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

Hum Mol Genet. 2011 Mar 1;20(5):1034-41. doi: 10.1093/hmg/ddq537. Epub 2010 Dec 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Anticonvulsants / adverse effects*
  • Asian People / genetics*
  • Carbamazepine / adverse effects*
  • Child
  • Child, Preschool
  • Cohort Studies
  • Drug-Related Side Effects and Adverse Reactions / etiology
  • Drug-Related Side Effects and Adverse Reactions / genetics*
  • Female
  • Genetic Predisposition to Disease* / etiology
  • Genome-Wide Association Study*
  • Genotype
  • HLA-A Antigens / genetics*
  • Humans
  • Infant
  • Japan
  • Male
  • Middle Aged
  • Young Adult

Substances

  • Anticonvulsants
  • HLA-A Antigens
  • HLA-A*31:01 antigen
  • Carbamazepine