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.

Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury

“…To stimulate a T-cell response the drug must bind to human leukocyte antigen (HLA) and in some way crosslink specific T-cell receptors. Recently, a number of cutaneous drug reactions have been strongly associated with expression of HLA alleles (e.g., abacavir hypersensitivity [HLA-B*57:01], 2 carbamazepine hypersensitivity in Caucasians, and Japanese [HLA-A*31:01], 3,4 carbamazepine-induced Stevens Johnson syndrome in Han Chinese [HLA-B*15:02]), 5 which implies a direct/indirect effect of the gene product on the disease. For abacavir and carbamazepine, it has been possible to relate the genetic association to the mechanism of disease by characterizing drug-specific CD8þ T-cell responses in volunteers expressing HLA-B*57:01 and B*15:02, respectively.…”

Genetic and immune predictors for hypersensitivity syndrome to antiepileptic drugs

“…HLA-A*3101 was recently associated with CBZ-HSR, CBZ-maculopapular exanthema and CBZ-SJS/TEN in North European Caucasians, 77 while HLA-B*1511 is associated with CBZ-SJS/TEN, 78 and HLA-A*3101 with CBZ-cutaneous ADRs in Japanese. 79 HLA-B*1502 was associated with CBZ-induced SJS/TEN, but not with CBZ-induced mild maculopapular eruptions in central China. 80 HLA-B*1502 was a risk factor for ox-CBZ-induced mild maculopapular eruptions, 81 ox-CBZ-SJS/TEN and PHY-SJS/TEN.…”

Genetic Biomarkers in Epilepsy

“…In the European population, an association of HLA-A*3101 was found for all hypersensitivity syndromes with CBZ treatment [95], but not with LTG or PHT [96]. The HLA-A*3101 allele was also identified in the Japanese population as risk factor for CBZ-induced cutaneous adverse drug reactions [97].…”