Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population

TLDR

Carbamazepine is associated with cutaneous adverse drug reactions such as Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug‑induced hypersensitivity syndrome. The study aimed to identify genetic susceptibility to carbamazepine‑induced cutaneous adverse drug reactions. A genome‑wide association study was performed on 53 affected individuals and 882 general‑population controls in Japan. The GWAS identified 12 SNPs in a 430‑kb linkage‑disequilibrium block on chromosome 6p21.33, with rs1633021 showing the strongest association (P = 1.18 × 10⁻¹³); HLA‑A*3101 was present in 60.7 % of carbamazepine‑induced cADR cases versus 12.5 % of tolerant controls (OR = 10.8, 95 % CI 5.9–19.6), indicating a shared genetic risk for SJS, TEN, and DIHS and providing a basis for personalized anticonvulsant therapy.

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.