HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans

N Engl J Med. 2011 Mar 24;364(12):1134-43. doi: 10.1056/NEJMoa1013297.

Abstract

Background: Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations.

Methods: We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions.

Results: The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18).

Conclusions: The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticonvulsants / adverse effects*
  • Anticonvulsants / therapeutic use
  • Carbamazepine / adverse effects*
  • Carbamazepine / therapeutic use
  • Drug Hypersensitivity / genetics*
  • European Continental Ancestry Group / genetics*
  • Exanthema / chemically induced
  • Exanthema / genetics
  • Genome-Wide Association Study
  • Genotype
  • HLA-A Antigens / genetics*
  • Histocompatibility Testing
  • Humans
  • Polymorphism, Single Nucleotide
  • Stevens-Johnson Syndrome / chemically induced
  • Stevens-Johnson Syndrome / genetics

Substances

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