| Literature DB >> 25217962 |
Graham A Heap1, Michael N Weedon2, Claire M Bewshea3, Abhey Singh4, Mian Chen5, Jack B Satchwell5, Julian P Vivian6, Kenji So4, Patrick C Dubois7, Jane M Andrews8, Vito Annese9, Peter Bampton10, Martin Barnardo5, Sally Bell11, Andy Cole12, Susan J Connor13, Tom Creed14, Fraser R Cummings15, Mauro D'Amato16, Tawfique K Daneshmend4, Richard N Fedorak17, Timothy H Florin18, Daniel R Gaya19, Emma Greig20, Jonas Halfvarson21, Alisa Hart22, Peter M Irving23, Gareth Jones24, Amir Karban25, Ian C Lawrance26, James C Lee27, Charlie Lees24, Raffi Lev-Tzion28, James O Lindsay29, John Mansfield30, Joel Mawdsley31, Zia Mazhar32, Miles Parkes27, Kirstie Parnell33, Timothy R Orchard34, Graham Radford-Smith35, Richard K Russell36, David Reffitt37, Jack Satsangi24, Mark S Silverberg38, Giacomo C Sturniolo39, Mark Tremelling40, Epameinondas V Tsianos41, David A van Heel42, Alissa Walsh43, Gill Watermeyer44, Rinse K Weersma45, Sebastian Zeissig46, Jamie Rossjohn6, Arthur L Holden47, Tariq Ahmad3.
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(-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.Entities:
Mesh：
Substances：
Year: 2014 PMID： 25217962 PMCID： PMC6379053 DOI： 10.1038/ng.3093
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330