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. Satchwel; Julian P. Vivian; Kenji So; Patrick C. Dubois; Jane M. Andrews; Vito Annese; Peter Bampton; Martin Barnardo; Sally Bell; Andy Cole; Susan J. Connor; Tom Creed; Fraser R. Cummings; Mauro D'Amato; Tawfique K. Daneshmend; Richard N. Fedorak; Timothy H. Florin; Daniel R. Gaya; Emma Greig; Jonas Halfvarson; Alisa Hart; Peter M. Irving; Gareth Jones; Amir Karban; Ian C. Lawrance; James C. Lee; Charlie Lees; Raffi Lev-Tzion; James 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; Gill Watermeyer; Rinse K. Weersma; Sebastian Zeissig; Jamie Rossjohn; Arthur L. Holden; Tariq Ahmad; Int Serious Adverse Events Consort

doi:10.1038/ng.3093

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

Journal article

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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. Satchwel, Julian P. Vivian, Kenji So, Patrick C. Dubois, Jane M. Andrews, …

Nature genetics, Vol.46(10), pp.1131-1134

01/10/2014

DOI: https://doi.org/10.1038/ng.3093

PMCID: PMC6379053

PMID: 25217962

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

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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Title: HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants
Creators - without role: Graham A. Heap - Royal Devon and Exeter Hospital
Michael N. Weedon - University of Exeter
Claire M. Bewshea - Royal Devon and Exeter Hospital
Abhey Singh - Royal Devon and Exeter Hospital
Mian Chen - University of Oxford
Jack B. Satchwel - University of Oxford
Julian P. Vivian - Monash University
Kenji So - Royal Devon and Exeter Hospital
Patrick C. Dubois - University of Cambridge
Jane M. Andrews - Royal Adelaide Hospital
Vito Annese - Florence
Peter Bampton - Flinders University
Martin Barnardo - University of Oxford
Sally Bell - St. Vincent's Birmingham
Andy Cole - Royal Derby Hospital
Susan J. Connor - Liverpool Hospital
Tom Creed - University Hospitals Bristol NHS Foundation Trust
Fraser R. Cummings - University Hospital Southampton NHS Foundation Trust
Mauro D'Amato - Karolinska Institutet
Tawfique K. Daneshmend - Royal Devon and Exeter Hospital
Richard N. Fedorak - University of Alberta
Timothy H. Florin - University of Queensland
Daniel R. Gaya - Glasgow Royal Infirmary
Emma Greig - Taunton & Somerset NHS Fdn Trust, Dept Gastroenterol, Taunton, Somerset, England
Jonas Halfvarson - Örebro University
Alisa Hart - College Station Medical Center
Peter M. Irving - Guy's and St Thomas' NHS Foundation Trust
Gareth Jones - Western General Hospital
Amir Karban - College Station Medical Center
Ian C. Lawrance - University of Western Australia
James C. Lee - University of Cambridge
Charlie Lees - Western General Hospital
Raffi Lev-Tzion - College Station Medical Center
James Lindsay - Queen Mary University of London
John Mansfield - Newcastle University
Joel Mawdsley - West Middlesex University Hospital
Zia Mazhar - Basildon & Thurrock Hosp NHS Trust, Dept Gastroenterol, Basildon, Essex, England
Miles Parkes - University of Cambridge
Kirstie Parnell - University of Exeter
Timothy R. Orchard - Imperial College Healthcare NHS Trust
Graham Radford-Smith - Royal Brisbane and Women's Hospital
Richard K. Russell - Yorkhill Hosp, Dept Paediat Gastroenterol, Glasgow, Lanark, Scotland
David Reffitt - Lewisham & Greenwich NHS Trust, Dept Gastroenterol, London, England
Jack Satsangi - Western General Hospital
Mark S. Silverberg - Mount Sinai Hospital
Giacomo C. Sturniolo - University of Padua
Mark Tremelling - Norwich University
Epameinondas V. Tsianos - University of Ioannina
David A. van Heel - Queen Mary University of London
Alissa Walsh - St. Vincent's Birmingham
Gill Watermeyer - Groote Schuur Hospital
Rinse K. Weersma - University Medical Center Groningen
Sebastian Zeissig - Kiel University
Jamie Rossjohn - Monash University
Arthur L. Holden - Int Serious Adverse Events Consortium, Chicago, IL USA
Tariq Ahmad - Royal Devon and Exeter Hospital
Int Serious Adverse Events Consort
Publication Details: Nature genetics, Vol.46(10), pp.1131-1134
Publisher: Springer Nature
Number of pages: 4
Grant note: International Serious Adverse Events Consortium (iSAEC) AMS-SGCL9-Lee / Academy of Medical Sciences (AMS) G0700545 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission NIHR-RP-R3-12-026 / National Institute for Health Research; National Institute for Health Research (NIHR) WT097835MF / Wellcome Trust Institutional Strategic Support Award; Wellcome Trust M11-2 / Crohn"s and Colitis UK Crohn's and Colitis UK ETM/75 / Chief Scientist Office MC_UU_12010/7 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC)
Identifiers: 9925590208331
Academic Unit: Prince Sattam Bin Abdulaziz University
Language: English
Resource Type: Journal article