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.

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Acknowledgements

The International Serious Adverse Events Consortium (iSAEC) funded the sample collection and genotyping. The UK National Institute for Health Research (NIHR) provided research nurse support to facilitate recruitment at all UK research sites. We thank Crohn's and Colitis UK for funding support and publicizing this study to its members. A Wellcome Trust Institutional Strategic Support Award (WT097835MF) generously supported the work in this study. Genotyping was undertaken at the Broad Institute, Cambridge, Massachusetts, USA. We thank all the clinicians who assisted with sample collection as part of the IBD Pharmacogenetics Study Group (listed in the Supplementary Note) and the International IBD Genetics Consortium, as well as S. Marriott for her assistance during the trial initiation. We acknowledge The International Serious Adverse Events Scientific Management Committee members (listed in the Supplementary Note), T. Frayling, S. Lin and K. Hunt for kindly providing comments on the draft manuscript, as well as C. Heard and M. Parkinson for their ongoing administrative support to the study. We also thank all the patients for their time and participation.

Author information

Author notes

    • Graham A Heap
    •  & Michael N Weedon

    These authors contributed equally to this work.

Affiliations

  1. IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK.

    • Graham A Heap
    • , Claire M Bewshea
    • , Abhey Singh
    • , Kenji So
    • , Tawfique K Daneshmend
    •  & Tariq Ahmad
  2. Precision Medicine Exeter, University of Exeter, Exeter, UK.

    • Graham A Heap
    • , Michael N Weedon
    • , Claire M Bewshea
    • , Kirstie Parnell
    •  & Tariq Ahmad
  3. Oxford Transplant Centre, Oxford University Hospital National Health Service (NHS) Trust, Oxford, UK.

    • Mian Chen
    • , Jack B Satchwell
    •  & Martin Barnardo
  4. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.

    • Julian P Vivian
    •  & Jamie Rossjohn
  5. Department of Gastroenterology, King's College Hospital, London, UK.

    • Patrick C Dubois
  6. IBD Service, Department of Gastroenterology and University of Adelaide at Royal Adelaide Hospital, Adelaide, South Australia, Australia.

    • Jane M Andrews
  7. Division of Gastroenterology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy.

    • Vito Annese
  8. Flinders Medical Centre, Flinders University of South Australia, Adelaide, South Australia, Australia.

    • Peter Bampton
  9. Department of Gastroenterology, St. Vincent's Hospital, Fitzroy, Victoria, Australia.

    • Sally Bell
  10. Gastroenterology and Hepatology, Royal Derby Hospital, Derby, UK.

    • Andy Cole
  11. Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia.

    • Susan J Connor
  12. Joint Clinical Research Unit, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

    • Tom Creed
  13. Department of Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.

    • Fraser R Cummings
  14. Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden.

    • Mauro D'Amato
  15. Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada.

    • Richard N Fedorak
  16. The University of Queensland School of Medicine, South Brisbane, Queensland, Australia.

    • Timothy H Florin
  17. Gastroenterology Unit, Glasgow Royal Infirmary, Glasgow, UK.

    • Daniel R Gaya
  18. Department of Gastroenterology, Taunton and Somerset NHS Foundation Trust, Taunton, UK.

    • Emma Greig
  19. Division of Gastroenterology, Örebro University Hospital and School of Health and Medical Sciences, Örebro University, Örebro, Sweden.

    • Jonas Halfvarson
  20. Department of Medicine, St. Mark's Hospital and Academic Institute, North West London Hospitals NHS Trust, London, UK.

    • Alisa Hart
  21. Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, UK.

    • Peter M Irving
  22. Department of Gastroenterology, Western General Hospital, Edinburgh, UK.

    • Gareth Jones
    • , Charlie Lees
    •  & Jack Satsangi
  23. Department of Gastroenterology, Rambam Medical Center, Haifa, Israel.

    • Amir Karban
  24. Centre for Inflammatory Bowel Diseases, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.

    • Ian C Lawrance
  25. Department of Gastroenterology, Cambridge University Hospitals NHS Trust, Cambridge, UK.

    • James C Lee
    •  & Miles Parkes
  26. Paediatric Gastroenterology and Nutrition Unit, Shaare Zedek Medical Centre, Jerusalem, Israel.

    • Raffi Lev-Tzion
  27. Department of Gastroenterology, Barts and The London NHS Trust, London, UK.

    • James O Lindsay
  28. Department of Gastroenterology, Newcastle University Hospitals NHS Trust, Newcastle, UK.

    • John Mansfield
  29. Department of Gastroenterology, West Middlesex University Hospital NHS Trust, Isleworth, UK.

    • Joel Mawdsley
  30. Department of Gastroenterology, Basildon and Thurrock Hospital NHS Trust, Basildon, UK.

    • Zia Mazhar
  31. Department of Medicine, Imperial College Healthcare NHS, London, UK.

    • Timothy R Orchard
  32. Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.

    • Graham Radford-Smith
  33. IBD Group, Queensland Institute of Medical Research and University of Queensland School of Medicine, Herston Campus, Brisbane, Queensland, Australia.

    • Graham Radford-Smith
  34. Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, UK.

    • Richard K Russell
  35. Department of Gastroenterology, Lewisham and Greenwich NHS Trust, London, UK.

    • David Reffitt
  36. Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Mark S Silverberg
  37. Gastroenterologia, Univerita di Padova, Padova, Italy.

    • Giacomo C Sturniolo
  38. Department of Gastroenterology, Norfolk and Norwich Hospital NHS Trust, Norwich, UK.

    • Mark Tremelling
  39. 1st Division of Internal Medicine and Division of Gastroenterology, Faculty of Medicine, University of Ioannina, Ioannina, Greece.

    • Epameinondas V Tsianos
  40. Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • David A van Heel
  41. Department of Gastroenterology, St. Vincent's Hospital, Sydney, New South Wales, Australia.

    • Alissa Walsh
  42. Gastrointestinal Clinic, Groote Schuur Hospital, Cape Town, South Africa.

    • Gill Watermeyer
  43. Department of Gastroenterology and Hepatology, University Medical Center Groningen and the University of Groningen, Groningen, the Netherlands.

    • Rinse K Weersma
  44. Department of Internal Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany.

    • Sebastian Zeissig
  45. The International Serious Adverse Events Consortium, Chicago, Illinois, USA.

    • Arthur L Holden

Consortia

  1. International Serious Adverse Events Consortium

    A complete list of all consortia members is provided in the Supplementary Note.

  2. IBD Pharmacogenetics Study Group

    A complete list of all consortia members is provided in the Supplementary Note.

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Contributions

G.A.H., K.S., T.K.D., D.A.v.H., P.C.D., A.L.H. and T.A. participated in the conception, design and coordination of the study. C.M.B. was the project manager and coordinated recruitment. G.A.H., M.N.W. and T.A. analyzed the data and participated in writing the paper. K.P. performed DNA preparation. The International Serious Adverse Events Consortium advised on the GWAS, performed genotyping and participated in writing the paper. A.C., T.C., P.C.D., E.G., P.M.I., J.O.L., J. Mawdsley, Z.M., T.R.O., D.R., G.A.H., A.S. and T.A. performed adjudication of the cases. M.C., J.B.S. and M.B. performed the SSP-based HLA genotyping. J.R. and J.P.V. performed the in silico structural analysis. K.S., J.M.A., V.A., P.B., S.B., A.C., S.J.C., T.C., F.R.C., M.D., T.K.D., R.N.F., T.H.F., D.R.G., E.G., J.H., A.H., P.M.I., G.J., A.K., I.C.L., J.C.L., C.L., R.L.-T., J.O.L., J. Mansfield, J. Mawdsley, Z.M., M.P., T.R.O., G.R.-S., R.K.R., D.R., J.S., M.S.S., G.C.S., M.T., E.V.T., A.W., G.W., R.K.W. and S.Z. contributed a substantial number of samples in line with International Committee of Medical Journal Editors criteria. All authors assisted in the writing, reviewing and approval of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Graham A Heap or Tariq Ahmad.

Integrated supplementary information

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–4, Supplementary Note and Supplementary Tables 1–7

About this article

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DOI

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

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