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HLA-A*3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans.

par McCormack, M;Alfirevic, A;Bourgeois, Stefan;Farrell, JF;Kasperavičiūtė, Dalia;Carrington, Mark;Sills, Gj;Marson, T;Jia, X;de Bakker, PIW;Chinthapalli, K;Molokhia, M;Johnson, MR;O’Connor, GD;Chaila, E;Alhusaini, Saud;Shianna, KV;Radtke, RA;Heinzen, Erin L;Walley, N;Pandolfo, Massimo ;Pichler, W;Park, BK;Depondt, Chantal ;Sisodiya, Sanjay M;Goldstein, David B;Deloukas, P;Delanty, Norman;Cavalleri, Gianpiero L;Pirmohamed, M; [et al.]
Référence The New England journal of medicine, 364, 12, page (1134-1143)
Publication Publié, 2011-03-24

Article révisé par les pairs

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Résumé :

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%. Copyright © 2011 Massachusetts Medical Society.