JP2018011584A - Method for evaluating risk of onset of severe drug eruption accompanied by ophthalmic complications, and kit used for the method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for evaluating the risk of onset of severe drug eruption accompanied by ophthalmic complications which is preferable for evaluating the risk of onset of severe drug eruption accompanied by ophthalmic complications of Japanese which is particularly the risk of onset of drug eruption accompanied by ophthalmic complications out of SJS and TEN.SOLUTION: An evaluation method of the risk of onset of severe drug eruption accompanied by ophthalmic complications of an embodiment has: a typing process of typing a genotype of one or more SNPs selected from the group consisting of 108 specific SNPs of the subject by using the nucleic acid derived from the subject; and an evaluation process of evaluating the risk of onset of severe drug eruption accompanied by ophthalmic complications of the subject based on a typing result obtained by the typing process.SELECTED DRAWING: None

Description

  Embodiments of the present invention relate to a method for evaluating the risk of developing severe drug eruption accompanied by ocular complications, and a kit used in the method.

  Among drug eruptions (dermatoses caused by drugs that enter the body), severe drug eruptions are likely to cause mucosal eruptions and organ damage in addition to systemic skin lesions, which may be life-threatening. It is a drug eruption. In severe drug eruptions, there are diseases that cause serious eye complications and, at worst, lead to blindness. Major examples of severe drug eruption include Stevens-Johnson syndrome (SJS) (epidermal exfoliation is less than 10% of the skin area) and its progressive form of toxic epidermal necrolysis (TEN) (epidermal exfoliation is the skin area 10% or more). The eye complication rate in SJS / TEN is reported to be about 40%. Further, there is no difference in ophthalmic findings between SJS and TEN. In SJS / TEN with ocular complications, when the surface of the eye becomes scarred after the onset of drug eruption, severe dry eye damage, profound eyelashes, etc. persist throughout life. In ophthalmology, patients in the chronic stage are often examined, and diagnosis is based on ocular findings. Therefore, SJS / TEN with eye complications are collectively referred to as Stevens-Johnson syndrome in a broad sense.

  In severe drug eruptions such as SJS / TEN, it is important to make a definitive diagnosis as soon as possible in order to perform appropriate treatment early from the onset. Patients with SJS / TEN with severe ocular complications must develop acute conjunctivitis, hemorrhagic erosions in the lips and mouth, and periodontitis at onset. In addition, cold-like symptoms often precede drug administration. However, diagnosis of SJS / TEN is not always easy.

  For severe drug eruptions such as SJS / TEN with ocular complications, it is expected that the onset prevention and early diagnosis will be possible if the onset risk can be evaluated before onset. For example, SNP (single nucleotide polymorphism) frequencies in SJS patient groups and non-SJS patient groups are comprehensively analyzed, and SNPs with significantly high frequencies in SJS patient groups have been reported. In addition, SNPs of patients with severe drug eruption with ocular complications, in particular SJS / TEN patients with ocular complications presumed to have developed due to cold medicine, were comprehensively analyzed. 64 SNPs are observed more frequently in the patient group compared to SNPs in the healthy non-patient group, and based on the genotype of these SNPs, the risk of developing severe drug eruption with ocular complications To be evaluated.

  In a conventional comprehensive gene analysis of gene polymorphisms related to the onset of SJS / TEN accompanied by serious ocular complications, Affymetrix's microarray type SNP analysis kit “Axiom (registered trademark) Genome-Wide ASI 1 Array” Is used for genome-wide association study (GWAS) for Japanese. The microarray was designed to maximize the genomic coverage of less frequent alleles (MAF> 1%) found in consensus sequences of East Asian genomes based on Caucasian and Asian genetic polymorphism data. It is an array and is not necessarily suitable for Japanese genetic analysis. For this reason, in the conventional GWAS, some of the disease-related gene polymorphisms peculiar to Japanese may have been overlooked.

JP 2010-193765 A Japanese Patent Laying-Open No. 2015-107095

  The problem to be solved by the present invention is to develop an eye complication suitable for evaluating the risk of developing a serious drug eruption accompanied by ocular complications in Japanese, in particular, an onset risk of SJS and TEN with ocular complications. It is to provide a method for evaluating the risk of developing severe drug eruption.

  The method for evaluating the risk of developing severe drug eruption with ocular complications according to the embodiment uses one or more SNP genes selected from the group consisting of specific 108 SNPs of the subject using nucleic acid derived from the subject. A typing process for typing a mold, and an evaluation process for evaluating the risk of developing severe drug eruption accompanied by eye complications of the subject based on the typing result obtained by the typing process. The 108 specific SNPs are rs16824605, rs12407492, rs614350, rs1418929, rs1339697, rs79798614, rs871141, rs76217877, rs75019707, rs17019101, rs78929670, rs12622778, rs13383303, rs13010016, rs4679631, rs10164284, rs55742142, 346 , Rs13319930, rs2920193, rs13434731, rs117369903, rs77885120, rs13151271, rs17516386, rs59783747, rs1801075, rs74763702, rs2731849, rs75814077, rs76701269, rs513165, rs17136947, rs76533382, rs75249189, rs876038, rs10223 rs73667472, rs2435909, rs6986203, rs73339061, rs7822062, rs59134671, rs78226500, rs10829414, rs11016267, rs7108440, rs7950561, rs11038410, rs12146638, rs117732390, rs74539361, rs7479018, rs7943614, rs190043383, rs476190731, rs17619015 rs16942579, rs12594972, rs118152764, rs16957918, rs73444105, rs75765821, rs36012474, rs76130486, rs6497035, rs9933632, rs9944315, rs117496909, rs11648177, rs79852170, rs78054468, rs276943, rs5447, rs6041265, rs2031149, rs62212413, rs4811310, rs2426427, rs4140429, rs6068177, rs rs4518503, rs4323313, rs2294837, rs872307, rs76132714, rs78537991, rs59567566, and rs78605884.

  Hereinafter, the evaluation method of the onset risk of severe drug eruption accompanied by ocular complications of the embodiment and the kit used for the method will be described.

  In the present specification, “the risk of developing severe drug eruption with ocular complications” refers to the risk (risk rate) of developing severe drug eruption with ocular complications when a drug is taken. Specifically, severe skin symptoms (for example, changes due to necrotizing disorders such as erythema, blisters, erosion, etc.) are seen in the skin including the mucous membrane, and serious conjunctivitis develops in the eyes. Say ease. SJS and TEN are mainly mentioned as serious drug eruption accompanied by ocular complications. In the following, “the risk of developing severe drug eruption with ocular complications” is sometimes simply referred to as “risk of onset”.

  In the present specification, “rsXXXXXXX (X is an arbitrary number)” indicates a reference number of the SNP database (dbSNP BUILD124) of NCBI (National Center for Biotechnology Information).

  In the present specification, “typing a single nucleotide polymorphism (SNP)” means whether the SNP is A (adenine), G (guanine), or C (cytosine). It means specifying whether it is T (thymine).

  In the present specification, an allele refers to each type having different bases that can be taken at a certain polymorphic site. As used herein, a genotype refers to a combination of alleles that oppose each other at a certain polymorphic site. Furthermore, there are three types of genotypes which are combinations of alleles at a certain polymorphic site. A combination of the same alleles is called a homotype, and a combination of different alleles is called a heterotype.

  In the present specification, a high-risk allele is a single nucleotide polymorphism allele associated with a severe drug eruption associated with ocular complications, and is more frequent than a non-patient group in patients with severe drug eruptions associated with ocular complications A high allele. On the other hand, a low risk allele in the present specification refers to an allele that opposes a high risk allele at a certain polymorphic site.

  HLA functions as a histocompatibility antigen in humans, and the HLA gene is located on human chromosome 6. In the present specification, “typing an HLA gene” means identifying the genotype of the subject's HLA gene. In the present specification, the genotype of the HLA gene conforms to the international standard approved by the HLA naming committee of the World Health Organization.

(First embodiment)
The method for evaluating the risk of developing severe drug eruption with ocular complications according to the first embodiment (hereinafter sometimes referred to as “onset risk evaluation method”) uses a subject-derived nucleic acid to identify a specific subject. A typing process for typing one or more SNP genotypes selected from the group consisting of 108 SNPs, and a severe drug eruption associated with ocular complications of the subject based on the typing result obtained by the typing process And an evaluation step for evaluating the risk of onset. The 108 SNPs are the SNPs of SJS / TEN patients and normal subjects who have so-called common cold-related eye complications that are presumed to have been caused by cold medicines such as general cold medicine and antipyretic analgesics. The SJS / TEN patient group was statistically significantly more frequent than the healthy subject group (Example 1 described later). This exhaustive analysis was searched by genotyping using a DNA microarray (“Japonica array (registered trademark of Tohoku University)”) equipped with SNPs having a base sequence characteristic to Japanese. . Therefore, the 108 SNPs contain a genetic polymorphism related to the onset of SJS / TEN that is unique to Japanese, and the first implementation using at least one of the 108 SNPs as a risk assessment marker. The onset risk evaluation method of the form is very suitable for the onset risk evaluation for Japanese, especially for the onset risk evaluation of cold drug-related severe drug eruption with eye complications for Japanese.

The 108 SNPs used as risk assessment markers in the first embodiment are rs16824605, rs12407492, rs614350, rs1418929, rs1339697, rs79798614, rs871141, rs76217877, rs75019707, rs17019101, rs78929670, rs12622778, rs13383303, rs13010016, rs4679631, rs42142, , Rs62274115, rs34684758, rs56271032, rs76130979, rs761993309, rs13319930, rs2920193, rs13434731, rs117369903, rs77885120, rs13151271, rs17516386, rs59783747, rs1801075, rs74763702, rs2731849, rs75814077, rs513165, rs1713638 , Rs62504065, rs2120482, rs71510630, rs715667630, rs73667472, rs2435909, rs6986203, rs73339061, rs7822062, rs59134671, rs78226500, rs10829414, rs11016267, rs7108440, rs7950561, rs11038410, rs12146638, rs117732390, rs7451361, rs7451 , Rs7148580, rs1567620, rs2100432, rs1694 579
rs4811310, rs2426427, rs4140429, rs6068173, rs6068252, rs4811369, rs6068271, rs7450590, rs12661585, rs12663784, rs4518503, rs4323313, rs2294837, rs872307, rs76132714, rs78537991, rs59567566, and rs78605884.

  rs16824605 is a SNP at the 170996th base of human chromosome 1, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs16824605, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs16824605 has the G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs12407492 is a SNP at the base of 29813527 of human chromosome 1, and is a T / G polymorphism. As is clear from the results of Example 1 described later, in rs12407492, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the T allele. It was done. That is, when the subject's rs12407492 has a G allele, the subject evaluates that the onset risk is high, and when the subject does not have the G allele, the subject evaluates that the onset risk is low.

  rs614350 is a SNP at the 66592000th base of human chromosome 1, and is a T / C polymorphism. As will be apparent from the results of Example 1 described later, in rs614350, it is confirmed that the risk of onset is statistically significantly higher in humans having the C allele than in humans having the T allele. It was done. That is, when the subject's rs614350 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs1418929 is a SNP at the 101939518th base of human chromosome 1 and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs1418929, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs1418929 has an A allele, the subject evaluates that the onset risk is high, and when the subject does not have the A allele, the subject evaluates that the onset risk is low.

  rs1339697 is a SNP at the 111045565th base of human chromosome 1, and is a C / T polymorphism. As will be apparent from the results of Example 1 described later, in rs1339697, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs1339697 has a T allele, the subject evaluates that the risk of onset is high, and when the subject does not have a T allele, the subject evaluates that the risk of onset is low.

  rs79798614 is an SNP of the 189065417th base of human chromosome 1, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs79798614, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs79798614 has a G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs871141 is a SNP at the base of 244376500 of human chromosome 1, and is an A / C polymorphism. As will be apparent from the results of Example 1 described later, in rs871141, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the A allele. It was done. That is, when the subject's rs871141 has a C allele, the subject is evaluated as having a high onset risk, and when the subject has no C allele, the subject is evaluated as having a low onset risk.

  rs76217877 is a SNP at the 27559188th base of human chromosome 2, and is a G / C polymorphism. As is clear from the results of Example 1 described later, in rs76217877, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the G allele. It was done. That is, when the subject's rs76217877 has a C allele, the subject evaluates that the risk of onset is high, and when the subject does not have the C allele, the subject evaluates that the risk of onset is low.

  rs75019707 is a SNP at the 37530457th base of human chromosome 2, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs75019707, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs75019707 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs17019101 is a SNP of the 60494383 base of human chromosome 2, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs17019101, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs17019101 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs78929670 is a SNP of the 1662887478th base of human chromosome 2, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs78929670, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs78929670 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs12622778 is a SNP of the 183878469th base of human chromosome 2, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs12622778, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs12622778 has a C allele, the subject is evaluated as having a high onset risk, and when the subject has no C allele, the subject is evaluated as having a low onset risk.

  rs13383303 is a SNP at the base of 196961265 of human chromosome 2, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs13383303, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs13383303 has an A allele, the subject evaluates that the onset risk is high, and when the subject does not have the A allele, the subject evaluates that the onset risk is low.

  rs13010016 is a SNP of the 223655029 base of human chromosome 2, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs13010016, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs13010016 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs4679631 is a SNP at the 60091156th base of human chromosome 3, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs4679631, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs4679631 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs1016284 is a SNP of the 118706164th base of human chromosome 3, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs1016284, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs1016284 has the G allele, the subject is evaluated as having a high onset risk, and when the subject has no G allele, the subject is evaluated as having a low onset risk.

  rs55742142 is a SNP of the 118737542th base of human chromosome 3 and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs55742142, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs55742142 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs62274115 is a SNP at the 148325405 base of human chromosome 3, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs62274115, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs62274115 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs34684758 is a SNP at the 164267710th base of human chromosome 3 and is a G / A polymorphism. As will be apparent from the results of Example 1 described later, in rs34684758, it is confirmed that the risk of onset is statistically significantly higher in humans having the A allele than in humans having the G allele. It was done. That is, when the subject's rs34684758 has an A allele, the subject is evaluated as having a high risk of onset, and when the subject has no A allele, the subject is evaluated as having a low risk of onset.

  rs56271032 is a SNP at the 172154210th base of human chromosome 3 and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs56271032, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject rs56271032 has the G allele, the subject is evaluated as having a high risk of onset, and when the subject does not have the G allele, the subject is evaluated as having a low risk of onset.

  rs76130979 is a SNP at the 172711833 base of human chromosome 3, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs76130979, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs76130979 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs13319930 is a SNP at the 178648355th base of human chromosome 3, and is a T / G polymorphism. As is clear from the results of Example 1 described later, in rs13319930, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the T allele. It was done. That is, when the subject's rs13319930 has the G allele, the subject is evaluated as having a high onset risk, and when the subject has no G allele, the subject is evaluated as having a low onset risk.

  rs2920193 is a SNP at the 4339999th base of human chromosome 4, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs2920193, it is confirmed that the risk of onset is statistically significantly higher in humans who have the G allele than in humans who have the A allele. It was done. That is, when the subject's rs2920193 has a G allele, the subject is evaluated as having a high risk of onset, and when the subject does not have a G allele, the subject is evaluated as having a low risk of onset.

  rs13434731 is a SNP at the 4348876 base of human chromosome 4, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs13434731, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs13434731 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs117369903 is a SNP at the 20635296th base of human chromosome 4, and is a G / A polymorphism. As will be apparent from the results of Example 1 described later, in rs117369903, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs117369903 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs77885120 is a SNP of the 22239231th base of human chromosome 4, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs77885120, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs77885120 has a G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs13151271 is a SNP at the 25023875th base of human chromosome 4, and is an A / C polymorphism. As is clear from the results of Example 1 described later, in rs13151271, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the A allele. It was done. That is, when the subject's rs13151271 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs17516386 is a SNP at the base of 97657325 of human chromosome 4, and is a G / T polymorphism. As will be apparent from the results of Example 1 described later, in rs17516386, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the G allele. It was done. That is, when the subject's rs17516386 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs59783747 is a SNP of the 181469727 base of human chromosome 4, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs59783747, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs59783747 has a G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs1801075 is a SNP at the 1317949th base of human chromosome 5, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs1801075, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs1801075 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs74763702 is a SNP of the 7567103th base of human chromosome 5, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs74763702, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs74763702 has a C allele, the subject evaluates that the risk of onset is high, and when the subject does not have the C allele, the subject evaluates that the risk of onset is low.

  rs2731849 is a SNP at the 82509879th base of human chromosome 5, and is a C / A polymorphism. As is clear from the results of Example 1 described later, in rs2731849, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the C allele. It was done. That is, when the subject's rs2731849 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs75814077 is a SNP of the 111023923 base of human chromosome 5, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs75814077, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the A allele than in humans who possess the G allele. It was done. That is, when the subject's rs75814077 has an A allele, the subject evaluates that the onset risk is high, and when the subject does not have the A allele, the subject evaluates that the onset risk is low.

  rs76701269 is a SNP at the 129345412 base of human chromosome 5 and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs76701269, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the T allele than in humans who possess the C allele. It was done. That is, when the subject's rs76701269 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs513165 is a SNP at the 179249073 base of human chromosome 5, and is a C / A polymorphism. As is clear from the results of Example 1 described later, in rs513165, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the A allele. It was done. That is, when the subject's rs513165 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs7450590 is a SNP of the 68707987th base of human chromosome 6 and is a C / T polymorphism. As will be apparent from the results of Example 1 described later, in rs7450590, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs7450590 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs12661585 is a SNP at the 9635410th base of human chromosome 6, and is an A / G polymorphism. As will be apparent from the results of Example 1 described later, in rs12661585, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs12661585 has the G allele, the subject is evaluated as having a high onset risk, and when the subject has no G allele, the subject is evaluated as having a low onset risk.

  rs12663784 is a SNP at the 96050094 base of human chromosome 6, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs12663784, it is confirmed that the risk of onset is statistically significantly higher in humans holding the A allele than in humans holding the G allele. It was done. That is, when the subject's rs12663784 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs4518503 is an SNP of the 996083310 base of human chromosome 6, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs4518503, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs4518503 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs4323313 is a SNP at the 96150527th base of human chromosome 6, and is a G / A polymorphism. As will be apparent from the results of Example 1 described later, in rs4323313, it is confirmed that the risk of onset is statistically significantly higher in humans having the A allele than in humans having the G allele. It was done. That is, when the subject's rs4323313 has an A allele, the subject evaluates that the risk of onset is high, and when the subject does not have the A allele, the subject evaluates that the risk of onset is low.

  rs2294837 is a SNP of the 96440392 base of human chromosome 6, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs2294837, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs2294837 has a T allele, the subject evaluates that the risk of onset is high, and when the subject does not have a T allele, the subject evaluates that the risk of onset is low.

  rs872307 is a SNP at the 108110297th base of human chromosome 6, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs872307, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs872307 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs76132714 is a SNP at the 116145832 base of human chromosome 6, and is a C / A polymorphism. As is clear from the results of Example 1 described later, in rs76132714, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the C allele. It was done. That is, when the subject's rs76132714 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs78537991 is a SNP of the 116368899th base of human chromosome 6, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs78537991, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs78537991 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs59567566 is an SNP of the 133886684 base of human chromosome 6 and is an A / G polymorphism. As will be apparent from the results of Example 1 described later, in rs59567566, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs59567566 has a G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs78605884 is a SNP at the 138928169th base of human chromosome 6 and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs78605884, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs78605884 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs17136947 is a SNP at the 16994199th base of human chromosome 7, and is a G / A polymorphism. As will be apparent from the results of Example 1 described later, in rs17136947, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs17136947 has an A allele, the subject evaluates that the onset risk is high, and when the subject does not have the A allele, the subject evaluates that the onset risk is low.

  rs76533382 is a SNP at the 472361414 base of human chromosome 7, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs76533382, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs76533382 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs75249189 is a SNP of the 5027715th base of human chromosome 7, and is a G / A polymorphism. As will be apparent from the results of Example 1 described later, in rs75249189, it is confirmed that the risk of onset is statistically significantly higher in humans holding the A allele than in humans holding the G allele. It was done. That is, when the subject's rs75249189 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs876038 is a SNP at base 50308527 of human chromosome 7, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs876038, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs876038 has a C allele, the subject is evaluated as having a high onset risk, and when the subject has no C allele, the subject is evaluated as having a low onset risk.

  rs10259658 is a SNP of the 99265852 base of human chromosome 7, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs10259658, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs10259658 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs12537523 is a SNP of the 150750566 base of human chromosome 7, and is a G / A polymorphism. As will be apparent from the results of Example 1 described later, in rs12537523, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs12537523 has an A allele, the subject is evaluated as having a high risk of onset, and when the subject has no A allele, the subject is evaluated as having a low risk of onset.

  rs11136457 is a SNP of the 1997993 base of human chromosome 8, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs11136457, it is confirmed that the risk of onset is statistically significantly higher in humans who have the G allele than in humans who have the A allele. It was done. That is, when the subject's rs11136457 has a G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs62504065 is a SNP of the 619453rd base of human chromosome 8, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs62504065, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the T allele than in humans who possess the C allele. It was done. That is, when the subject's rs62504065 has a T allele, the subject evaluates that the risk of onset is high, and when the subject does not have a T allele, the subject evaluates that the risk of onset is low.

  rs2120482 is a SNP of the 6169780th base of human chromosome 8, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs2120482, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the T allele than in humans who possess the C allele. It was done. That is, when the subject's rs2120482 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs71510630 is a SNP of the 18732955th base of human chromosome 8, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs71510630, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs71510630 has the G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs73667472 is a SNP at the 19809695th base of human chromosome 8, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs73667472, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs73667472 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs2435909 is a SNP at the 73279104th base of human chromosome 8, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs2435909, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs2435909 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs6986203 is a SNP at the 76272578th base of human chromosome 8, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs6986203, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs6986203 has a C allele, the subject is evaluated as having a high onset risk, and when the subject has no C allele, the subject is evaluated as having a low onset risk.

  rs73339061 is a SNP of the 76277142 base of human chromosome 8, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs73339061, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the G allele than in humans who possess the A allele. It was done. That is, when the subject's rs73339061 has a G allele, the subject is evaluated as having a high onset risk, and when the subject has no G allele, the subject is evaluated as having a low onset risk.

  rs7822062 is a SNP at the 76282475th base of human chromosome 8, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs7822062, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the T allele than in humans who possess the C allele. It was done. That is, when the subject's rs7822062 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs59134671 is a SNP of the 7762630th base of human chromosome 8, and is an A / C polymorphism. As is clear from the results of Example 1 described later, in rs59134671, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the A allele. It was done. That is, when the subject's rs59134671 has the C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs78226500 is a SNP at the 13003803 base of human chromosome 10, and is a C / A polymorphism. As is clear from the results of Example 1 described later, in rs78226500, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the C allele. It was done. That is, when the subject's rs78226500 has an A allele, the subject is evaluated as having a high risk of onset, and when the subject has no A allele, the subject is evaluated as having a low risk of onset.

  rs10829414 is a SNP at the 130271977 base of human chromosome 10, and is a T / G polymorphism. As is clear from the results of Example 1 described later, in rs10829414, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the T allele. It was done. That is, when the subject's rs10829414 has the G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs11016267 is a SNP at the 130276925th base of human chromosome 10, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs11016267, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs11016267 has the G allele, the subject is evaluated as having a high onset risk, and when the subject has no G allele, the subject is evaluated as having a low onset risk.

  rs7108440 is a SNP of the 1673636th base of human chromosome 11, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs7108440, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs7108440 has a G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs7950561 is a SNP of the 1675607th base of human chromosome 11, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs7950561, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs7950561 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs11038410 is a SNP at the 1677196th base of human chromosome 11, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs11038410, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs11038410 has the G allele, the subject is evaluated as having a high onset risk, and when the subject has no G allele, the subject is evaluated as having a low onset risk.

  rs12146638 is a SNP of the 1679464th base of human chromosome 11, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs12146638, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs12146638 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs117732390 is a SNP of the 36173970th base of human chromosome 11, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs117732390, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs117732390 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs74539361 is a SNP at the 42857779th base of human chromosome 11, and is a G / A polymorphism. As will be apparent from the results of Example 1 described later, in rs74539361, it is confirmed that the risk of onset is statistically significantly higher in humans holding the A allele than in humans holding the G allele. It was done. That is, when the subject's rs74539361 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs7479018 is a SNP at the 69563733th base of human chromosome 11, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs7479018, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs7479018 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs7943614 is a SNP of the 126579050th base of human chromosome 11, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs7943614, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs7943614 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs190043383 is a SNP at the 32906865th base of human chromosome 12, and is a C / G polymorphism. As will be apparent from the results of Example 1 described later, in rs190043383, it is confirmed that the risk of onset is statistically significantly higher in humans having the G allele than in humans having the C allele. It was done. That is, when the subject's rs190043383 has the G allele, the subject evaluates that the onset risk is high, and when the subject does not have the G allele, the subject evaluates that the onset risk is low.

  rs4761641 is a SNP at base 95001686 of human chromosome 12 and is a T / C polymorphism. As will be apparent from the results of Example 1 described later, in rs4761641, it is confirmed that the risk of onset is statistically significantly higher in humans having the C allele than in humans having the T allele. It was done. That is, when the subject's rs4761641 has a C allele, the subject is evaluated as having a high onset risk, and when the subject has no C allele, the subject is evaluated as having a low onset risk.

  rs117619073 is a SNP at the 102091409th base of human chromosome 13, and is a C / A polymorphism. As will be apparent from the results of Example 1 described later, in rs117619073, it is confirmed that the risk of onset is statistically significantly higher in humans having the A allele than in humans having the C allele. It was done. That is, when the subject's rs117619073 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs58895553 is a SNP of the 108291544th base of human chromosome 13, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs58895553, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs58895553 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs1539131 is a SNP of the 108319451 base of human chromosome 13, and is a C / A polymorphism. As is clear from the results of Example 1 described later, in rs1539131, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the C allele. It was done. That is, when the subject's rs1539131 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs7148580 is a SNP of the 75881211th base of human chromosome 14, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs7148580, it is confirmed that the risk of onset is statistically significantly higher in humans possessing T allele than in humans possessing C allele. It was done. That is, when the subject's rs7148580 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs1567620 is a SNP at the base of 57694854 of human chromosome 15, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs1567620, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs1567620 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs2100432 is a SNP at the 60687844th base of human chromosome 15, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs2100432, it is confirmed that the risk of onset is statistically significantly higher in humans who have the A allele than in humans who have the G allele. It was done. That is, when the subject's rs2100432 has an A allele, the subject is evaluated as having a high risk of onset, and when the subject has no A allele, the subject is evaluated as having a low risk of onset.

  rs16942579 is a SNP of the 60750787th base of human chromosome 15, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs16942579, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs16942579 has a G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs12594972 is a SNP of the 60607649th base of human chromosome 15, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs12594972, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs12594972 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs118152764 is a SNP at the 73721357th base of human chromosome 15, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs118152764, it is confirmed that the risk of onset is statistically significantly higher in humans who have the G allele than in humans who have the A allele. It was done. That is, when the subject's rs118152764 has the G allele, the subject evaluates that the onset risk is high, and when the subject does not have the G allele, the subject evaluates that the onset risk is low.

  rs16957918 is a SNP of the 7137465th base of human chromosome 15, and is a C / A polymorphism. As is clear from the results of Example 1 described later, in rs16957918, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the C allele. It was done. That is, when the subject's rs16957918 has an A allele, the subject is evaluated as having a high risk of onset, and when the subject has no A allele, the subject is evaluated as having a low risk of onset.

  rs73444105 is a SNP of the base at position 73786604 of human chromosome 15, and is a T / G polymorphism. As will be apparent from the results of Example 1 described later, in rs73444105, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the T allele. It was done. That is, when the subject's rs73444105 has a G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs75765821 is a SNP at the 73961212 base of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs75765821, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs75765821 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs36012474 is a SNP at the 74026926th base of human chromosome 15, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs36012474, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs36012474 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs76130486 is a SNP at the 74064379th base of human chromosome 15, and is a C / T polymorphism. As is apparent from the results of Example 1 described later, in rs76130486, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the T allele than in humans who possess the C allele. It was done. That is, when the subject's rs76130486 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs6497035 is a SNP of the 93937304th base of human chromosome 15, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs6497035, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs6497035 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs9933632 is a SNP at the 49940758th base of human chromosome 16, and is a G / T polymorphism. As is clear from the results of Example 1 described later, in rs9933632, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the T allele than in humans who possess the G allele. It was done. That is, when the subject's rs9933632 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs9944315 is a SNP at the 49994804th base of human chromosome 16, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs9944315, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the A allele than in humans who possess the G allele. It was done. That is, when the subject's rs9944315 has an A allele, the subject evaluates that the onset risk is high, and when the subject does not have the A allele, the subject evaluates that the onset risk is low.

  rs117496909 is a SNP at the 49464415th base of human chromosome 16, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs117496909, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs117496909 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs11648177 is a SNP at the 49499248th base of human chromosome 16, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs11648177, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs11648177 has the G allele, the subject evaluates that the risk of onset is high, and when the subject does not have the G allele, the subject evaluates that the risk of onset is low.

  rs79852170 is a SNP at the 79932686th base of human chromosome 16, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs79852170, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs79852170 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs78054468 is a SNP of the 4192825th base of human chromosome 18, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs78054468, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs78054468 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs276943 is a SNP of the 28608794th base of human chromosome 18, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs276943, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs276943 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs5447 is a SNP of the base at position 49481243 of human chromosome 19, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs5447, it is confirmed that the risk of onset is statistically significantly higher in humans possessing C allele than in humans possessing T allele. It was done. That is, when the subject's rs5447 has the C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs6041265 is a SNP at the 12307489th base of human chromosome 20, and is an A / G polymorphism. As will be apparent from the results of Example 1 described later, in rs6041265, it is confirmed that the risk of onset is statistically significantly higher in humans having the A allele than in humans having the G allele. It was done. That is, when the subject's rs6041265 has an A allele, the subject evaluates that the risk of onset is high, and when the subject does not have the A allele, the subject evaluates that the risk of onset is low.

  rs2031149 is a SNP of the 12334081th base of human chromosome 20, and is a G / A polymorphism. As is apparent from the results of Example 1 described later, in rs2031149, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs2031149 has the G allele, the subject evaluates that the onset risk is high, and when the subject does not have the G allele, the subject evaluates that the onset risk is low.

  rs62212413 is a SNP of the 38595612 base of human chromosome 20, and is a G / T polymorphism. As is clear from the results of Example 1 described later, in rs62212413, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the G allele. It was done. That is, when the subject rs62212413 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject does not have a T allele, the subject is evaluated as having a low risk of onset.

  rs4811310 is a SNP at the 50817889th base of human chromosome 20, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs4811310, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs4811310 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs2426427 is an SNP at the 50882351th base of human chromosome 20, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs2426427, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the A allele than in humans who possess the G allele. It was done. That is, when the subject's rs2426427 has an A allele, the subject is evaluated as having a high risk of onset, and when the subject has no A allele, the subject is evaluated as having a low risk of onset.

  rs4140429 is a SNP of the 51026784th base of human chromosome 20, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs4140429, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the A allele than in humans who possess the G allele. It was done. That is, when the subject's rs4140429 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs6068173 is a SNP of the 51046034 base of human chromosome 20, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs6068173, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs6068173 has a C allele, the subject is evaluated as having a high onset risk, and when the subject has no C allele, the subject is evaluated as having a low onset risk.

  rs6068252 is a SNP of the 51180373rd base of human chromosome 20, and is a T / G polymorphism. As is clear from the results of Example 1 described later, in rs6068252, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the T allele than in humans who possess the G allele. It was done. That is, when the subject's rs6068252 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs4811369 is a SNP at the 51196711 base of human chromosome 20, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs4811369, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs4811369 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs6068271 is a SNP at the 5122246th base of human chromosome 20, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs6068271, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs6068271 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  If the nucleic acid derived from the subject subjected to genetic polymorphism typing includes a nucleic acid reflecting the base sequence of the region containing at least one of the 108 SNPs in the genomic DNA of the subject (human) Good. Preferably, it is the genomic DNA of the subject, but it may also be an amplification product obtained by amplifying a partial region by PCR or the like using the genomic DNA as a template. The genomic DNA derived from the subject may be a nucleic acid extracted and purified from a biological sample collected from the subject, or may be a nucleic acid before purification.

  The method for typing SNP in the typing step is not particularly limited, and may be a sequence analysis method based on the Sanger method, a single base detection method, or a MALDI-TOF mass spectrometry method. May be. Examples of the single nucleotide detection method include various known methods used in gene mutation and polymorphism detection, such as PCR-SSO (sequence specific oligonucleotide) method, PCR-SSP (sequence specific primer) method, and modifications thereof. Can be used. The PCR-SSO method is a method in which a probe that specifically hybridizes to a specific allele (allele-specific probe) is used for typing according to the presence or absence of an association with the probe. Examples of the method include a microarray method using a substrate in which an allele-specific probe of a specific allele of SNP is immobilized on the substrate. The PCR-SSP method is a method in which PCR is performed using a primer that specifically hybridizes to a specific allele (allele specific probe), and typing is performed depending on the presence or absence of a PCR product. Examples of the modified methods include invader method, Taqman (registered trademark) probe method, QProbe method, and Scorpion-ARMS method. Since it is excellent in detection sensitivity, it is preferable to be a method of detecting using fluorescence, and since it is excellent in detection sensitivity and accuracy, invader method, Taqman (registered trademark) probe method, QProbe method, Scorpion-ARMS method A method using a probe or primer that recognizes a specific allele, such as a microarray method, is preferable.

  Nucleic acid molecules such as probes and primers used for typing the 108 SNPs can be designed and synthesized by a conventional method based on the base sequence information of the partial region containing each SNP in the human genome, for example. For example, a nucleic acid molecule that can hybridize to a partial region containing SNP in genomic DNA or a complementary strand thereof can be used as a nucleic acid molecule for typing the SNP. The nucleic acid molecule thus designed can be synthesized using any method well known in the art. For example, synthesis may be requested from a synthesis manufacturer, or may be synthesized independently using a commercially available synthesizer.

  In the first embodiment, the risk of developing a subject is evaluated based on the typing result (that is, genotype) of at least one of the 108 SNPs. When judging only from the typing result of one of the 108 SNPs, the evaluation is performed for each SNP as described above. However, it is possible to evaluate the risk of onset more accurately by evaluating by combining the typing results of a plurality of SNPs than by judging only from the typing result of one SNP.

  For example, a plurality of SNPs (preferably all SNPs) out of the 108 are typed on a nucleic acid derived from a subject, and among the obtained typing results, all the SNPs are genotypes with a low risk of onset. If the subject has a low risk of onset (is a low risk group) and all SNPs are genotypes with a high risk of onset, the subject has a high risk of onset (high It is an onset risk group). Moreover, among the obtained typing results, when some of the genotype SNPs with high onset risk are included, although the onset risk is higher than the low onset risk group, the onset is slightly higher than the high onset risk group. It can be evaluated that the risk is low (it is a moderate risk group).

  The onset risk can be evaluated based on the odds ratio. In particular, when the onset risk is evaluated using the typing results of a plurality of SNPs, the odds ratio of each SNP can be compared, and the magnitude of the onset risk can be more finely evaluated based on the magnitude. Here, the odds ratio is the frequency obtained in the same manner in the non-patient group as the ratio of the frequency of one allele or genotype to the frequency of another allele or genotype in the group of severe drug rash patients with eye complications. Divided by the ratio. For example, when the odds ratio of a specific allele of a certain SNP is greater than 1, the allele is an allele frequently observed in a group of severe drug eruption patients with ocular complications. Subjects with a high risk of onset. On the other hand, when the odds ratio of the allele is smaller than 1, the allele is an allele of the allele that is frequently observed in the disease, and the lower the odds ratio, the lower the risk of developing the subject having the allele. Similarly, genotypes can be used to predict and evaluate the risk of developing a subject.

  When calculating the odds ratio for alleles, the odds ratio is the ratio of the frequency of high-risk alleles to low-risk alleles in patients with severe drug rash with eye complications, and the frequency of high-risk alleles and low-risk alleles in non-patient groups. What is necessary is just to obtain | require as what remove | divided by ratio. In order to determine the odds ratio in the genotype, the odds ratio is determined in consideration of whether the high-risk allele follows a dominant genetic model or a recessive genetic model. That is, when the high-risk allele follows the dominant genetic model, the high-risk allele homozygous and heterozygous are risk factors, and when the high-risk allele follows the recessive genetic model, the high-risk allele homozygous Become. Therefore, the odds ratio when the high-risk allele follows the dominant genetic model is calculated as the sum of the homozygous and heterozygous frequencies of the high-risk allele in patients with severe drug eruption with eye complications. What is necessary is just to divide the allele homozygous frequency ratio by the frequency ratio obtained similarly in the non-patient group. If the high-risk allele follows the recessive inheritance model, determine the sum of the low-risk allele homozygous frequency and heterozygous frequency in the group of severe drug eruption patients with ocular complications. What is necessary is just to divide | segment the ratio of the said sum by the ratio of the frequency similarly calculated | required in the non-patient group.

  The frequency of SJS / TEN with ocular complications varies depending on the genotype of the SNP. In addition, the genotype of each SNP may be high risk or low risk. Therefore, the relative risk can be evaluated by combining a plurality of SNP genotypes.

  As an example, how much the genotype of the high risk factor or the genotype of the low risk factor affects the onset can be predicted by quantifying each factor, that is, the genotype of the SNP. For example, risk values and weighting factors are set in advance for the SNP genotypes correlated with the incidence of severe drug eruption with the above-mentioned eye complications, and the weighting factors are multiplied for the genotypes of subjects. Calculate the risk level. It is evaluated that the combined risk value multiplied by the genotype weighting coefficient, which is evaluated to be high risk of developing severe drug eruption with ocular complications, and low risk of developing severe drug eruption with ocular complications. The risk of developing severe drug eruption accompanied by eye complications in a subject can be predicted based on the difference from the sum of the risk values multiplied by the genotype weighting coefficient. The numerical value of the weighting coefficient may not be set individually for the SNP genotype, but may be given to the total risk level of the high risk factor and the low risk factor, or the total risk level of the SNP. . In this way, it is possible to predict how likely SJS / TEN with ocular complications will develop in consideration of high risk factors and low risk factors.

(Second Embodiment)
The method for evaluating the risk of developing severe drug eruption with ocular complications according to the second embodiment is one selected from the group consisting of specific 82 gene polymorphisms of the subject using nucleic acid derived from the subject. A typing process for typing the genotype of the above gene polymorphism, and an evaluation process for evaluating the risk of developing a severe drug eruption with eye complications of the subject based on the typing result obtained by the typing process. . The 82 gene polymorphisms were detected by genotyping using the microarray "Japonica array (registered trademark)" and imputation (pseudo-reconstruction) for Japanese people. The drug-related SJS / TEN patient group is a gene polymorphism that was statistically significantly more frequent (Example 1 below). For this reason, as in the first embodiment, the onset risk evaluation method of the second embodiment using at least one of the 82 genetic polymorphisms as a risk evaluation marker is an onset risk evaluation for Japanese, particularly Japan. It is very suitable for assessing the risk of developing cold-related severe drug eruption with eye complications.

  The 82 gene polymorphisms used as risk assessment markers in the second embodiment are rs16957958, rs61615643, rs76040382, rs143542085, rs73442102, rs16957893, rs59339222, rs73442036, rs16957901, rs16957905, rs73417046, rs28817075, rs2415149, rs150925273, rs58566848, 734 , Rs58354121, rs200559765, rs16957918, rs73442077, rs16957928, rs111709993, rs142602354, rs112265165, rs74022999, rs74023000, rs111550497, rs113677323, rs73444107, rs73444110, rs16957940, rs112460473, rs113129661, rs11 , Rs150996688, rs139799391, rs143746363, rs117508212, rs17765936, rs12324361, rs80137767, rs118076475, rs79432474, rs144821791, rs78493906, rs111743418, rs111586775, rs113825850, rs16958054, rs76343330, rs1 17 : 73931269: T: TC CC, rs200373183, rs113301740, rs112113314, rs75765821, rs78709247, rs76571485, rs76495667, rs75219305, rs111283628, rs141245755, rs111277087, rs11574496, rs76213482, rs6500265, rs9888871, and rs9933632.

  rs16957958 is a SNP at the 73800344th base of human chromosome 15, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs16957958, it is confirmed that the risk of onset is statistically significantly higher in humans possessing C allele than in humans possessing T allele. It was done. That is, when the subject's rs16957958 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs61615643 is a SNP of the 73809564th base of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs61615643, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs61615643 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs76040382 is a SNP of the 73811302 base of human chromosome 15, and is a C / A polymorphism. As will be apparent from the results of Example 1 described later, in rs76040382, it is confirmed that the risk of onset is statistically significantly higher in humans having the A allele than in humans having the C allele. It was done. That is, when the subject's rs76040382 has an A allele, the subject is evaluated as having a high risk of onset, and when the subject has no A allele, the subject is evaluated as having a low risk of onset.

  rs143542085 is a SNP of the base at position 7379462 of human chromosome 15, and is a C / T polymorphism. As will be apparent from the results of Example 1 described later, in rs143542085, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs143542085 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs73442102 is a SNP at the 73786345th base of human chromosome 15, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs73442102, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs73442102 has the G allele, the subject is evaluated as having a high onset risk, and when the subject has no G allele, the subject is evaluated as having a low onset risk.

  rs16957893 is a SNP at the base of the 73729483 position of human chromosome 15, and is a G / C polymorphism. As will be apparent from the results of Example 1 described later, in rs16957893, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the G allele. It was done. That is, when the subject's rs16957893 has a C allele, the subject evaluates that the risk of onset is high, and when the subject does not have the C allele, the subject evaluates that the risk of onset is low.

  rs59339222 is a SNP of the base at position 73732728 of human chromosome 15, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs59339222, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs59339222 has the G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs73442036 is a SNP at the 73733767th base of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs73442036, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs73442036 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs16957901 is a SNP at the base of 73733791 of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs16957901, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs16957901 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs16957905 is a SNP at the 73734130th base of human chromosome 15, and is a G / T polymorphism. As is clear from the results of Example 1 described later, in rs16957905, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the T allele than in humans who possess the G allele. It was done. That is, when the subject's rs16957905 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs73442046 is a SNP at the 73735744th base of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs73442046, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs73442046 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs28817075 is a SNP at the 7737929th base of human chromosome 15, and is a G / A polymorphism. As is apparent from the results of Example 1 described later, in rs28817075, it is confirmed that the risk of onset is statistically significantly higher in humans who have the A allele than in humans who have the G allele. It was done. That is, when the subject's rs28817075 has an A allele, the subject is evaluated as having a high risk of onset, and when the subject has no A allele, the subject is evaluated as having a low risk of onset.

  rs2415149 is a SNP at the 73742097th base of human chromosome 15, and is a G / A polymorphism. As will be apparent from the results of Example 1 described later, in rs2415149, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs2415149 has an A allele, the subject is evaluated as having a high risk of onset, and when the subject has no A allele, the subject is evaluated as having a low risk of onset.

  rs150925273 is a SNP at the base of the 73742796 position of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs150925273, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs150925273 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs58566848 is a SNP of the base at position 73743158 of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs58566848, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the T allele than in humans who possess the C allele. It was done. That is, when the subject's rs58566848 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs73442061 is a SNP of the 7378272th base of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs73442061, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs73442061 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs58354121 is a SNP of the base at position 7374949 of human chromosome 15, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs58354121, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs58354121 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs200559765 is a gene polymorphism of the 7137427th base of human chromosome 15, and is a TATTA / T polymorphism. As is clear from the results of Example 1 described later, in rs200559765, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the T allele than in humans who possess the TATTA allele. It was done. That is, when the subject's rs200559765 has a T allele, the subject evaluates that the risk of onset is high, and when the subject does not have a T allele, the subject evaluates that the risk of onset is low.

  rs16957918 is a SNP of the 7137465th base of human chromosome 15, and is a C / A polymorphism. As is clear from the results of Example 1 described later, in rs16957918, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the C allele. It was done. That is, when the subject's rs16957918 has an A allele, the subject is evaluated as having a high risk of onset, and when the subject has no A allele, the subject is evaluated as having a low risk of onset.

  rs73442077 is a SNP of the 7276415th base of human chromosome 15, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs73442077, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs73442077 has the G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs16957928 is a SNP at the 73765088 base of human chromosome 15, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs16957928, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs16957928 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs111709993 is a SNP at the 7655598th base of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs111709993, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs111709993 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs142602354 is a genetic polymorphism of the 7376015th base of human chromosome 15, and is a TGTAAG / T polymorphism. As is clear from the results of Example 1 described later, in rs142602354, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the TGTAAG allele. It was done. That is, when the subject's rs142602354 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs112265165 is a gene polymorphism of the 7337949th base of human chromosome 15, and is a CAT / C polymorphism. As is clear from the results of Example 1 described later, in rs112265165, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the CAT allele. It was done. That is, when the subject's rs112265165 has a C allele, the subject evaluates that the onset risk is high, and when the subject does not have the C allele, the subject evaluates that the onset risk is low.

  rs74022999 is a SNP at the 73780454th base of human chromosome 15, and is a G / A polymorphism. As will be apparent from the results of Example 1 described later, in rs74022999, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs74022999 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs74023000 is a SNP at the 73780455th base of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs74023000, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs74023000 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs111550497 is a SNP of the 73781941 base of human chromosome 15, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs111550497, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs111550497 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs113677323 is a SNP at the 73786689 base of human chromosome 15, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs113677323, it is confirmed that the risk of onset is statistically significantly higher in humans possessing C allele than in humans possessing T allele. It was done. That is, when the subject's rs113677323 has the C allele, the subject evaluates that the onset risk is high, and when the subject does not have the C allele, the subject evaluates that the onset risk is low.

  rs73444107 is a SNP at the 73788371 base of human chromosome 15, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs73444107, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs73444107 has a G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs73444110 is a SNP at the 797465th base of human chromosome 15, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs73444110, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs73444110 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs16957940 is a SNP at the base of the 73793037 position of human chromosome 15, and is a T / C polymorphism. As will be apparent from the results of Example 1 described later, in rs16957940, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs16957940 has a C allele, the subject evaluates that the onset risk is high, and when the subject does not have the C allele, the subject evaluates that the onset risk is low.

  rs112460473 is a gene polymorphism at nucleotide 73794270 of human chromosome 15, and is an AT / A polymorphism. As will be apparent from the results of Example 1 described later, in rs112460473, it is confirmed that the risk of onset is statistically significantly higher in humans who have the A allele than in humans who have the AT allele. It was done. That is, when the subject's rs112460473 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs113702379 is a SNP of the base at position 7395162 of human chromosome 15, and is a C / A polymorphism. As will be apparent from the results of Example 1 described later, in rs113702379, it is confirmed that the risk of onset is statistically significantly higher in humans having the A allele than in humans having the C allele. It was done. That is, when the subject's rs113702379 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs113262661 is a SNP of the base at position 7395183 of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs113262661, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs113262661 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs16957950 is a SNP of the base at position 73798267 of human chromosome 15, and is a G / C polymorphism. As will be apparent from the results of Example 1 described later, in rs16957950, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the G allele. It was done. That is, when the subject's rs16957950 has a C allele, the subject evaluates that the risk of onset is high, and when the subject does not have the C allele, the subject evaluates that the risk of onset is low.

  rs16957955 is a SNP of the base at the 7395595th position of human chromosome 15, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs16957955, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the G allele than in humans who possess the A allele. It was done. That is, when the subject's rs16957955 has a G allele, the subject evaluates that the onset risk is high, and when the subject does not have the G allele, the subject evaluates that the onset risk is low.

  rs11858423 is a SNP of the 73799226 base of human chromosome 15, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs11858423, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs11858423 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs112979086 is a SNP at the 73822918th base of human chromosome 15, and is a G / T polymorphism. As is clear from the results of Example 1 described later, in rs112979086, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the G allele. It was done. That is, when the subject's rs112979086 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs7172519 is a SNP at the 73829466th base of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs7172519, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs7172519 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs144321653 is a gene polymorphism of the 73831412th base of human chromosome 15, and is a TCCCA / T polymorphism. As will be apparent from the results of Example 1 described later, in rs144321653, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the T allele than in humans who possess the TCCCA allele. It was done. That is, when the subject's rs144321653 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs113841704 is a SNP at the 73835950th base of human chromosome 15, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs113841704, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs113841704 has an A allele, the subject is evaluated as having a high risk of onset, and when the subject has no A allele, the subject is evaluated as having a low risk of onset.

  rs150996688 is a gene polymorphism of the 73838898th base of human chromosome 15, and is an ATT / A polymorphism. As will be apparent from the results of Example 1 described later, in rs150996688, it is confirmed that the risk of onset is statistically significantly higher in humans having the A allele than in humans having the ATT allele. It was done. That is, when the subject's rs150996688 has an A allele, the subject is evaluated as having a high risk of onset, and when the subject has no A allele, the subject is evaluated as having a low risk of onset.

  rs139799391 is a SNP of the 73840521 base of human chromosome 15, and is a C / G polymorphism. As is clear from the results of Example 1 described later, in rs139799391, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the C allele. It was done. That is, when the subject's rs139799391 has a G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs143746363 is a SNP at the 73843939th base of human chromosome 15, and is a G / A polymorphism. As will be apparent from the results of Example 1 described later, in rs143746363, it is confirmed that the risk of onset is statistically significantly higher in humans having the A allele than in humans having the G allele. It was done. That is, when the subject's rs143746363 has an A allele, the subject is evaluated as having a high risk of onset, and when the subject has no A allele, the subject is evaluated as having a low risk of onset.

  rs117508212 is a SNP of the 73845184th base of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs117508212, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs117508212 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs17765936 is a SNP at the 73845990th base of human chromosome 15, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs17765936, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs17765936 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs12324361 is a SNP at the 73849834 base of human chromosome 15, and is a T / C polymorphism. As will be apparent from the results of Example 1 described later, in rs12324361, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs12324361 has a C allele, the subject is evaluated as having a high onset risk, and when the subject has no C allele, the subject is evaluated as having a low onset risk.

  rs80137767 is a SNP at the 73861444th base of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs80137767, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the T allele than in humans who possess the C allele. It was done. That is, when the subject's rs80137767 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs118076475 is a SNP at the 73867034 base of human chromosome 15, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs118076475, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs118076475 has an A allele, the subject is evaluated as having a high risk of onset, and when the subject has no A allele, the subject is evaluated as having a low risk of onset.

  rs79432474 is a SNP of the 73868026th base of human chromosome 15, and is a C / G polymorphism. As is clear from the results of Example 1 described later, in rs79432474, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the C allele. It was done. That is, when the subject's rs79432474 has the G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs144821791 is a genetic polymorphism of the 73868696th base of human chromosome 15, and is a GTCTC / G polymorphism. As is clear from the results of Example 1 described later, in rs144821791, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the GTCTC allele. It was done. That is, when the subject's rs144821791 has the G allele, the subject is evaluated as having a high onset risk, and when the subject has no G allele, the subject is evaluated as having a low onset risk.

  rs78493906 is a SNP of the 73872571 base of human chromosome 15, and is a G / A polymorphism. As will be apparent from the results of Example 1 described later, in rs78493906, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs78493906 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs111743418 is a SNP at the 73877776 base of human chromosome 15, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs111743418, it is confirmed that the risk of onset is statistically significantly higher in humans having the A allele than in humans having the G allele. It was done. That is, when the subject's rs111743418 has an A allele, the subject is evaluated as having a high onset risk, and when the subject has no A allele, the subject is evaluated as having a low onset risk.

  rs111586775 is a SNP of the 73880318th base of human chromosome 15, and is a C / G polymorphism. As is clear from the results of Example 1 described later, in rs111586775, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the C allele. It was done. That is, when the subject's rs111586775 has the G allele, the subject is evaluated as having a high onset risk, and when the subject has no G allele, the subject is evaluated as having a low onset risk.

  rs113825850 is a SNP at the 73884966 base of human chromosome 15, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs113825850, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs113825850 has an A allele, the subject is evaluated as having a high risk of onset, and when the subject has no A allele, the subject is evaluated as having a low risk of onset.

  rs16958054 is a SNP at the 73893619 base of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs16958054, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs16958054 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs76343330 is an SNP of the 73895826 base of human chromosome 15, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs76343330, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs76343330 has a G allele, the subject is evaluated as having a high onset risk, and when the subject has no G allele, the subject is evaluated as having a low onset risk.

  rs113403314 is a SNP of the 73899701 base of human chromosome 15, and is an A / C polymorphism. As is clear from the results of Example 1 described later, in rs113403314, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the A allele. It was done. That is, when the subject's rs113403314 has a C allele, the subject evaluates that the onset risk is high, and when the subject does not have the C allele, the subject evaluates that the onset risk is low.

  rs112801975 is a SNP of the 73902434th base of human chromosome 15, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs112801975, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs112801975 has a C allele, the subject is evaluated as having a high onset risk, and when the subject has no C allele, the subject is evaluated as having a low onset risk.

  rs79582718 is a SNP at the 73910290th base of human chromosome 15, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs79582718, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs79582718 has the G allele, the subject is evaluated as having a high onset risk, and when the subject has no G allele, the subject is evaluated as having a low onset risk.

  rs16958094 is a SNP at the 73915464th base of human chromosome 15, and is an A / G polymorphism. As will be apparent from the results of Example 1 described later, in rs16958094, it is confirmed that the risk of onset is statistically significantly higher in humans having the G allele than in humans having the A allele. It was done. That is, when the subject's rs16958094 has a G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs17186070 is a SNP at the 73921207th base of human chromosome 15, and is a C / G polymorphism. As is clear from the results of Example 1 described later, in rs17186070, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the C allele. It was done. That is, when the subject's rs17186070 has a G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs140051738 is a SNP at the 73923008 base of human chromosome 15, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs140051738, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the G allele than in humans who possess the A allele. It was done. That is, when the subject's rs140051738 has the G allele, the subject evaluates that the onset risk is high, and when the subject does not have the G allele, the subject evaluates that the onset risk is low.

  rs112470810 is a SNP at the 73929511 base of human chromosome 15, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs112470810, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs112470810 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs79825162 is a SNP at the 73930057 base of human chromosome 15, and is a C / A polymorphism. As is clear from the results of Example 1 described later, in rs79825162, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the C allele. It was done. That is, when the subject's rs79825162 has an A allele, the subject evaluates that the risk of onset is high, and when the subject does not have an A allele, the subject evaluates that the risk of onset is low.

  chr15: 73931269: T: TCCC is a genetic polymorphism of the 73931269th base of human chromosome 15, and is a T / TCCC polymorphism. As will be apparent from the results of Example 1 described later, in chr15: 73931269: T: TCCC, the risk of onset is statistically higher in humans having the TCCC allele than in humans having the T allele. Significantly higher. That is, if the subject's chr15: 73931269: T: TCCC has a TCCC allele, the subject is evaluated as having a high risk of onset, and if the subject has no TCCC allele, the subject is evaluated as having a low risk of onset. .

  rs200373183 is a gene polymorphism at the 73938063 base of human chromosome 15, and is an A / AAAGG polymorphism. As is clear from the results of Example 1 described later, in rs200373183, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the AAAAGG allele than in humans possessing the A allele. It was done. That is, when the subject's rs200373183 has the AAAAGG allele, the subject is evaluated as having a high risk of onset, and when the subject has no AAAGG allele, the subject is evaluated as having a low risk of onset.

  rs113301740 is a SNP of the 73947198th base of human chromosome 15, and is a C / A polymorphism. As is clear from the results of Example 1 described later, in rs113301740, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the A allele than in humans who possess the C allele. It was done. That is, when the subject's rs113301740 has an A allele, the subject evaluates that the onset risk is high, and when the subject does not have the A allele, the subject evaluates that the onset risk is low.

  rs112113314 is a SNP at the 73960695th base of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs112113314, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs112113314 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs75765821 is a SNP at the 73961212 base of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs75765821, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs75765821 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs78709247 is a SNP at the 73968759th base of human chromosome 15, and is an A / C polymorphism. As will be apparent from the results of Example 1 described later, in rs78709247, it is confirmed that the risk of onset is statistically significantly higher in humans having the C allele than in humans having the A allele. It was done. That is, when the subject's rs78709247 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs76571485 is a SNP of the 73974470th base of human chromosome 15, and is a G / A polymorphism. As is clear from the results of Example 1 described later, in rs76571485, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the A allele than in humans possessing the G allele. It was done. That is, when the subject's rs76571485 has an A allele, the subject evaluates that the onset risk is high, and when the subject does not have the A allele, the subject evaluates that the onset risk is low.

  rs76495667 is a SNP of the 73982674 base of human chromosome 15, and is a T / C polymorphism. As is clear from the results of Example 1 described later, in rs76495667, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the T allele. It was done. That is, when the subject's rs76495667 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs75219305 is a SNP at the 73984556th base of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs75219305, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs75219305 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs111283628 is a SNP of the 73984601 base of human chromosome 15, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs111283628, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the T allele than in humans possessing the C allele. It was done. That is, when the subject's rs111283628 has a T allele, the subject is evaluated as having a high risk of onset, and when the subject has no T allele, the subject is evaluated as having a low risk of onset.

  rs141245755 is a genetic polymorphism of the 73987595th base of human chromosome 15, and is a TG / T polymorphism. As is clear from the results of Example 1 described later, in rs141245755, it is confirmed that the risk of onset is statistically significantly higher in humans who have T alleles than in humans who have TG alleles. It was done. That is, when the subject's rs141245755 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs111277087 is a SNP at the 73991724th base of human chromosome 15, and is a T / G polymorphism. As will be apparent from the results of Example 1 described later, in rs111277087, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the T allele. It was done. That is, when the subject's rs111277087 has the G allele, the subject evaluates that the risk of onset is high, and when the subject does not have the G allele, the subject evaluates that the risk of onset is low.

  rs11574496 is a SNP at the 74003971 base of human chromosome 15, and is an A / G polymorphism. As is clear from the results of Example 1 described later, in rs11574496, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the G allele than in humans possessing the A allele. It was done. That is, when the subject's rs11574496 has a G allele, the subject is evaluated as having a high risk of onset, and when the subject has no G allele, the subject is evaluated as having a low risk of onset.

  rs76213482 is a SNP at the 49951988 base of human chromosome 16, and is a G / C polymorphism. As is clear from the results of Example 1 described later, in rs76213482, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the G allele. It was done. That is, when the subject's rs76213482 has the C allele, the subject is evaluated as having a high onset risk, and when the subject has no C allele, the subject is evaluated as having a low onset risk.

  rs6500265 is a SNP of the 49946670th base of human chromosome 16, and is a C / T polymorphism. As is clear from the results of Example 1 described later, in rs6500265, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the T allele than in humans who possess the C allele. It was done. That is, when the subject's rs6500265 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  rs9888871 is a SNP at the 4949941th base of human chromosome 16, and is a G / C polymorphism. As is clear from the results of Example 1 described later, in rs9888871, it is confirmed that the risk of onset is statistically significantly higher in humans possessing the C allele than in humans possessing the G allele. It was done. That is, when the subject's rs9888871 has a C allele, the subject is evaluated as having a high risk of onset, and when the subject has no C allele, the subject is evaluated as having a low risk of onset.

  rs9933632 is a SNP at the 49940758th base of human chromosome 16, and is a G / T polymorphism. As is clear from the results of Example 1 described later, in rs9933632, it is confirmed that the risk of onset is statistically significantly higher in humans who possess the T allele than in humans who possess the G allele. It was done. That is, when the subject's rs9933632 has a T allele, the subject is evaluated as having a high onset risk, and when the subject has no T allele, the subject is evaluated as having a low onset risk.

  The onset risk evaluation method of the second embodiment is the risk of onset of the first embodiment, except that one or more gene polymorphisms selected from the group consisting of the 82 gene polymorphisms are used as risk evaluation markers. It can be carried out in the same manner as the evaluation method.

  Nucleic acid derived from a subject subjected to genetic polymorphism typing includes a nucleic acid reflecting a base sequence of a region containing at least one of the 82 genetic polymorphisms in the genomic DNA of the subject (human). Just do it. Preferably, it is the genomic DNA of the subject, but it may also be an amplification product obtained by amplifying a partial region by PCR or the like using the genomic DNA as a template. The genomic DNA derived from the subject may be a nucleic acid extracted and purified from a biological sample collected from the subject, or may be a nucleic acid before purification.

  Nucleic acid molecules such as probes and primers used for typing the 82 gene polymorphisms can be designed and synthesized by a conventional method based on the base sequence information of the partial region containing each gene polymorphism of the human genome, for example. it can. For example, a nucleic acid molecule that can hybridize to a partial region containing a gene polymorphism in genomic DNA or a complementary strand thereof can be used as a nucleic acid molecule for typing the gene polymorphism. The nucleic acid molecule thus designed can be synthesized using any method well known in the art. For example, synthesis may be requested from a synthesis manufacturer, or may be synthesized independently using a commercially available synthesizer. The 82 genetic polymorphisms can be typed in the same manner as the onset risk evaluation method of the first embodiment.

  In the second embodiment, the risk of developing a subject is evaluated based on at least one typing result (ie, genotype) of the 82 genetic polymorphisms. When judging only from the typing result of one of the 82 genetic polymorphisms, each genetic polymorphism is evaluated as described above. However, the risk of onset can be evaluated with higher accuracy by evaluating a combination of typing results of a plurality of gene polymorphisms than by judging only from the typing result of one gene polymorphism. In the onset risk evaluation method of the second embodiment, the onset risk evaluation from the typing results of the 82 gene polymorphisms can be performed in the same manner as the onset risk evaluation method of the first embodiment.

  Since a more reliable evaluation result can be obtained, the risk evaluation markers used in the onset risk evaluation method of the second embodiment include rs16957893, rs12324361, rs113301740, rs6500265, rs9888871, and rs9933632, in particular. One or more SNPs selected from the group are preferred, one or more SNPs selected from the group consisting of rs16957893, rs6500265, rs9888871, and rs9933632 are more preferred, and selected from the group consisting of rs16957893, rs6500265, and rs9888871 More preferred is one or more SNPs.

  In the onset risk evaluation method of the first embodiment and the onset risk evaluation method of the second embodiment, typing for other SNPs known to have a high frequency in patients with severe drug eruption such as SJS / TEN. The risk of onset may be evaluated in consideration of the results. Examples of such SNP include SNPs described in Patent Document 1 or Patent Document 2.

  The frequency of onset of SJS / TEN with ocular complications may vary depending on the genotype of the HLA gene. Therefore, in the onset risk evaluation method of the first embodiment and the onset risk evaluation method of the second embodiment, the onset risk may be evaluated in consideration of the typing result of the HLA gene. HLA gene typing can be performed by a conventional method.

  In particular, in a subject whose HLA gene genotype is A * 02: 06, the rs16957893 genotype has a C allele, the rs6500265 genotype has a T allele, or the rs9888871 genotype is C. With alleles, the risk of developing severe drug eruption with ocular complications can be assessed with a very high odds ratio. Therefore, in the onset risk evaluation method of the second embodiment, in the typing step, one or more SNP genotypes selected from the group consisting of rs16957893, rs6500265, and rs9888871 of the subject and the gene of the HLA gene It is preferable to type the mold. The typing result in the typing process is when the genotype of rs16957893 has a C allele, the genotype of rs6500265 has a T allele, or the genotype of rs9888871 has a C allele, and the genotype of the HLA gene Is A * 02: 06, it is evaluated that the risk of developing severe drug eruption with eye complications in the subject is high.

  In the onset risk evaluation method of the first embodiment and the onset risk evaluation method of the second embodiment, the results of other biomarkers are added to the typing results of the gene polymorphisms listed as risk evaluation markers. The onset risk may be evaluated. For example, the biomarker is selected from the group consisting of interleukin-6 (IL-6), interleukin-8 (IL-8), and MCP-1 (Monocyte Chemical Protein-1) in the tear fluid of the subject. The concentration of one or more substances to be used can be mentioned. The concentration of these substances in tears increases markedly from the acute phase to the subacute phase of severe drug eruption. Therefore, by combining the typing results of the 108 SNPs or the 82 genetic polymorphisms with the result of tear concentration of biomarkers such as IL-6 at the time of onset, not only the risk of onset is evaluated, Early diagnosis is also possible.

  In SJS / TEN accompanied by ocular complications, suddenly high fever around 40 ° C. and generalized rash and erosion gradually decrease and usually disappear in about 6 to 8 weeks. This period is called the acute period. On the other hand, on the surface of the eye, inflammation may continue to the same extent as in the acute phase even after systemic findings have improved, and this period may be referred to as the subacute phase.

  A subject who is evaluated as having a high risk of onset by the onset risk evaluation method of the first embodiment and the onset risk evaluation method of the second embodiment can take preventive measures against severe drug eruption such as SJS / TEN. . In addition, subjects who are evaluated as having a high risk of onset can receive sufficient attention in advance of taking medication under the guidance of a doctor, and can start treatment immediately if a severe drug eruption occurs. it can.

(Third embodiment)
The risk assessment kit for severe drug eruption according to the third embodiment (hereinafter sometimes referred to as “onset risk assessment kit”) is a nucleic acid molecule for typing the genotype of rs16957893, and the genotype of rs12324361. A nucleic acid molecule for typing the genotype of rs113301740, a nucleic acid molecule for typing the genotype of rs6500265, a nucleic acid molecule for typing the genotype of rs9888871, and a genotype of rs9933632 Including one or more selected from the group consisting of nucleic acid molecules.

Examples of the nucleic acid molecule for typing the genotype of rs16957893 include a polynucleotide having a sequence homologous (identical) or complementary to a partial base sequence containing rs16957893 in the human genome.
Examples of the nucleic acid molecule for typing the genotype of rs12324361 include a polynucleotide having a sequence homologous (identical) or complementary to a partial base sequence containing rs12324361 in the human genome.
Examples of the nucleic acid molecule for typing the genotype of rs113301740 include a polynucleotide having a sequence homologous (identical) or complementary to a partial base sequence containing rs113301740 in the human genome.
Examples of the nucleic acid molecule for typing the rs6500265 genotype include a polynucleotide having a sequence homologous (identical) or complementary to a partial base sequence containing rs6500265 in the human genome.
Examples of the nucleic acid molecule for typing the rs9888871 genotype include a polynucleotide having a sequence homologous (identical) or complementary to a partial base sequence containing rs9888871 in the human genome.
Examples of the nucleic acid molecule for typing the rs9933632 genotype include a polynucleotide having a sequence homologous (identical) or complementary to a partial base sequence containing rs9933632 in the human genome.

  A nucleic acid molecule for typing a genotype such as rs16957893 can be generally designed in the same manner as a probe for hybridization or a primer for PCR. The base length of a nucleic acid molecule for typing a genotype such as rs16957893 is such that the base length of the region that recognizes the target SNP to be typed is a genotype specific to a single-stranded nucleic acid molecule such as cDNA containing each SNP. Any length that can be hybridized is acceptable. Specifically, the base length of the region that recognizes the SNP to be typed can be, for example, 10 to 50 bases long, preferably 10 to 30 bases long, and more preferably 15 to 30 bases long.

  By preparing nucleic acid molecules such as probes and primers used for typing the six SNPs as a kit, a risk assessment method using these as risk assessment markers can be performed more easily. The kit may include only a nucleic acid molecule for typing only one of the six SNPs, and a nucleic acid molecule for typing each of two or more of the six SNPs. May be included, and nucleic acid molecules for typing all 6 SNPs may be included. These nucleic acid molecules may be included in the onset risk assessment kit as a dry powder, may be included as a solution dissolved in water or a suitable solvent such as Tris buffer, and are fixed to the substrate. May be included.

  In addition, it is preferable that the evaluation risk evaluation kit includes reagents, instruments, and the like for extracting and purifying nucleic acid from a biological sample collected from a subject.

  Although several embodiments of the present invention have been described, these embodiments are presented by way of example and are not intended to limit the scope of the invention. These embodiments can be implemented in various other forms, and various omissions, replacements, and changes can be made without departing from the spirit of the invention. These embodiments and their modifications are included in the scope and gist of the invention, and are also included in the invention described in the claims and the equivalents thereof.

  EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated concretely, this invention is not limited to the following Example.

[Example 1]
DNA microarray equipped with SNPs with a base sequence characteristic for Japanese to search for genetic predisposition in Japanese with SJS / TEN with eye complications presumed to be caused by cold medicine GWAS was performed using an imputation by “Japonica Array (registered trademark)” and 1KJPN panel (entire genome reference panel: developed by Tohoku Medical Megabank Organization, Tohoku University). GWAS using the microarray was performed according to the manufacturer's instructions.

(sample)
The GWAS was conducted on a total of 808 Japanese people, including 117 SJS / TEN patients and 691 healthy controls with serious ocular complications presumed to be caused by cold medicine. Severe dry eye, eyelash proneness, Ryukyu adhesion, and eye sequelae such as chronic conjunctival invasion into the cornea, and severe with pseudomembranous and epithelial defects on the acute ocular surface (cornea and / or conjunctiva) Conjunctivitis was a serious ocular complication. All SJS / TEN patients targeted in this experiment were taking a cold medicine (for example, NSAIDs or a multi-component cold medicine) to improve general cold symptoms several days before the onset of the disease.

(GWAS)
All samples for genotyping passed the recommended sample quality control metric (dish QC> 0.82) for “Axiom Array”, but samples from 3 healthy controls were over-call rate (genotype determined for all SNPs) The ratio of SNPs made was less than 97%, so it was not used for the subsequent analysis. According to the QQ (Quantile-Quantile) plot of the distribution of test statistics for comparison of genotype frequencies in SJS / TEN patients and healthy controls, the inflation factor λ of all tested SNPs is 1.024, and the HLA region Excluding (human chromosome 6: 29645038..33360787), it decreased to 1.021.

  For the imputation, the clustering plots were classified using the Ps classification function in “SNP Polisher package (version 1.5.2)” (Affymetrix). SNPs assigned to “recommended” by the Ps classification were retained. SNPs with [SNP Call rate] <99.0%, [HWE p-value] <0.0001, and [minor allele frequency (MAF)] <0.5% were excluded. “SNP Call rate” means the proportion of samples that can be genotyped out of all samples typed for each SNP, and “HWE” is an abbreviation for Hardy-Weinberg equilibria. . As a previous step, first, these SNPs were analyzed with software “SHAPEIT (v2.r644)” (option: burn 10, prune 10, main 25) for estimation of haplotypes. The genotype imputation is based on an imputation program “IMPUTE2 (ver. 2.3.1) using a Japanese whole genome reference panel (1KJPN) consisting of whole genome analysis of 1070 healthy Japanese. (Option: Ne 2000, k hap 1000, k 120, burnin 15, iter 50).

  After genome-wide imputation genotyping using “Japonica Array®”, [SNP Call rate] ≧ 95%, [MAF] ≧ 1% in healthy controls for quality control of SNP, and Data cleaning was performed by setting a threshold value such that [HWE p value] ≧ 0.001. 6,714,496 SNPs that passed the quality control filter and autosomal insertions and indels were used for GWAS.

(Genotyping assay)
In GWAS, the p-value calculated by the chi-square test of allele frequency is less than 10 ^−7, which is significantly different from the onset of SJS / TEN with ocular complications presumed to have been caused by cold medicine. About the SNP with which the correlation was confirmed, the genotype of each sample was confirmed using the commercially available genotyping assay kit "TaqMan SNP genetyping assay" (Applied Biosystems). In order to verify the GWAS results, samples were added and genotypes were typed for samples of 138 Japanese SJS / TEN patients and 883 healthy controls.

(Statistical analysis)
For GWAS validation and retrial, we applied Chi-square test or Fisher exact test on 2 × 2 contingency tables for allele frequency, dominant model, and recessive model. The odds ratio (OR) and confidence interval (CI) were calculated using a reference major allele. Meta-analysis was performed by the Mantel-Henzel method. Heterogeneity between tests was performed using the Breslow Day test.

As a result of genotyping using “Japonica array (registered trademark)”, 108 SNPs having a p value calculated by chi-square test of allele frequency of 10 ⁻⁴ or less were found. The results of genotyping of these 108 SNPs are shown in Tables 1-5. In Tables 1 to 5, “Case” indicates the result of the sample of the SJS / TEN patient, and “Control” indicates the result of the sample of the healthy control. “DD”, “Dd”, and “dd” indicate the number of homo-type samples of the minor allele, the number of hetero-type samples, and the number of homo-type samples of the major allele, respectively. These 108 SNPs were significantly correlated with the onset of cold drug-related SJS / TEN with ocular complications that were presumed to have developed because of cold drugs. It is useful as a risk assessment marker for the onset of cold drug-related severe drug eruption.

As disclosed in Patent Document 2, it is known that the genotype of the HLA gene has a significant correlation with the onset of SJS / TEN accompanied by ocular complications presumed to be caused by cold medicine. It has been. In fact, even with “Japonica array (registered trademark)” genotyping, many SNPs with high p-values were present in the HLA-A region in chromosome 6. Therefore, 82 SNPs were found from SNPs in regions other than the HLA gene region by searching for SNPs having a p-value of less than 10 ⁻⁷ in the chi-square test in the allele frequency model. The results of genotyping of these 82 SNPs are shown in Tables 6-9. In Tables 6 to 9, “Case”, “Control”, “DD”, “Dd”, and “dd” are the same as those in Tables 1 to 5. These 82 SNPs are significantly correlated with the onset of SJS / TEN with ocular complications whose genotype is presumed to have been triggered by a cold drug, and thus severe drugs with ocular complications It is useful as a risk assessment marker for the development of rash.

Of these 82 SNPs, 4 had a MAF greater than 0.05, and these 4 SNPs were located on human chromosome 16. Of these four, there was strong linkage disequilibrium (LD) between rs6500265 and rs9933632, and between rs9888871 and rs76213482. The remaining 78 polymorphisms had MAF greater than 0.01 and less than 0.02, all located within a single LD block on human chromosome 15. For verification, rs16957893, rs12324361 and rs113301740 were selected from the LD block on chromosome 15, rs9888871 from one LD block on chromosome 16, and rs6500265 and rs9933632 from the remaining LD block, respectively. For verification analysis of these 6 SNPs, TaqMan assay was performed on samples derived from a total of 808 patients including 117 SJS / TEN patients and 691 healthy controls subjected to GWAS. Genome-wide significant (p <5 × 10 ⁻⁸ ) correlation was observed for three of them, rs9888871, rs6500265, and rs9933632. The results of the TaqMan assay are shown in Table 10. In the table, “Case” and “Control” are the same as those in Tables 1 to 5, and “P-value” is a Chi-square test comparing the allele frequency or genotype frequency of the SJS / TEN patient group and the healthy control group. Alternatively, it is a p-value calculated by Fisher's exact test (“*”), “OR” is an odds ratio, and “CI” means a confidence interval.

Table 11 shows the results of genotyping the samples of 138 Japanese SJS / TEN patients and 883 healthy controls in order to verify the results of the 6 SNPs. In the table, “Case”, “Control”, “P-value”, “*”, “OR”, and “CI” are the same as those in Table 10. As a result, genome-wide significant (p <5 × 10 ⁻⁸ ) correlation was observed in four of the six SNPs, rs9933632, rs6500265, rs9888871, and rs16957893.

(Analysis of interaction with HLA gene genotype)
Next, rs16957893 (rs12324361 and rs11330174 are present in the same LD block), rs6500265 (rs9933632 is present in the same LD block), and rs9888871, and HLA-A * 02: 06 The samples obtained from GWAS were examined using samples from which HLA gene genotype information was obtained (samples derived from 117 SJS / TEN patients and 628 healthy controls). The results are shown in Tables 12-13. In the table, “Case”, “Control”, “P-value”, “*”, “OR”, and “CI” are the same as those in Table 10.

  As a result, the C allele that is a high-risk allele of rs16957893, the T allele that is a high-risk allele of rs6500265, and the C allele that is a high-risk allele of rs9888871 and HLA-A * 02: 06 have a high synergistic effect. In particular, in the high risk allele of rs16957893, the odds ratio was 110 times when the HLA genotype (A * 02: 06 was used in combination) compared to the case where only rs16957893 was used as the risk evaluation marker.

Claims (9)

Using nucleic acid derived from the subject, the subject's rs16824605, rs12407492, rs614350, rs1418929, rs1339697, rs79798614, rs871141, rs76217877, rs75019707, rs17019101, rs78929670, rs12622778, rs13383303, rs13010016, rs4679631, rs1016284, 274 , Rs76130979, rs13319930, rs2920193, rs13434731, rs117369903, rs77885120, rs13151271, rs17516386, rs59783747, rs1801075, rs74763702, rs2731849, rs75814077, rs76701269, rs513165, rs17136947, rs76533382, rs75249189, rs865838rs Rs73667472, rs2435909, rs6986203, rs73339061, rs7822062, rs59134671, rs78226500, rs10829414, rs11016267, rs7108440, rs7950561, rs11038410, rs12146638, rs117732390, rs74539361, rs7479018, rs7943614, rs190043383, rs4761907 , Rs16942579, rs12594972, rs118152764, rs16957918, rs73 444105, rs75765821, rs36012474, rs76130486, rs6497035, rs9933632, rs9944315, rs117496909, rs11648177, rs79852170, rs78054468, rs276943, rs5447, rs6041265, rs2031149, rs62212413, rs4811310, rs2426427,
One or more single nucleotide polymorphisms (SN) selected from the group consisting of rs4140429, rs6068173, rs6068252, rs4811369, rs6068271, rs7450590, rs12661585, rs12663784, rs4518503, rs4323313, rs2294837, rs872307, rs76132714, rs78537991, rs59567566, and rs78605884 A typing process for typing the genotype of
Based on the typing result obtained by the typing step, an evaluation step for evaluating the risk of developing severe drug eruption with eye complications of the subject,
A method for evaluating the risk of developing a severe drug eruption with ocular complications. The typing result in the typing process is
If the genotype of rs16824605 has a G allele,
If the genotype of rs12407492 has a G allele,
If the genotype of rs614350 has a C allele,
If the genotype of rs1418929 has an A allele,
If the genotype of rs1339697 has a T allele,
If the genotype of rs79798614 has a G allele,
If the genotype of rs871141 has a C allele,
If the genotype of rs76217877 has a C allele,
If the genotype of rs75019707 has an A allele,
If the genotype of rs17019101 has a C allele,
If the rs78929670 genotype has an A allele,
If the genotype of rs12622778 has a C allele,
If the genotype of rs13383303 has an A allele,
If the genotype of rs13010016 has a T allele,
If the genotype of rs4679631 has a T allele,
If the genotype of rs1016284 has a G allele,
If the genotype of rs55742142 has a C allele,
If the genotype of rs62274115 has a T allele,
If the rs34684758 genotype has an A allele,
If the genotype of rs56271032 has a G allele,
If the genotype of rs76130979 has a T allele,
If the genotype of rs13319930 has a G allele,
If the genotype of rs2920193 has a G allele,
If the genotype of rs13434731 has a T allele,
If the genotype of rs117369903 has an A allele,
If the genotype of rs77885120 has a G allele,
If the genotype of rs13151271 has a C allele,
If the genotype of rs17516386 has a T allele,
If the genotype of rs59783747 has a G allele,
If the genotype of rs1801075 has a C allele,
If the genotype of rs74763702 has a C allele,
If the genotype of rs2731849 has an A allele,
If the rs75814077 genotype has an A allele,
If the genotype of rs76701269 has a T allele,
If the genotype of rs513165 has a C allele,
If the genotype of rs17136947 has an A allele,
If the genotype of rs76533382 has a C allele,
When the genotype of rs75249189 has an A allele,
If the genotype of rs876038 has a C allele,
If the genotype of rs10259658 has a T allele,
If the rs12537523 genotype has an A allele,
If the genotype of rs11136457 has a G allele,
If the genotype of rs62504065 has a T allele,
If the genotype of rs2120482 has a T allele,
If the genotype of rs71510630 has a G allele,
If the genotype of rs73667472 has a C allele,
If the genotype of rs2435909 has an A allele,
If the genotype of rs6986203 has a C allele,
If the genotype of rs73339061 has a G allele,
When the genotype of rs7822062 has a T allele,
If the genotype of rs59134671 has a C allele,
If the genotype of rs78226500 has an A allele,
If the genotype of rs10829414 has a G allele,
If the genotype of rs11016267 has a G allele,
If the genotype of rs7108440 has a G allele,
If the rs7950561 genotype has an A allele,
If the genotype of rs11038410 has a G allele,
If the genotype of rs12146638 has a T allele,
If the genotype of rs117732390 has a T allele,
If the genotype of rs74539361 has an A allele,
If the rs7479018 genotype has a T allele,
If the genotype of rs7943614 has a T allele,
If the genotype of rs190043383 has a G allele,
If the genotype of rs4761641 has a C allele,
If the genotype of rs117619073 has an A allele,
If the genotype of rs58895553 has a T allele,
If the genotype of rs1539131 has an A allele,
If the genotype of rs7148580 has a T allele,
If the genotype of rs1567620 has a T allele,
If the genotype of rs2100432 has an A allele,
If the genotype of rs16942579 has a G allele,
If the genotype of rs12594972 has a C allele,
If the genotype of rs118152764 has a G allele,
If the rs16957918 genotype has an A allele,
If the genotype of rs73444105 has a G allele,
If the genotype of rs75765821 has a T allele,
If the genotype of rs36012474 has a C allele,
If the genotype of rs76130486 has a T allele,
If the genotype of rs6497035 has a T allele,
If the genotype of rs9933632 has a T allele,
If the rs9944315 genotype has an A allele,
If the genotype of rs117496909 has an A allele,
If the genotype of rs11648177 has a G allele,
If the genotype of rs79852170 has a T allele,
If the rs78054468 genotype has an A allele,
If the genotype of rs276943 has a T allele,
If the genotype of rs5447 has a C allele,
If the genotype of rs6041265 has an A allele,
If the genotype of rs2031149 has a G allele,
If the genotype of rs62212413 has a T allele,
If the genotype of rs4811310 has a T allele,
If the genotype of rs2426427 has an A allele,
If the genotype of rs4140429 has an A allele,
If the genotype of rs6068173 has a C allele,
If the genotype of rs6068252 has a T allele,
If the genotype of rs4811369 has a T allele,
If the genotype of rs6068271 has a T allele,
If the genotype of rs7450590 has a T allele,
If the genotype of rs12661585 has a G allele,
When the genotype of rs12663784 has an A allele,
If the genotype of rs4518503 has a T allele,
If the genotype of rs4323313 has an A allele,
If the genotype of rs2294837 has a T allele,
If the genotype of rs872307 has a C allele,
If the genotype of rs76132714 has an A allele,
If the genotype of rs78537991 has a C allele,
the genotype of rs59567566 has a G allele, or
If the rs78605884 genotype has a C allele,
The method for evaluating the risk of developing a serious drug eruption with eye complications according to claim 1, wherein in the evaluation step, it is evaluated that the risk of developing a serious drug rash with eye complications of the subject is high. Using nucleic acid derived from the subject, rs16957958, rs61615643, rs76040382, rs143542085, rs73442102, rs16957893, rs59339222, rs73442036, rs16957901, rs16957905, rs73442046, rs28817075, rs2415149, rs150925273, rs58566848, rs73442061, rs58354, rs73442061, rs58354, rs73442061, rs58354121 Rs16957928, rs111709993, rs142602354, rs112265165, rs74022999, rs74023000, rs111550497, rs113677323, rs73444107, rs73444110, rs16957940, rs112460473, rs113702379, rs113262661, rs16957950, rs16957955, rs11858423, rs113979086, rs717 , Rs17765936, rs12324361, rs80137767, rs80180767, rs118076475, rs79432474, rs144821791, rs78493906, rs111743418, rs111586775, rs113825850, rs16958054, rs76343330, rs113403314, rs112801975, rs79582718, rs16958094, rs17186070, rs140051738 , Rs113301740, rs112113314, rs75765 821, rs78709247, rs76571485, rs76495667, rs75219305, rs111283628, rs141245755, rs111277087, rs11574496, rs76213482, rs6500265, rs9888871, and rs9933632
Typing a genotype of one or more gene polymorphisms selected from the group consisting of:
Based on the typing result obtained by the typing step, an evaluation step for evaluating the risk of developing severe drug eruption with eye complications of the subject,
A method for evaluating the risk of developing a severe drug eruption with ocular complications. The typing result in the typing process is
If the genotype of rs16957958 has a C allele,
If the genotype of rs61615643 has a T allele,
If the genotype of rs76040382 has an A allele,
If the genotype of rs143542085 has a T allele,
If the genotype of rs73442102 has a G allele,
If the genotype of rs16957893 has a C allele,
If the genotype of rs59339222 has a G allele,
If the genotype of rs73442036 has a T allele,
If the genotype of rs16957901 has a T allele,
If the genotype of rs16957905 has a T allele,
If the rs73442046 genotype has a T allele,
If the rs28817075 genotype has an A allele,
If the genotype of rs2415149 has an A allele,
If the genotype of rs150925273 has a T allele,
If the genotype of rs58566848 has a T allele,
If the genotype of rs73442061 has a T allele,
If the genotype of rs58354121 has a C allele,
If the genotype of rs200559765 has a T allele,
If the rs16957918 genotype has an A allele,
If the genotype of rs73442077 has a G allele,
If the genotype of rs16957928 has an A allele,
If the genotype of rs111709993 has a T allele,
If the genotype of rs142602354 has a T allele,
If the genotype of rs112265165 has a C allele,
If the rs74022999 genotype has an A allele,
If the genotype of rs74023000 has a T allele,
If the genotype of rs111550497 has a C allele,
If the genotype of rs113677323 has a C allele,
If the genotype of rs73444107 has a G allele,
If the rs73444110 genotype has an A allele,
If the genotype of rs16957940 has a C allele,
If the genotype of rs112460473 has an A allele,
If the genotype of rs113702379 has an A allele,
If the genotype of rs113262661 has a T allele,
If the genotype of rs16957950 has a C allele,
If the genotype of rs16957955 has a G allele,
If the genotype of rs11858423 has an A allele,
If the genotype of rs112979086 has a T allele,
If the genotype of rs7172519 has a T allele,
If the genotype of rs144321653 has a T allele,
If the genotype of rs113841704 has an A allele,
If the genotype of rs150996688 has an A allele,
If the genotype of rs139799391 has a G allele,
If the genotype of rs143746363 has an A allele,
If the genotype of rs117508212 has a T allele,
When the genotype of rs17765936 has a C allele,
If the genotype of rs12324361 has a C allele,
If the genotype of rs80137767 has a T allele,
If the genotype of rs118076475 has an A allele,
If the genotype of rs79432474 has a G allele,
If the genotype of rs144821791 has a G allele,
If the genotype of rs78493906 has an A allele,
If the genotype of rs111743418 has an A allele,
If the genotype of rs111586775 has a G allele,
When the genotype of rs113825850 has an A allele,
If the genotype of rs16958054 has a T allele,
If the genotype of rs76343330 has a G allele,
If the genotype of rs113403314 has a C allele,
If the genotype of rs112801975 has a C allele,
If the genotype of rs79582718 has a G allele,
If the genotype of rs16958094 has a G allele,
If the genotype of rs17186070 has a G allele,
If the genotype of rs140051738 has a G allele,
If the genotype of rs112470810 has a C allele,
When the genotype of rs79825162 has an A allele,
chr15: 73931269: If the T: TCCC genotype has a TCCC allele,
If the genotype of rs200373183 has an AAAGG allele,
If the genotype of rs113301740 has an A allele,
If the genotype of rs112113314 has a T allele,
If the genotype of rs75765821 has a T allele,
If the genotype of rs78709247 has a C allele,
If the rs76571485 genotype has an A allele,
When the genotype of rs76495667 has a C allele,
If the genotype of rs75219305 has a T allele,
If the genotype of rs111283628 has a T allele,
If the genotype of rs141245755 has a T allele,
If the genotype of rs111277087 has a G allele,
If the genotype of rs11574496 has a G allele,
If the genotype of rs76213482 has a C allele,
If the genotype of rs6500265 has a T allele,
the genotype of rs9888871 has a C allele, or
When the genotype of rs9933632 has a T allele,
The evaluation method of the onset risk of severe drug eruption with eye complications according to claim 3, wherein in the evaluation step, it is evaluated that the onset risk of severe drug eruption with eye complication of the subject is high.   The severe complication with ocular complications according to claim 3 or 4, wherein in the typing step, one or more SNP genotypes selected from the group consisting of rs16957893, rs12324361, rs113301740, rs6500265, rs9888871, and rs9933632 are typed. A method for evaluating the risk of developing drug eruptions. In the typing step, one or more SNP genotypes selected from the group consisting of rs16957893, rs6500265, and rs9888871 of the subject and a genotype of the HLA gene are typed,
The typing result in the typing step is when the genotype of rs16957893 has a C allele, the genotype of rs6500265 has a T allele, or the genotype of rs9888871 has a C allele, and the genotype of the HLA gene The severe drug eruption with ocular complications according to claim 3, wherein the evaluation step evaluates that the risk of developing severe drug eruption with ocular complications is high in the evaluation step when A * 02: 06 Of assessing the risk of developing the disease.   The evaluation method of the onset risk of the severe drug eruption with an eye complication as described in any one of Claims 1-6 whose said severe drug eruption is a cold medicine related severe drug eruption.   Nucleic acid molecule for typing genotype of rs16957893, nucleic acid molecule for typing genotype of rs12324361, nucleic acid molecule for typing genotype of rs113301740, nucleic acid molecule for typing genotype of rs6500265, of rs9888871 A kit for evaluating the risk of developing severe drug eruption, comprising one or more selected from the group consisting of a nucleic acid molecule for typing a genotype and a nucleic acid molecule for typing a genotype of rs9933632.   The evaluation kit for risk of developing severe drug eruption according to claim 8, wherein the nucleic acid molecule is immobilized on a substrate.