title: Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population.
abstract: An anticonvulsant, carbamazepine (CBZ), is known to show incidences of cutaneous adverse drug reactions (cADRs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS). To identify a gene(s) susceptible to CBZ-induced cADRs, we conducted a genome-wide association study (GWAS) in 53 subjects with the CBZ-induced cADRs, including SJS, TEN and DIHS, and 882 subjects of a general population in Japan. Among the single nucleotide polymorphisms (SNPs) analyzed in the GWAS, 12 SNPs showed significant association with CBZ-induced cADRs, and rs1633021 showed the smallest P-value for association with CBZ-induced cADRs (P = 1.18 × 10⁻¹³). These SNPs were located within a 430 kb linkage disequilibrium block on chromosome 6p21.33, including the HLA-A locus. Thus, we genotyped the individual HLA-A alleles in 61 cases and 376 patients who showed no cADRs by administration of CBZ (CBZ-tolerant controls) and found that HLA-A*3101 was present in 60.7% (37/61) of the patients with CBZ-induced cADRs, but in only 12.5% (47/376) of the CBZ-tolerant controls (odds ratio = 10.8, 95% confidence interval 5.9-19.6, P = 3.64 × 10⁻¹⁵), implying that this allele has the 60.7% sensitivity and 87.5% specificity when we apply HLA-A*3101 as a risk predictor for CBZ-induced cADRs. Although DIHS is clinically distinguished from SJS and TEN, our data presented here have indicated that they share a common genetic factor as well as a common pathophysiological mechanism. Our findings should provide useful information for making a decision of individualized medication of anticonvulsants.
authors.affiliation: Research Group for Pharmacogenomics, RIKEN Center for Genomic Medicine, Yokohama 230-0045, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ozeki
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.forename: Amara
authors.initials: A
authors.lastname: Yowang
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shirakata
authors.forename: Zenro
authors.initials: Z
authors.lastname: Ikezawa
authors.forename: Masafumi
authors.initials: M
authors.lastname: Iijima
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shiohara
authors.forename: Koji
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000927:Anticonvulsants / Q000009:adverse effects*; D044466:Asian People / Q000235:genetics*; D002220:Carbamazepine / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000209:etiology; D055106:Genome-Wide Association Study; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics*; D006801:Humans; D007223:Infant; D007564:Japan; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D015234:HLA-A Antigens; C506273:HLA-A*31:01 antigen; D002220:Carbamazepine