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

  1. Author:
    McCormack, M.
    Alfirevic, A.
    Bourgeois, S.
    Farrell, J. J.
    Kasperaviciute, D.
    Carrington, M.
    Sills, G. J.
    Marson, T.
    Jia, X. M.
    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.
    Pirmohamed, M.

  2. Author Address

    [Alfirevic, Ana] Univ Liverpool, Wolfson Ctr Personalised Med, Dept Mol & Clin Pharmacol, Inst Translat Med, Liverpool L69 3GL, Merseyside, England. [McCormack, Mark; Alhusaini, Saud; Delanty, Norman; Cavalleri, Gianpiero L.] Royal Coll Surgeons Ireland, Dublin 2, Ireland. [O'Connor, Gerard D.; Chaila, Elijah; Delanty, Norman] Beaumont Hosp, Div Neurol, Dublin 9, Ireland. [Marson, Tony] Walton Ctr Neurol, Liverpool, Merseyside, England. [Bourgeois, Stephane; Deloukas, Panos] Wellcome Trust Sanger Inst, Hinxton, England. [Chinthapalli, Krishna; Sisodiya, Sanjay M.] Natl Soc Epilepsy, Gerrards Cross, Bucks, England. [Farrell, John J.] Boston Univ, Dept Med, Boston, MA 02215 USA. [Carrington, Mary] Harvard Univ, Massachusetts Gen Hosp, MIT, Sch Med,Ragon Inst, Boston, MA USA. [Jia, Xiaoming] Harvard Univ, Sch Med, Harvard MIT Div Hlth Sci & Technol, Boston, MA 02115 USA. [de Bakker, Paul I. W.] Harvard Univ, Brigham & Womens Hosp, Div Genet, Dept Med,Med Sch, Boston, MA 02115 USA. [Kasperaviciute, Dalia; Chinthapalli, Krishna; Sisodiya, Sanjay M.] UCL, Dept Clin & Expt Epilepsy, Inst Neurol, London, England. [Molokhia, Mariam] Kings Coll London, Dept Primary Care & Publ Hlth Sci, Div Hlth & Social Care Res, London WC2R 2LS, England. [Johnson, Michael R.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Ctr Neurosci, London, England. [Carrington, Mary] NCI, Canc & Inflammat Program, Lab Expt Immunol, SAIC Frederick, Frederick, MD 21701 USA. [de Bakker, Paul I. W.] Harvard & MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [de Bakker, Paul I. W.] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr, Dept Med Genet, Div Biomed Genet, Utrecht, Netherlands. [Shianna, Kevin V.; Heinzen, Erin L.; Walley, Nicole; Goldstein, David B.] Duke Univ, Sch Med, Ctr Human Genome Variat, Durham, NC USA. [Radtke, Rodney A.] Duke Univ, Sch Med, Dept Med Neurol, Durham, NC USA. [Pandolfo, Massimo; Depondt, Chantal] Univ Libre Bruxelles, Dept Neurol, Hop Erasme, Brussels, Belgium. [Pichler, Werner] Univ Bern, Dept Rheumatol Clin Immunol & Allergol, Bern, Switzerland.;Alfirevic, A, Univ Liverpool, Wolfson Ctr Personalised Med, Dept Mol & Clin Pharmacol, Inst Translat Med, Block A,Waterhouse Bldgs,1-5 Brownlow St, Liverpool L69 3GL, Merseyside, England.;ana.alfirevic@liv.ac.uk
    1. Year: 2011
    2. Date: Mar
  2. Journal: New England Journal of Medicine
    1. 364
    2. 12
    3. Pages: 1134-1143
  4. Type of Article: Article
  5. ISSN: 0028-4793
  1. 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 = 3.5x10(-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%.

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External Sources

  1. View record in Web of Science®
  2. WOS: 000288701100008

Library Notes

  1. Fiscal Year: FY2010-2011
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