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    HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants

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    URI
    http://hdl.handle.net/11287/593811
    Author
    Heap, Graham A.
    Weedon, M. N.
    Bewshea, Claire M.
    Singh, A.
    Chen, M.
    Satchwell, J. B.
    Vivian, J. P.
    So, K.
    Dubois, P. C.
    Andrews, J. M.
    Annese, V.
    Bampton, P.
    Barnardo, M.
    Bell, S.
    Cole, A.
    Connor, S. J.
    Creed, T.
    Cummings, F. R.
    D'Amato, M.
    Daneshmend, T. K.
    Fedorak, R. N.
    Florin, T. H.
    Gaya, D. R.
    Greig, E.
    Halfvarson, J.
    Hart, Anthony
    Irving, P. M.
    Jones, G.
    Karban, A.
    Lawrance, I. C.
    Lee, J. C.
    Lees, C.
    Lev-Tzion, R.
    Lindsay, J. O.
    Mansfield, J.
    Mawdsley, J.
    Mazhar, Z.
    Parkes, M.
    Parnell, K.
    Orchard, T. R.
    Radford-Smith, G.
    Russell, R. K.
    Reffitt, D.
    Satsangi, J.
    Silverberg, M. S.
    Sturniolo, G. C.
    Tremelling, M.
    Tsianos, E. V.
    van Heel, D. A.
    Walsh, A.
    Watermeyer, G.
    Weersma, R. K.
    Zeissig, S.
    Rossjohn, J.
    Holden, A. L.
    International Serious Adverse Events, Consortium
    I. B. D. Pharmacogenetics Study Group
    Ahmad, Tariq
    Date
    2014-10-01
    Journal
    Nature genetics
    Type
    Journal Article
    Multicenter Study
    Research Support, Non-U.S. Gov't
    Publisher
    Nature
    DOI
    10.1038/ng.3093
    Metadata
    Show full item record
    Abstract
    Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 x 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.
    Citation
    Nat Genet. 2014 Oct;46(10):1131-4.
    Publisher URL
    http://dx.doi.org/10.1038/ng.3093
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