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

Graham Heap, Michael Weedon, Claire Bewshea, Abhey Singh, Mian Chen, Jack Satchwell, Julian Vivian, Kenji So, Patrick Dubois, Jane Andrews, Vito Annese, Peter Bampton, Martin Barnardo, Sally Bell, Andy Cole, Susan Connor, Tom Creed, Fraser Cummings, Mauro D'Amato, Tawfiqu DaneshmendRichard Fedorak, Timothy Florin, Daniel Gaya, Emma Greig, Jonas Halfvarson, Ailsa Hart, Peter Irving, Gareth Jones, Amir Karban, Ian Lawrance, James Lee, Charlie Lees, Raffi Lev-Tzion, James Lindsay, John Mansfield, Joel Mawdsley, Zia Mazhar, Miles Parkes, Kirstie Parnell, Timothy Orchard, Graham Radford-Smith, Richard Russell, David Reffitt, Jack Satsangi, Mark Silverberg, Giacomo Sturniolo, Mark Tremelling, Epameinondas Tsianos, David van Heel, Alissa Walsh, Gill Watermeyer, Rinse Weersma, Sebastian Zeissig, Jamie Rossjohn, Arthur Holden, Acuth Shenoy, Ahmed Dawood, Alan Ireland, Alan Lobo, Alison Simmons, Alistair McNair, Andre Franke, Andy Bell, Andy Milestone, Anita Modi, Anjan Dhar, Anne Willmott, Anthony Akobeng, Asheesh Sharma, Barney Hawthorne, Basant Chaudhary, Cathryn Edwards, Cathryn Preston, Charles Murray, Charlie Charlton, Chris MacDonald, Colin Jones, Craig Mowat, Daniel Gavin, David Campbell, David Elphick, David Grimes, David Watts, Deb Ghosh, Debasish Das, Deven Vani, Elaine Spalding, Emma Wesley, Gareth Davies, George McFaul, Gill Watts, Guy Chung-Faye, Helen Clarke, Helen Dalal, Ian Gee, James Hart, Jimmy Limdi, Jo Taylor, John Beckly, John Fell, John Gordon, John Green, John Puntis, Jon Simmons, Jonathan Quinlan, Jonathan Snook, Kathleen Holding, Konstantinos Katsanos, Lucy Smyth, Malcolm Smith, Marcus Auth, Marcus Harbord, Marianne Mortimore, Mark Smith, Mark Thomas, Mark Tighe, Matthew Brookes, Melanie Lockett, Michael Delaney, Michael Schultz, Mundre Pradeep, Naomi Edney, Natalie Direkze, Neeraj Prasad, Neil Shah, Nick Croft, Paul Banim, Paul Dunckley, Pierre Ellul, Pradeep Bhandari, Pritash Patel, Rachel Cooney, Rakesh Chaudhary, Rebecca Saich, Renata D'Inca, Richard D'Souza, Richard Felwick, Richard P Pollok, Richard Shenderay, Rosemary Phillips, Sandip Sen, Sean Weaver, Shaji Sebastian, Shani deSilva, Sheldon Cooper, Simon Campbell, Simon Everett, Simon Lal, Simon Panter, Sree Subramanian, Stefan Schreiber, Stephen Foley, Stephen Lewis, Steve Gore, Stuart Bloom, Subramaniam Ramakrishnan, Sue Cullen, Sunil Sonwalker, Suren Kanegasundaram, Tariq Iqbal, Tony Lopez, Vibeke Andersen, Zinu Philipose, Angus Watson, Chris Hawkey, Matt Nelson, Sally John, Jeffrey Waring, Scott Patterson, Bryan Barratt, Joe Walker, Peter Shaw, Steve Lewitzky, Michael Dunn, Tariq Ahmad

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    98 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 × 10 â '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

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    Heap, G., Weedon, M., Bewshea, C., Singh, A., Chen, M., Satchwell, J., Vivian, J., So, K., Dubois, P., Andrews, J., Annese, V., Bampton, P., Barnardo, M., Bell, S., Cole, A., Connor, S., Creed, T., Cummings, F., D'Amato, M., ... Ahmad, T. (2014). HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nature Genetics, 46(10), 1131-1134. https://doi.org/10.1038/ng.3093