Journal article
HLA-DQA1–HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants
GA Heap, MN Weedon, CM Bewshea, A Singh, M Chen, JB Satchwell, JP Vivian, K So, PC Dubois, JM Andrews, V Annese, P Bampton, M Barnardo, S Bell, A Cole, SJ Connor, T Creed, FR Cummings, M D'Amato, TK Daneshmend Show all
Nature Genetics | Published : 2014
DOI: 10.1038/ng.3093
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 × 10 â '16). We replicated..
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Awarded by Medical Research Council
Funding Acknowledgements
The International Serious Adverse Events Consortium (iSAEC) funded the sample collection and genotyping. The UK National Institute for Health Research (NIHR) provided research nurse support to facilitate recruitment at all UK research sites. We thank Crohn's and Colitis UK for funding support and publicizing this study to its members. A Wellcome Trust Institutional Strategic Support Award (WT097835MF) generously supported the work in this study. Genotyping was undertaken at the Broad Institute, Cambridge, Massachusetts, USA. We thank all the clinicians who assisted with sample collection as part of the IBD Pharmacogenetics Study Group (listed in the Supplementary Note) and the International IBD Genetics Consortium, as well as S. Marriott for her assistance during the trial initiation. We acknowledge The International Serious Adverse Events Scientific Management Committee members (listed in the Supplementary Note), T Frayling, S. Lin and K. Hunt for kindly providing comments on the draft manuscript, as well as C. Heard and M. Parkinson for their ongoing administrative support to the study. We also thank all the patients for their time and participation.