Journal Article

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

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

2014

Overview

Graham Heap, Tariq Ahmad and colleagues show that common variants in the HLA-DQA1–HLA-DRB1 region confer susceptibility to thiopurine-induced pancreatitis in individuals undergoing treatment for inflammatory bowel diseases. These findings could help identify patients at risk of developing this serious adverse reaction to thiopurine therapy. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/43 / 45/77 / 631/208/205/2138 / 692/308/2056 / 692/699/1503/257 / 692/700/565/1436 / Agriculture / Animal Genetics and Genomics / Azathioprine - adverse effects / Azathioprine - chemistry / Azathioprine - metabolism / Biomedicine / Cancer Research / Complications and side effects / Crohn's disease / Drug therapy / Gene Frequency / Gene Function / Genetic aspects / Genetic Predisposition to Disease - genetics / Genetics / Genetik / Genome-Wide Association Study / Genomes / Genotype / Haplotypes / Health aspects / Histocompatibility / HLA-DQ alpha-Chains - chemistry / HLA-DQ alpha-Chains - genetics / HLA-DQ alpha-Chains - metabolism / HLA-DRB1 Chains - chemistry / HLA-DRB1 Chains - genetics / HLA-DRB1 Chains - metabolism / Human Genetics / Humans / Immunosuppressive agents / Immunosuppressive Agents - adverse effects / Immunosuppressive Agents - chemistry / Immunosuppressive Agents - metabolism / Inflammatory bowel disease / Inflammatory Bowel Diseases - drug therapy / letter / Medical research / Mercaptopurine - adverse effects / Mercaptopurine - chemistry / Mercaptopurine - metabolism / Methods / Models, Molecular / Molecular Structure / Pancreatitis / Pancreatitis - chemically induced / Pancreatitis - genetics / Polymorphism, Single Nucleotide / Protein Binding / Protein Structure, Tertiary / Risk Factors / Studies