequences, and more specifically, perfectly complementary.

[0048] In this specification, the composition is dbSNP database rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs7 One or more SNPs selected from the group consisting of 3202933, rs72622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 are detected using a diagnostic marker.

[0049] In this specification, SNP rs35372932 is defined as a substitution of the 3,2597,208th base on chromosome 6 from C to T.

[0050] In this specification, SNP rs79736818 is defined as a substitution in which the 148357581st base on chromosome 5 is replaced from A to G.

[0051] In this specification, SNP rs3129871 is defined as a substitution of the base at position 32438565 on chromosome 6, where C is replaced with A.

[0052] In this specification, SNP rs9557291 is defined as a substitution of the 99761210th base on chromosome 13 from G to A.

[0053] In this specification, SNP rs11724428 is defined as a substitution in which the base at position 112598451 on chromosome 4 is changed from G to A.

[0054] In this specification, SNP rs11123552 is defined as a substitution of the 120454245th base on chromosome 2 from C to G.

[0055] In this specification, SNP rs62124613 is defined as a nucleotide with a T substitution at the 2038646th base on chromosome 2.

[0056] In this specification, SNP rs77389536 is defined as a substitution of the 102408368th base on chromosome 10 from T to C.

[0057] In this specification, SNP rs206887084 is defined as a substitution of the 94620980th base on chromosome 12 from G to A.

[0058] In this specification, SNP rs9557291 is defined as a substitution of the 99761210th base on chromosome 13 from G to A.

[0059] In this specification, SNP rs372025 is defined as a substitution of the 107077214th base on chromosome 4 from T to C.

[0060] In this specification, SNP rs8058114 is defined as a substitution of the 12603772nd base on chromosome 16 from G to A.

[0061] In this specification, SNP rs143395859 is defined as a substitution of the 27293404th base on chromosome 7, where G is replaced with A.

[0062] In this specification, SNP rs57833801 is defined as a substitution of the 121777405th base on chromosome 2 from G to A.

[0063] In this specification, SNP rs139830888 is defined as a substitution of the 147872742nd base on chromosome 7 from G to A.

[0064] In this specification, SNP rs9384423 is defined as a substitution in which the base at position 156089071 on chromosome 6 is changed from A to G.

[0065] In this specification, SNP rs6097064 is defined as a substitution of the base at position 37952348 on chromosome 20 from A to C.

[0066] In this specification, SNP rs2175562 is defined as a substitution of the 140398639th base on chromosome 4 from A to G.

[0067] In this specification, SNP rs3924164 is defined as a substitution of the 76,737,927th base on chromosome 18 from C to T.

[0068] In this specification, SNP rs11206477 is defined as a substitution in which the base at position 54941621 on chromosome 1 is changed from C to A.

[0069] In this specification, SNP rs62225078 is defined as a substitution of the 4,774,0975th base on chromosome 22 from T to A.

[0070] In this specification, SNP rs73202933 is defined as a substitution of the 89819306th base on chromosome 12 from T to C.

[0071] In this specification, SNP rs72622187 is defined as a substitution of the 6078051st base on chromosome 3 from G to A.

[0072] In this specification, SNP rs139141104 is defined as a substitution of the 31021244th base on chromosome 6 from A to G.

[0073] In this specification, SNP rs9994092 is defined as a substitution of the base at position 65570396 on chromosome 4 from C to A.

[0074] In this specification, SNP rs1762852884 is defined as a substitution of the 30994936th base on chromosome 6 from A to C.

[0075] In this specification, SNP rs2335545 is defined as a substitution of the 2916111th base on chromosome 16 from C to T.

[0076] In this specification, SNP rs9688895 is defined as a substitution of the 38465523rd base on chromosome 6 from C to A.

[0077] In this specification, SNP rs144130219 is defined as a substitution of the 98725782nd base on chromosome 13 from T to C.

[0078] In this specification, SNP rs78831487 is defined as a substitution of the base at position 6537140 on chromosome 19 from T to C.

[0079] In this specification, SNP rs456449 is defined as a substitution of the 38851003rd base on chromosome 21 from G to A.

[0080] In this specification, SNP rs13250548 is defined as a substitution in which the 35650882nd base on chromosome 8 is replaced from A to G.

[0081] In this specification, SNP rs77068773 is defined as a substitution in which the base at position 23204196 on chromosome 21 is changed from A to T.

[0082] In this specification, SNP rs3025035 is defined as a substitution of the base at position 43783622 on chromosome 6 from C to T.

[0083] In this specification, SNP rs2088142 is defined as a substitution of the base at position 33691285 on chromosome 15 from G to A.

[0084] In this specification, SNP rs1276175 is defined as a substitution of the 30945691st base on chromosome 5 from G to A.

[0085] In this specification, SNP rs144157017 is defined as a substitution in which the base at position 50740465 on chromosome 6 is changed from A to G.

[0086] In this specification, SNP rs59594955 is defined as a substitution of the 38443346th base on chromosome 6 from A to C.

[0087] In this specification, SNP rs28717999 is defined as a substitution in which the base at position 65571223 on chromosome 4 is changed from A to G.

[0088] The aforementioned SNPs may each be located on the nucleotide sequences of SEQ ID NOs. 1 to 38. The nucleotide sequences of SEQ ID NOs. 1 to 38 are shown with the nucleotide corresponding to the SNP position according to the present invention represented by 'r', and the sequence 10nt in the 5' direction and the sequence 10nt in the 3' direction are displayed relative to the SNP position. For example, the nucleotide sequence of SEQ ID NO (rs_id, rs35372932) shows the SNP position represented by 'r', with nucleotide sequences of 10nt length on each side relative to this, resulting in a total sequence of 21nt. Furthermore, if the nucleotide represented by 'r' is identified as, for example, a multiple allele T or a minority allele C, the sequence catalog identification number is used. <223> The items are indicated as r=t or c. The base sequences of SEQ ID NOs. 1 to 38 are used for the purpose of identifying the location of SNPs in individuals, particularly humans, and therefore, the present invention is not limited by the length or indicated range of the base sequences of SEQ ID NOs. 1 to 38.

[0089] In this specification, the term "detection" encompasses all actions including measuring and confirming the presence or absence of a substance of interest, or measuring and confirming changes in the level of the substance of interest (expression level). In the same context, measuring the expression level of the SNP in this invention means measuring the presence or absence of expression (i.e., measuring the presence or absence of expression), or measuring the qualitative and quantitative level of change of the SNP. Such measurements can be carried out without limitation, including both qualitative (analysis) and quantitative methods. The types of qualitative and quantitative methods for measuring the presence or absence of SNPs are well known in the art, and the experimental methods described herein are included therein. Specific SNP level comparison methods for each method are well known in the art.

[0090] In this specification, "drug hypersensitivity reaction," also known as drug allergy, refers to a reaction mediated by immunological mechanisms in patients sensitized to a drug. Drug allergies are cases in which adverse reactions occur due to immune mechanisms, unrelated to the drug's inherent pharmacological effects, and type B reactions account for approximately 6-10%. Hypersensitivity reactions are classified into types 1-4 (types 1-4 hypersensitivity reactions) depending on the mechanism of occurrence, and they manifest in diverse ways depending on the drug; the same drug can induce hypersensitivity reactions with different mechanisms in different patients. For example, cephalosporins, which are commonly used antibiotics, can induce type 1 hypersensitivity reactions such as urticaria and anaphylaxis in some patients, and type 4 hypersensitivity reactions such as exanthematous rash also frequently occur. Hypersensitivity reactions to quinolone antibiotics, which have seen increased use recently, are also frequently observed. These include type 1 hypersensitivity reactions such as urticaria, as well as severe type 4 hypersensitivity reactions such as DRESS syndrome, SJS, and TEN, requiring caution.

[0091] In this specification, "immediate-type drug hypersensitivity reaction" generally occurs within one hour after drug administration and primarily manifests as symptoms such as urticaria, angioedema, and anaphylaxis. Immediate-type reactions are mainly caused by IgE antibody-mediated immune responses or direct stimulation of mast cells by the drug, and may manifest as one or a combination of reactions such as urticaria, angioedema, rhinitis, airway constriction, itching, vomiting, diarrhea, and anaphylaxis.

[0092] In this specification, "delayed-type drug hypersensitivity reaction" refers to a reaction that occurs several days to several weeks after drug administration and is characterized by vasculitis, blood cell abnormalities, rashes (fixed drug eruption, exfoliative dermatitis, acute generalized exanthematous pustulosis (AGEP), DRESS syndrome, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), arthralgia, proteinuria, lymphadenopathy, etc.), due to mechanisms involving complement system activation, antigen-antibody complex formation, and immune cell activation. Delayed-type hypersensitivity reactions mainly occur 1 to 8 weeks after drug administration, but in patients who have been previously sensitized and experienced mild symptoms, they may occur immediately after drug administration.

[0093] In this specification, the drug hypersensitivity reaction may be one or more selected from the group consisting of anaphylaxis, angioedema, urticaria, maculopapular rash, DRESS syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, and fixed drug eruption.

[0094] In this specification, the drug may be one or more selected from the group consisting of NSAIDs (including aspirin), acetaminophen, cephalosporins, antibiotics, contrast agents, chemotherapeutic agents, H2 blockers, allopurinol, and anticonvulsants, but is not limited thereto.

[0095] In this specification, the NSAIDs are acemetacin, acetylsalicylic acid, bufexamac, diclofenac, diclofenac sodium, diflunisal, dipyrone (metamizole), metamizole sodium, ethenzamide, etofenamate, flufenamic acid, flurbiflofen, ibuprofen, indomethacin, isocicam, kebzon, ketoprofen, ketrolac, lonazolac, lornoxicam, meclofenamic acid, mefena One or more of the following may be selected from the group consisting of niflumic acid, mofebutazone, nabumetone, naproxen, (+)-ibuprofen, (-)-ibuprofen, (+)-naproxen, niflumic acid, oxaprozin, oxyfenbutazone, phenylbutazone, piroxicam, propifenazone, salicylamide, sulindac, tenoxicam, tiaprofenic acid, SC560, sulfasalazine, and tolmetine, but is not limited to these.

[0096] In this specification, the radioactive contrast agent may be one or more selected from the group consisting of iohexo, iopamidol, Ioversol, iodixanol, iopromide, ioxaglate, and diatrizoate, but is not limited thereto.

[0097] In this specification, the antibiotic may be a β-lactam antibiotic (penicillin or cephalosporin), but is not limited thereto.

[0098] In this specification, the drug hypersensitivity reaction may occur in a Korean person, but is not limited to that.

[0099] In this specification, the term “diagnosis” encompasses all concepts including determining the susceptibility of an object to a particular disease or disorder, determining whether an object currently has a particular disease or disorder, determining the prognosis of an object suffering from a particular disease or disorder, or terametrics (e.g., monitoring the condition of an object to provide information regarding therapeutic efficacy). In this specification, such diagnosis may, but is not limited to, early diagnosis or disease prediction.

[0100] In this specification, the diagnosis refers to a diagnosis of drug hypersensitivity. In the present invention, the drug hypersensitivity may preferably be a hereditary drug hypersensitivity induced by a genetic predisposition, or it may be a condition in which the symptoms are exacerbated by environmental influences in addition to the genetic predisposition.

[0101] In this specification, "primer" refers to a short single-strand oligonucleotide that acts as a starting point for DNA synthesis. The primer specifically binds to a template polynucleotide under suitable buffer and temperature conditions, and DNA is synthesized when a DNA polymerase adds a nucleoside triphot phosphate containing bases complementary to the template DNA to the primer and ligates them together. Primers generally consist of 15 to 30 base sequences, and the melting temperature (Tm) at which they bind to the template strand varies depending on the base composition and length. The primer sequence does not need to be perfectly complementary to some of the template base sequences; sufficient complementarity within the range of hybridization with the template to enable the primer's specific action is sufficient. Therefore, in this invention, primer pairs, which are detection formulations according to the present invention, can be easily designed by referring to the base sequence of the cDNA or genomic DNA at the SNP site. Primers for detecting SNPs do not need to have a perfectly complementary sequence to each gene sequence; it is sufficient if they have a length and complementarity suitable for the purpose of amplifying a specific section of mRNA or cDNA through DNA synthesis and measuring the amount of mRNA. The primers for the amplification reaction consist of a set (pair) that binds complementaryly to the template (or sense) at both ends and the opposite end (antisense) of the specific section of mRNA to be amplified.

[0102] In this specification, "probe" refers to a fragment of polynucleotide such as RNA or DNA, ranging in length from a few to several hundred base pairs, that can specifically bind to mRNA, cDNA (complementary DNA), DNA, etc., of a specific gene. The probe is labeled, and the presence or absence, expression level, etc., of the target mRNA or cDNA to which it is bound can be confirmed. The selection of the probe and hybridization conditions can be appropriately selected using techniques commonly known in the industry. The probe can be used in diagnostic methods for detecting alleles (or alleles). The diagnostic methods include detection methods based on nucleic acid hybridization, such as Southern blotting, and the probe can also be provided in a form pre-bound to a DNA chip substrate using a DNA chip method. In the present invention, the primer or probe can be chemically synthesized using phosphoramidite solid support synthesis methods or other widely known methods.

[0103] In this specification, primers or probes can be chemically synthesized using phosphoramidite solid support synthesis methods or other widely known methods. Furthermore, primers or probes can be modified in a variety of ways by methods commonly known in the art, provided that they do not interfere with hybridization with the target polynucleotide to be detected. Examples of such modifications include methylation, capping, substitution with one or more congeners of native nucleotides, and modifications between nucleotides, such as uncharged conjugates (e.g., methylphosphonates, phosphotriesters, phosphorodiamidates, carbamates, etc.) or charged conjugates (e.g., phosphorothioates, phosphorodithioates, etc.), and the attachment of fluorescent or enzymatic labeling materials.

[0104] Furthermore, the present invention provides a diagnostic kit for drug hypersensitivity reactions comprising the above-mentioned composition.

[0105] In this specification, the kit may be, but is not limited to, an RT-PCR kit or a microarray chip kit.

[0106] The aforementioned kit can predict or make an early diagnosis of drug hypersensitivity reactions by confirming SNP markers, which are diagnostic markers for drug hypersensitivity reactions, through amplification, or by confirming the expression level of SNP markers with the mRNA expression level.

[0107] The RT-PCR kit may include a primer pair capable of amplifying nucleic acids containing the SNP site, as well as other appropriate containers such as test tubes, reaction buffer, deoxyribonucleotides (dNTPs), enzymes such as Taq polymerase and reverse transcriptase, DNase, RNAse inhibitors, DEPC water, sterile water, etc. It may also include a primer pair specific to the gene used as a quantitative control group.

[0108] The microarray chip kit may include a microarray having a substrate on which nucleic acids containing the SNP sites are immobilized. The microarray may consist of a conventional microarray, except that it contains the polynucleotide, primer or probe of the present invention. Nucleic acid hybridization on a microarray and detection of the hybridization results are well known in the art. For example, the detection can be performed by labeling a nucleic acid sample with a labeling substance that can generate a detectable signal, such as a fluorescent substance containing Cy3 and Cy5, hybridizing it on a microarray, and detecting the signal generated from the labeling substance to detect the hybridization results.

[0109] In this invention, the terms "individual" or "subject" mean a subject for which disease onset prediction or diagnosis is made.

[0110] In the present invention, the "sample" can be used without limitation as long as it is taken from the subject to be targeted for disease prediction or diagnosis, and may include, for example, cells or tissues obtained by biopsy, blood, whole blood, serum, plasma, saliva, cerebrospinal fluid, various secretions, urine, feces, etc. Preferably, it can be selected from the group consisting of blood, plasma, serum, saliva, nasal fluid, sputum, ascites, vaginal secretions, and urine, and preferably blood, plasma, or serum. The sample may be pretreated before use for detection or diagnosis. For example, this may include homogenization, filtration, distillation, extraction, concentration, inactivation of interfering components, addition of reagents, etc.

[0111] Furthermore, the present invention relates to the dbSNP database, which records the base sequence of SNP sites in a sample obtained from a subject. rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114 , rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73202933, rs72622187, rs13914 The present invention provides a method for providing information necessary for diagnosing drug hypersensitivity reactions, including a step of determining that a subject has developed a drug hypersensitivity reaction if one or more single nucleotide polymorphisms selected from the group consisting of 1104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 are present.

[0112] Furthermore, the present invention relates to the dbSNP database, which records the base sequence of SNP sites in a sample obtained from a subject. rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114, r s143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73202933, rs72622187, rs139141104 The present invention provides a method for providing information necessary for predicting the onset of drug hypersensitivity reactions, including a step of determining that a subject is at high risk of developing a drug hypersensitivity reaction if one or more single nucleotide polymorphisms selected from the group consisting of rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 are present.

[0113] Furthermore, the present invention provides a method for providing information necessary for diagnosing delayed-type drug hypersensitivity reactions, which includes the step of determining that a subject has a delayed-type drug hypersensitivity reaction if one or more single nucleotide polymorphisms selected from the group consisting of dbSNP database rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 are present in the base sequence of an SNP site in a sample obtained from a patient with a drug hypersensitivity reaction.

[0114] Furthermore, the present invention relates to the dbSNP database, which records the base sequence of SNP sites in a sample obtained from a subject. rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058 114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73202933, rs72622187, r The present invention provides a diagnostic method for drug hypersensitivity reactions, which includes the step of determining that a subject has developed a drug hypersensitivity reaction if one or more single nucleotide polymorphisms selected from the group consisting of s139141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 are present.

[0115] Furthermore, the present invention relates to the dbSNP database, which records the base sequence of SNP sites in a sample obtained from a subject. rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs805811 4, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73202933, rs72622187, rs139 The present invention provides a method for predicting the onset of drug hypersensitivity reactions, which includes a step of determining that a subject is at high risk of developing a drug hypersensitivity reaction if one or more single nucleotide polymorphisms selected from the group consisting of 141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 are present.

[0116] In this specification, the method may be performed by one or more methods selected from the group consisting of sequencing, exome sequencing, microarray hybridization, allele-specific PCR, dynamic allele-specific hybridization, PCR extension analysis, and the Taqman method, but is not limited thereto.

[0117] Furthermore, the present invention uses the dbSNP database rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73202933, rs7 If one or more single nucleotide polymorphisms selected from the group consisting of 2622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999 are present, it is determined that the subject has developed a drug hypersensitivity reaction.

[0118] If it is determined that the subject has developed a drug hypersensitivity reaction, a method for treating drug hypersensitivity reactions can be provided, which includes the step of treating the subject's drug hypersensitivity reaction.

[0119] In the present invention, "treatment" means all actions that improve or beneficially alter the target disease and the metabolic abnormalities caused thereby, and may include methods such as chemotherapy, surgery, or biological therapy.

[0120] In the present invention, a treatment method commonly used for treating the drug hypersensitivity reaction may be used, or commonly used therapeutic agents for drug hypersensitivity reactions may be administered, for example, antihistamines, steroids, epinephrine, or bronchodilators, etc., but not limited to these.

[0121] Furthermore, the present invention relates to the dbSNP database rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs73202933, rs7 The present invention provides a composition comprising a detection formulation for one or more SNPs selected from the group consisting of 2622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999, for use in diagnosing or predicting the onset of drug hypersensitivity reactions.

[0122] Furthermore, the present invention relates to the dbSNP database rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs9557291, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078, rs7 The present invention provides applications for one or more SNP detection formulations selected from the group consisting of 3202933, rs72622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999.

[0123] While the present invention can be subjected to various transformations and has many embodiments, specific embodiments are illustrated in the drawings and described in detail in the detailed description. However, this should be understood not as limiting the present invention to specific embodiments, but rather as including all transformations, equivalents, and substitutes that fall within the spirit and technical scope of the present invention. In describing the present invention, if it is determined that a specific description of related known technology would obscure the gist of the present invention, such detailed description will be omitted.

[0124] The following are preferred embodiments to aid in understanding the present invention. However, the following embodiments are provided solely to facilitate understanding of the present invention and do not limit the scope of the present invention.

[0125] [Examples] Example 1. Experimental Method subject We recruited 378 patients with Drug Hypersensitivity Reactions (DHR) who visited Seoul Asan Hospital between 2012 and 2017. This study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Seoul Asan Hospital Institutional Review Board (2011-0939). Written informed consent was obtained from all participants for registration and blood sample collection. Blood samples were collected from each subject, and genotyping was analyzed using K-CHIP. K-CHIP was provided through the K-CHIP Consortium (http: / / kogo.or.kr) and designed by the Genome Science Center of the Korea Institute of Public Health. Control group data (N=3,780) were obtained from the Health Checkup Center of Severance Hospital in Korea, and genotyping was analyzed using K-CHIP (see Figure 1). To minimize batch effects, SNP genotyping was analyzed using a calling method based on K-medoid clustering. The EIGENSTRAT access method was applied to the integrated data, and principal component scores (PC scores) were calculated between the control group and the patient group (to match subjects with similar genetic information). A total of 10 control groups per patient matched with similar scores. The PC scores were used to identify subjects without a genetic background. The multidimensional scaling plot is shown in Figure 2.

[0126] Replication analysis From 2012 to 2015, genotyping was repeated in 185 additional DHR patients recruited at Seoul Asan Hospital. Genotyping of these patients was performed using the Axiom Asian chip (Affymetrix). The control group was registered at the Health Checkup Center of Severance Hospital (N=2,312), and genotyping was performed using the K-CHIP. All data were pooled and subject substitution was performed (see Figure 1).

[0127] Data Analysis Group DHR patients were divided into two groups: immediate response and delayed response. Comparative analysis was performed by comparing total DHR to the control group, comparing each DHR group to the control group, and finally comparing the immediate response group with the delayed response group.

[0128] quality control SNPs and subject quality were evaluated. All stages of quality control were performed using PLINK and ONETOOL. The p-value for the Hardy-Weinberg equilibrium (HWE) test was 1 × 10⁻⁶. -5 SNPs with a minor allele frequency (MAF) less than 0.05 or a genotypic analysis rate less than 0.95 were excluded. Additionally, individuals with a missing rate greater than 0.05 or an Identity-By-State (IBS) greater than 0.9 when combined with other individuals were excluded. These filtering procedures were applied separately to each case and the control group, and the cases and control groups were then combined. Furthermore, considering SNPs present in both groups, the same quality control procedures were applied to the pooled data. Fisher's exact test was used to test the equivalence of mean missing rates between each case and the control group, resulting in a 1 × 10⁻⁶ test. -5 SNPs that were significant enough to be meaningful were removed from the GWAS. This process is summarized in Figure 1a.

[0129] Statistical analysis using genotype substitution and inferred genotypes The GWAS with discovery data was performed using generalized logistic regression (GLR). Age and sex were included as covariates. Binary responses (control group vs. DHR) were also predicted using a logistic regression (LR) model. Both GLR and LR were applied using R statistical software (R Project for Statistical Computing, Vienna, Austria; www.r-project.org). 5×10 -8Significant SNPs across the entire genome were selected at a significant level. For fine mapping, SNPs located within ±5,000 base pairs of significant SNPs in the full genome were imputed. Imputation was performed using the Sanger imputation service (https: / / imputation.sanger.ac.uk). Using the Haplotype Reference Consortium release v1.1, the European Asian (CHB / JPT) 16 population, consisting of 64,940 haplotypes, was considered as the primary reference panel. Pre-phasing and imputation were performed using SHAPEIT17 and PBWT18, and imputation accuracy was evaluated using the INFO metric.

[0130] Example 1. Confirmation of the subject's characteristics The demographic characteristics of the study participants are summarized in Table 1.

[0131] The mean age of the DHR patients enrolled in the study (N=378) was 42.03 ± 14.82 years, and 247 patients (65.34%) were female. Of these, 295 cases (78.04%) showed immediate-type hypersensitivity reactions, and 83 cases (21.96%) showed delayed-type / non-immediate-type reactions. The most common causative drugs for immediate-type hypersensitivity reactions were NSAIDs, followed by antibiotics. A detailed list of causative drugs is shown in Table 2 below.

[0132] In the delayed-type reaction group, antibiotics were the most common causative drug, followed by anticonvulsants. The mean age of the control group (N=3,779) was 43.07±9.85 years, and a total of 1,236 patients (32.7%) were female. The mean age of the 185 DHR patients enrolled in the replication analysis was 50.38±16.58 years, and 105 patients (56.76%) were female. Of these 185 patients, 80 showed immediate-type hypersensitivity reactions, while 105 showed delayed-type hypersensitivity reactions. The control group consisted of 2,312 subjects, including a total of 921 women (39.84%), and the mean age of the subjects was 46.96±10.72 years. In the replication group, NSAIDs were the most common causative drug, followed by antibiotics (Table 2).

[0133] [Table 1]

[0134] [Table 2]

[0135] Example 2. Verification of GWAS analysis results A total of 265,878 SNPs passed quality control (genotypic analysis rate (call rate) > 98%, MAF > 0.05). First, the association between DHR (immediate and delayed response) in the two groups was analyzed. The QQ plot against LR is shown in Figure 3, and the analysis results were statistically significant.

[0136] As shown in Figure 4, only one SNP was found to be close to genome-wide significance (rs35372932, p=7.99E-08). The genome-level SNP was identified as rs35372932, and it was confirmed to be located in the upstream region of the HLA-DRB1 gene on chromosome 6 (see Table 3).

[0137] [Table 3]

[0138] Furthermore, as shown in Figure 5a, the points filled in purple in the region plot using genotype and alternative SNPs represent rs35372932, and the hue of the other points indicates a correlation with rs35372932. In other words, the most significant SNP was rs35372932.

[0139] Next, immediate-type and delayed-type reactions were analyzed independently and repeated. The QQ plots against GLR are shown in Figures 3b and 3c.

[0140] Furthermore, five meaningful SNPs on the full genome (rs11206477, rs62225078, rs73202933, rs72622187, and rs139141104) were compared between the delayed-type hypersensitivity group and the control group (see Tables 3 and 4).

[0141] As shown in Table 3 above, the most significant SNP, rs139141104, is located in the intron region of the MUC22 gene on chromosome 6.

[0142] As shown in Figure 6, a total of five SNPs (rs11206477, rs62225078, rs73202933, rs72622187, and rs139141104) were confirmed to be significant in the full-length genes. This is the same result as shown in Table 4.

[0143] In the region plot in Figure 5b, prepared using genotypes and alternative SNPs, the points filled in purple represent rs139141104, and the hue of the other points indicates their correlation with this genotype.

[0144] Finally, the inventors compared the phenotypes of drug hypersensitivity reactions.

[0145] As shown in Table 4, no meaningful SNPs were identified when comparing immediate-type and delayed-type hypersensitivity reactions.

[0146] [Table 4] JPEG0007856987000005.jpg247166JPEG0007856987000006.jpg79164

[0147] Example 3. Replication analysis Replication analysis was performed using alternative methods. A total of 75,077 SNPs passed quality control (genotyping rate >98%, MAF >0.03) (Figure 1).

[0148] As shown in Table 5, among the SNPs identified as meaningful in the discovery data analysis, only rs35372932 (p=0.008), located in the HLA-DRB1 upstream region of chromosome 6, was found to be statistically significant. This result supports the idea that rs35372932 can be used as a general marker not limited to the phenotype or causative drug of specific drug hypersensitivity reactions.

[0149] [Table 5]

[0150] Example 4. GCTA (Genome-wide Complex Trait Analysis) Analysis GCTA is one method for estimating heritability and is one of the methods that can estimate the heritability of SNPs.

[0151] The present inventors have identified hSNPs of genotype SNPs. 2 The proportion of phenotypic variations was calculated using (additive SNP heritability). The results showed that the prevalence of hSNPs was... 2 The estimated value was shown.

[0152] As shown in Figure 7, the prevalence of drug hypersensitivity reactions was 2 × 10⁻⁶ -2 As a result of setting this, the responsibility scale showed hSNP 2 The figure was 39.12%. This result, in light of previous studies, supports the finding that drug hypersensitivity reactions have a relatively high degree of heritability.

[0153] Based on the above examples, SNPs that were judged to be clinically significant in drug hypersensitivity reactions and their detailed types, immediate-type drug hypersensitivity reactions and delayed-type drug hypersensitivity reactions, were selected. Therefore, it is expected that the SNPs of the present invention can be usefully used for the early diagnosis and prediction of the onset of drug hypersensitivity reactions.

[0154] The above description of the present invention is illustrative, and a person with ordinary skill in the art to which the present invention pertains will understand that it can be easily modified into other specific forms without altering the technical idea or essential features of the present invention. Accordingly, the embodiments described above should be understood to be illustrative and not limiting in all respects. [Industrial applicability]

[0155] The specific SNPs identified in this invention as being closely related to the onset of drug hypersensitivity reactions are expected to be useful in developing genetic diagnostic reagents for diagnosing or predicting the onset of drug hypersensitivity reactions, and thus have industrial applicability.

Claims

1. A composition for determining or predicting drug hypersensitivity reactions, comprising a detection formulation for SNP rs35372932 in the dbSNP database, SNP rs35372932 is a variant in which the 3,2597,208th base on chromosome 6 is substituted from cytosine (C) to thymine (T). The detection formulation is a composition, which is a probe or a primer set.

2. The composition for determining a drug hypersensitivity reaction or predicting the onset of a drug hypersensitivity reaction according to claim 1, characterized in that the drug hypersensitivity reaction is an immediate-type drug hypersensitivity reaction or a delayed-type drug hypersensitivity reaction.

3. A composition for determining or predicting the onset of a drug hypersensitivity reaction according to claim 1, The composition further includes rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078 selected from the dbSNP database. The formulation comprises one or more SNP detection formulations selected from the group consisting of rs73202933, rs72622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999, wherein, rs79736818 is a variant in which the 148357581st base of chromosome 5 is substituted from adenine (A) to guanine (G). rs3129871 is a variant in which the 32438565th base on chromosome 6 is substituted from cytosine (C) to adenine (A). rs9557291 is a variant in which the 99761210th base on chromosome 13 is substituted from guanine (G) to adenine (A). rs11724428 is a variant in which the 112598451st base of chromosome 4 is substituted from guanine (G) to adenine (A). rs11123552 is a variant in which the 120454245th base on chromosome 2 is substituted from cytosine (C) to guanine (G). rs62124613 is a variant in which the 20386466th base on chromosome 2 is substituted from cytosine (C) to thymine (T). rs77389536 is a variant in which the 102408368th base on chromosome 10 is substituted from thymine (T) to cytosine (C). rs206887084 is a variant in which the 94620980th base on chromosome 12 is substituted from guanine (G) to adenine (A). rs372025 is a variant in which the 107077214th base on chromosome 4 is substituted from thymine (T) to cytosine (C). rs8058114 is a variant in which the 12603772nd base on chromosome 16 is substituted from guanine (G) to adenine (A). rs143395859 is a variant in which the 27293404th base on chromosome 7 is substituted from guanine (G) to adenine (A). rs57833801 is a variant in which the 121777405th base on chromosome 2 is substituted from guanine (G) to adenine (A). rs139830888 is a variant in which the 147872742nd base on chromosome 7 is substituted from guanine (G) to adenine (A). rs9384423 is a variant in which the 156089071st base on chromosome 6 is substituted from adenine (A) to guanine (G). rs6097064 is a variant in which the 3,795,2348th base on chromosome 20 is substituted from adenine (A) to cytosine (C). rs2175562 is a variant in which the 140398639th base on chromosome 4 is substituted from adenine (A) to guanine (G). rs3924164 is a variant in which the 76737927th base on chromosome 18 is substituted from cytosine (C) to thymine (T). rs11206477 is a variant in which the base at position 54941621 on chromosome 1 is substituted from cytosine (C) to adenine (A). rs62225078 is a variant in which the 47740975th base on chromosome 22 is substituted from thymine (T) to adenine (A). rs73202933 is a variant in which the base at position 89819306 on chromosome 12 is substituted from thymine (T) to cytosine (C). rs72622187 is a variant in which the 6078051st base on chromosome 3 is substituted from guanine (G) to adenine (A). rs139141104 is a variant in which the 31021244th base on chromosome 6 is substituted from adenine (A) to guanine (G). rs9994092 is a variant in which the 65570396th base on chromosome 4 is substituted from cytosine (C) to adenine (A). rs1762852884 is a variant in which the 30994936th base on chromosome 6 is substituted from adenine (A) to cytosine (C). rs2335545 is a substitution where cytosine (C) is replaced with thymine (T) at base position 2916111 of chromosome 16. rs9688895 is a variant in which the 38465523rd base on chromosome 16 is substituted from cytosine (C) to adenine (A). rs144130219 is a variant in which the 98725782nd base on chromosome 13 is substituted from thymine (T) to cytosine (C). rs78831487 is a variant in which the base at position 6537140 on chromosome 19 is substituted from thymine (T) to cytosine (C). rs456449 is a variant in which the 38851003rd base on chromosome 21 is substituted from guanine (G) to adenine (A). rs13250548 is a variant in which the 35650882nd base on chromosome 8 is substituted from adenine (A) to guanine (G). rs77068773 is a variant in which the 23204196th base on chromosome 21 is substituted from adenine (A) to thymine (T). rs3025035 is a variant in which the 43783622nd base on chromosome 6 is substituted from cytosine (C) to thymine (T). rs2088142 is a variant in which the base at position 33691285 on chromosome 15 is substituted from guanine (G) to adenine (A). rs1276175 is a variant in which the 30945691st base of chromosome 5 is substituted from guanine (G) to adenine (A). rs144157017 is a variant in which the base at position 50740465 on chromosome 6 is substituted from adenine (A) to guanine (G). rs59594955 is a variant in which the 38443346th base on chromosome 6 is substituted from adenine (A) to cytosine (C). rs28717999 is a variant in which the base at position 65571223 on chromosome 4 is substituted from adenine (A) to guanine (G). , composition.

4. If the SNP is one or more selected from the group consisting of rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, and rs206887084, then the composition is for determining drug hypersensitivity reactions or predicting the onset of illness in healthy individuals. If the SNP is one or more selected from the group consisting of rs9557291, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, and rs3924164, then the composition is for determining immediate-type drug hypersensitivity reactions or predicting the onset of illness in healthy individuals. If the SNP is one or more selected from the group consisting of 3) rs11206477, rs62225078, rs73202933, rs72622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, and rs144130219, then the composition is for determining delayed-type drug hypersensitivity reactions or predicting the onset of illness in healthy individuals. The composition for determining drug hypersensitivity reactions or predicting the onset of a drug hypersensitivity reaction according to claim 3, characterized in that the SNP is one or more selected from the group consisting of 4) rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999, wherein the composition is for distinguishing between immediate-type and delayed-type drug hypersensitivity reactions.

5. The composition for determining or predicting the onset of a drug hypersensitivity reaction according to claim 1, characterized in that the drug hypersensitivity reaction occurred in a Korean person.

6. A kit for determining drug hypersensitivity reactions, comprising the composition described in claim 1.

7. The kit according to claim 6, characterized in that the kit is an RT-PCR kit or a microarray chip kit.

8. A method for providing information necessary for determining drug hypersensitivity reactions, which includes the step of determining that a subject has developed a drug hypersensitivity reaction if the single nucleotide polymorphism rs35372932 in dbSNPs is present in the base sequence of an SNP site in a sample obtained from a subject, SNP rs35372932 is a cytosine (C) to thymine (T) substitution at base 32597208 on chromosome 6.

9. A method for providing information necessary for predicting the onset of a drug hypersensitivity reaction, which includes the step of determining that a subject is at high risk of developing a drug hypersensitivity reaction if the SNP described in claim 8 is present in the base sequence of the SNP site in a sample obtained from a subject, SNP rs35372932 is a variant in which the 3,2597,208th base on chromosome 6 is substituted from cytosine (C) to thymine (T).

10. The method according to 9, characterized in that the method is performed by one or more methods selected from the group consisting of sequencing, exome sequencing, microarray hybridization, allele-specific PCR, dynamic allele-specific hybridization, PCR extension analysis, and the Taqman method.

11. The use of a formulation for detecting SNP rs35372932 in dbSNP database for manufacturing a formulation for determining drug hypersensitivity reactions or predicting the onset of disease, SNP rs35372932 is a variant in which the 3,2597,208th base on chromosome 6 is substituted from cytosine (C) to thymine (T). The detection formulation is a probe or primer set, used.

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