Journal
NATURE GENETICS
Volume 46, Issue 10, Pages 1131-1134Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3093
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Funding
- International Serious Adverse Events Consortium (iSAEC)
- Crohn's and Colitis UK
- Wellcome Trust Institutional Strategic Support Award [WT097835MF]
- Academy of Medical Sciences (AMS) [AMS-SGCL9-Lee] Funding Source: researchfish
- Chief Scientist Office [ETM/75, CZB/4/540, ETM/137] Funding Source: researchfish
- Crohn's and Colitis UK [M14-1, M11-2] Funding Source: researchfish
- Medical Research Council [MC_UU_12010/7, G0700545, G0800675, G0600329] Funding Source: researchfish
- National Institute for Health Research [ACF-2014-23-002, NIHR-RP-R3-12-026] Funding Source: researchfish
- MRC [MC_UU_12010/7, G0700545, G0600329, G0800675] Funding Source: UKRI
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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 H LA 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.
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