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

McCormack, M. et al. (2011) HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. New England Journal of Medicine, 364(12), pp. 1134-1143. (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.)

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sills, Dr Graeme
• Authors: McCormack, M., Alfirevic, A., Bourgeois, S., Farrell, J. J., Kasperavičiūtė, D., Carrington, M., Sills, G. J., Marson, T., Jia, X., de Bakker, P. I.W., Chinthapalli, K., Molokhia, M., Johnson, M. R., O'Connor, G. D., Chaila, E., Alhusaini, S., Shianna, K. V., Radtke, R. A., Heinzen, E. L., Walley, N., Pandolfo, M., Pichler, W., Park, B. K., Depondt, C., Sisodiya, S. M., Goldstein, D. B., Deloukas, P., Delanty, N., Cavalleri, G. L., and Pirmohamed, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Life Sciences
• Journal Name: New England Journal of Medicine
• Publisher: Massachusetts Medical Society
• ISSN: 0028-4793
• ISSN (Online): 1533-4406
• Copyright Holders: Copyright © 2011 assachusetts Medical Society
• First Published: First published in New England Journal of Medicine 364(12):1134-1143
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher