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

Mark McCormack, Ana Alfirevic, Stephane Bourgeois, John J. Farrell, Dalia Kasperaviciute, Mary Carrington, Graeme J. Sills, Tony Marson, Xiaoming Jia, Paul I. W. de Bakker, Krishna Chinthapalli, Mariam Molokhia, Michael R. Johnson, Gerard D. O'Connor, Elijah Chaila, Saud Alhusaini, Kevin V. Shianna, Rodney A. Radtke, Erin L. Heinzen, Nicole WalleyMassimo Pandolfo, Werner Pichler, B. Kevin Park, Chantal Depondt, Sanjay M. Sisodiya, David B. Goldstein, Panos Deloukas, Norman Delanty, Gianpiero L. Cavalleri, Munir Pirmohamed

Research output: Contribution to journalArticlepeer-review

769 Citations (Scopus)


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%.
Original languageEnglish
Pages (from-to)1134-1143
Number of pages10
JournalNew England Journal of Medicine
Issue number12
Publication statusPublished - 24 Mar 2011


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