Multicenter Study

. 2014 Oct;46(10):1131-4.

doi: 10.1038/ng.3093. Epub 2014 Sep 14.

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

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; International Serious Adverse Events Consortium; IBD Pharmacogenetics Study Group; Tariq Ahmad³

Affiliations

¹ 1] IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK. [2] Precision Medicine Exeter, University of Exeter, Exeter, UK. [3].
² 1] Precision Medicine Exeter, University of Exeter, Exeter, UK. [2].
³ 1] IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK. [2] Precision Medicine Exeter, University of Exeter, Exeter, UK.
⁴ IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK.
⁵ Oxford Transplant Centre, Oxford University Hospital National Health Service (NHS) Trust, Oxford, UK.
⁶ Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
⁷ Department of Gastroenterology, King's College Hospital, London, UK.
⁸ IBD Service, Department of Gastroenterology and University of Adelaide at Royal Adelaide Hospital, Adelaide, South Australia, Australia.
⁹ Division of Gastroenterology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy.
¹⁰ Flinders Medical Centre, Flinders University of South Australia, Adelaide, South Australia, Australia.
¹¹ Department of Gastroenterology, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
¹² Gastroenterology and Hepatology, Royal Derby Hospital, Derby, UK.
¹³ Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia.
¹⁴ Joint Clinical Research Unit, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
¹⁵ Department of Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
¹⁶ Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden.
¹⁷ Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada.
¹⁸ The University of Queensland School of Medicine, South Brisbane, Queensland, Australia.
¹⁹ Gastroenterology Unit, Glasgow Royal Infirmary, Glasgow, UK.
²⁰ Department of Gastroenterology, Taunton and Somerset NHS Foundation Trust, Taunton, UK.
²¹ Division of Gastroenterology, Örebro University Hospital and School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
²² Department of Medicine, St. Mark's Hospital and Academic Institute, North West London Hospitals NHS Trust, London, UK.
²³ Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
²⁴ Department of Gastroenterology, Western General Hospital, Edinburgh, UK.
²⁵ Department of Gastroenterology, Rambam Medical Center, Haifa, Israel.
²⁶ Centre for Inflammatory Bowel Diseases, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.
²⁷ Department of Gastroenterology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
²⁸ Paediatric Gastroenterology and Nutrition Unit, Shaare Zedek Medical Centre, Jerusalem, Israel.
²⁹ Department of Gastroenterology, Barts and The London NHS Trust, London, UK.
³⁰ Department of Gastroenterology, Newcastle University Hospitals NHS Trust, Newcastle, UK.
³¹ Department of Gastroenterology, West Middlesex University Hospital NHS Trust, Isleworth, UK.
³² Department of Gastroenterology, Basildon and Thurrock Hospital NHS Trust, Basildon, UK.
³³ Precision Medicine Exeter, University of Exeter, Exeter, UK.
³⁴ Department of Medicine, Imperial College Healthcare NHS, London, UK.
³⁵ 1] Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. [2] IBD Group, Queensland Institute of Medical Research and University of Queensland School of Medicine, Herston Campus, Brisbane, Queensland, Australia.
³⁶ Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, UK.
³⁷ Department of Gastroenterology, Lewisham and Greenwich NHS Trust, London, UK.
³⁸ Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
³⁹ Gastroenterologia, Univerita di Padova, Padova, Italy.
⁴⁰ Department of Gastroenterology, Norfolk and Norwich Hospital NHS Trust, Norwich, UK.
⁴¹ 1st Division of Internal Medicine and Division of Gastroenterology, Faculty of Medicine, University of Ioannina, Ioannina, Greece.
⁴² Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁴³ Department of Gastroenterology, St. Vincent's Hospital, Sydney, New South Wales, Australia.
⁴⁴ Gastrointestinal Clinic, Groote Schuur Hospital, Cape Town, South Africa.
⁴⁵ Department of Gastroenterology and Hepatology, University Medical Center Groningen and the University of Groningen, Groningen, the Netherlands.
⁴⁶ Department of Internal Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany.
⁴⁷ The International Serious Adverse Events Consortium, Chicago, Illinois, USA.

PMID: 25217962
PMCID: PMC6379053
DOI: 10.1038/ng.3093

Multicenter Study

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

Graham A Heap et al. Nat Genet. 2014 Oct.

. 2014 Oct;46(10):1131-4.

doi: 10.1038/ng.3093. Epub 2014 Sep 14.

Authors

Affiliations

¹ 1] IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK. [2] Precision Medicine Exeter, University of Exeter, Exeter, UK. [3].
² 1] Precision Medicine Exeter, University of Exeter, Exeter, UK. [2].
³ 1] IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK. [2] Precision Medicine Exeter, University of Exeter, Exeter, UK.
⁴ IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK.
⁵ Oxford Transplant Centre, Oxford University Hospital National Health Service (NHS) Trust, Oxford, UK.
⁶ Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
⁷ Department of Gastroenterology, King's College Hospital, London, UK.
⁸ IBD Service, Department of Gastroenterology and University of Adelaide at Royal Adelaide Hospital, Adelaide, South Australia, Australia.
⁹ Division of Gastroenterology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy.
¹⁰ Flinders Medical Centre, Flinders University of South Australia, Adelaide, South Australia, Australia.
¹¹ Department of Gastroenterology, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
¹² Gastroenterology and Hepatology, Royal Derby Hospital, Derby, UK.
¹³ Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia.
¹⁴ Joint Clinical Research Unit, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
¹⁵ Department of Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
¹⁶ Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden.
¹⁷ Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada.
¹⁸ The University of Queensland School of Medicine, South Brisbane, Queensland, Australia.
¹⁹ Gastroenterology Unit, Glasgow Royal Infirmary, Glasgow, UK.
²⁰ Department of Gastroenterology, Taunton and Somerset NHS Foundation Trust, Taunton, UK.
²¹ Division of Gastroenterology, Örebro University Hospital and School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
²² Department of Medicine, St. Mark's Hospital and Academic Institute, North West London Hospitals NHS Trust, London, UK.
²³ Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
²⁴ Department of Gastroenterology, Western General Hospital, Edinburgh, UK.
²⁵ Department of Gastroenterology, Rambam Medical Center, Haifa, Israel.
²⁶ Centre for Inflammatory Bowel Diseases, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.
²⁷ Department of Gastroenterology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
²⁸ Paediatric Gastroenterology and Nutrition Unit, Shaare Zedek Medical Centre, Jerusalem, Israel.
²⁹ Department of Gastroenterology, Barts and The London NHS Trust, London, UK.
³⁰ Department of Gastroenterology, Newcastle University Hospitals NHS Trust, Newcastle, UK.
³¹ Department of Gastroenterology, West Middlesex University Hospital NHS Trust, Isleworth, UK.
³² Department of Gastroenterology, Basildon and Thurrock Hospital NHS Trust, Basildon, UK.
³³ Precision Medicine Exeter, University of Exeter, Exeter, UK.
³⁴ Department of Medicine, Imperial College Healthcare NHS, London, UK.
³⁵ 1] Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. [2] IBD Group, Queensland Institute of Medical Research and University of Queensland School of Medicine, Herston Campus, Brisbane, Queensland, Australia.
³⁶ Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, UK.
³⁷ Department of Gastroenterology, Lewisham and Greenwich NHS Trust, London, UK.
³⁸ Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
³⁹ Gastroenterologia, Univerita di Padova, Padova, Italy.
⁴⁰ Department of Gastroenterology, Norfolk and Norwich Hospital NHS Trust, Norwich, UK.
⁴¹ 1st Division of Internal Medicine and Division of Gastroenterology, Faculty of Medicine, University of Ioannina, Ioannina, Greece.
⁴² Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁴³ Department of Gastroenterology, St. Vincent's Hospital, Sydney, New South Wales, Australia.
⁴⁴ Gastrointestinal Clinic, Groote Schuur Hospital, Cape Town, South Africa.
⁴⁵ Department of Gastroenterology and Hepatology, University Medical Center Groningen and the University of Groningen, Groningen, the Netherlands.
⁴⁶ Department of Internal Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany.
⁴⁷ The International Serious Adverse Events Consortium, Chicago, Illinois, USA.

PMID: 25217962
PMCID: PMC6379053
DOI: 10.1038/ng.3093

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.

PubMed Disclaimer

Conflict of interest statement

Competing Interests Statement

The International Serious Adverse Events Consortium funded this study. The authors declare no competing financial interests.

Figures

**Figure 1. Genome-wide association results for all SNPs post 1000 Genomes and HLA imputation.**
A Manhattan plot B Q-Q Plot

See this image and copyright information in PMC

References

1. Health and Social Care Information Centre. Quarterly Prescription Cost Analysis, England. 2013.
1. Prefontaine E, Lr S, Jk M, Cepoiu M. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn ’s disease (Review) Cochrane database Syst Rev. 2010 - PubMed
1. Timmer A, et al. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis (Review) Cochrane database Syst Rev. 2012 CD000478. - PubMed
1. Cosnes J, et al. Early administration of azathioprine vs conventional management of Crohn’s Disease: a randomized controlled trial. Gastroenterology. 2013;145:758–65.e2. quiz e14-5. - PubMed
1. Chaparro M, et al. Safety of Thiopurine Therapy in Inflammatory Bowel Disease: Long-term Follow-up Study of 3931 Patients. Inflamm Bowel Dis. 2013;19:1–7. - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Research Materials