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

Graham A Heap, Michael N Weedon, Claire M Bewshea, Abhey Singh, Mian Chen, Jack B Satchwell, Julian Vivian, Kenji So, Patrick C Dubois, Jane M Andrews, Vito Annese, Peter A Bampton, Martin C Barnardo, Sally Bell, Andrew Timothy Cole, Susan J Connor, Tom Creed, Fraser R Cummings, Mauro D'Amato, Tawfique K DaneshmendRichard N Fedorak, Timothy Florin, Daniel R Gaya, Emma Greig, Jonas Halfvarson, Alisa Hart, Peter M Irving, Gareth Jones, Amir Karban, Ian Lawrance, James C Lee, Charlie Lees, Raffi Lev-Tzion, James O Lindsay, John Mansfield, Joel Mawdsley, Zia Mazhar, Miles Parkes, Kirstie Parnell, Timothy R Orchard, Graham Radford-Smith, Richard K Russell, David Reffitt, Jack Satsangi, Mark S Silverberg, Giacomo C Sturniolo, Mark Tremelling, Epameinondas V Tsianos, David A van Heel, Alissa Walsh, Gillian Ann Watermeyer, Rinse K Weersma, Sebastian Zeissig, Jamie Rossjohn, Arthur L Holden, Tariq Ahmad

Research output: Contribution to journalArticleResearchpeer-review

109 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1131 - 1134
Number of pages4
JournalNature Genetics
Volume46
Issue number10
DOIs
Publication statusPublished - 2014

Cite this