HLA-A★3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans

By M. McCormack, A. Alfirevic, Stephane Bourgeois, J. Farrell, Dalia Kasperavičiūtė, M. Carrington, G. Sills, T. Marson, Xiaoming Jia, P. D. Bakker and 20 more. New England Journal of Medicine, 2011

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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 = 3.5×10−8). 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.)

Subfields: Dermatology, Pharmacology, Toxicology

View Paper: https://www.semanticscholar.org/paper/45845640fe3795bfa4feb78c3bd151f687fd2007

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Citations in the corpus

International Consensus on drug allergy (2014, background): “Internal organs can be affected either alone or with cutaneous symptoms (HSS/ DRESS/DiHS, vasculitis, SJS/TEN) and include hepatitis, renal failure, pneumonitis, anemia, neutropenia, and thrombocytopenia.”
The consequences of refractory epilepsy and its treatment. (2014, background): “For example, carbamazepine hypersensitivity may be predicted by the presence of the HLA-B*1502 allele in Han Chinese [210], and by that of the HLA-A*3101 allele in Caucasians [211].”
Imputing Amino Acid Polymorphisms in Human Leukocyte Antigens (2013, background): “We and others have previously demonstrated the potential of HLA imputation for a wide range of phenotypes including host control of HIV-1 replication [17,26], rheumatoid arthritis [27], ulcerative colitis [28], primary biliary cirrhosis [29], psoriasis [30], ankylosing spondylitis [31], multiple scl”