Journal
NEW ENGLAND JOURNAL OF MEDICINE
Volume 364, Issue 12, Pages 1134-1143Publisher
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1013297
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Funding
- U.K. Department of Health
- Department of Health
- National Health Service Chair of Pharmacogenetics
- Medical Research Council Centre for Drug Safety Science
- Wolfson Foundation
- Wellcome Trust Sanger Institute
- National Institute for Health Research
- Medical Research Council [G0400126]
- Wellcome Trust [084730]
- University College London Hospitals Charity
- Clinical Research and Development Committee [F136]
- National Institute for Health Research [08-08-SCC]
- Brainwave-the Irish Epilepsy Association [2009/001]
- Medical Research Charities Group of Ireland
- Health Research Board
- National Society for Epilepsy
- Fonds National de la Recherche Scientifique
- Fonds Erasme pour la Recherche Medicale
- Universite Libre de Bruxelles (Belgium)
- Health Research Board of Ireland
- Department of Health National Institute for Health Research Biomedical Research Centres
- National Cancer Institute [HHS-N261200800001E]
- National Cancer Institute, National Institutes of Health
- Medical Research Council [G0400126, G0700654B] Funding Source: researchfish
- MRC [G0400126] Funding Source: UKRI
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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 = 3.5x10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLAA*3101 allele (P = 1.1x10(-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%.
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