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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2011
Author McCormack Mark, Alfirevic Ana, Bourgeois Stephane, Farrell John J, Kasperavičiūtė Dalia, Carrington Mary, Sills Graeme J, Marson Tony, Jia Xiaoming, de Bakker Paul I W, Chinthapalli Krishna, Molokhia Mariam, Johnson Michael R, O'Connor Gerard D, Chaila Elijah, Alhusaini Saud, Shianna Kevin V, Radtke Rodney A, Heinzen Erin L, Walley Nicole, Pandolfo Massimo, Pichler Werner, Park B Kevin, Depondt Chantal, Sisodiya Sanjay M,
Project Investigating the primary immune response against drugs in humans
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Original article (peer-reviewed)

Journal The New England journal of medicine
Volume (Issue) 364(12)
Page(s) 1134 - 43
Title of proceedings The New England journal of medicine
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.).
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