title: HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants.
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.
authors.affiliation: 1] IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK. [2] Precision Medicine Exeter, University of Exeter, Exeter, UK. [3].
authors.forename: Graham A
authors.identifier: 0000000341316792
authors.initials: GA
authors.lastname: Heap
authors.affiliation: 1] Precision Medicine Exeter, University of Exeter, Exeter, UK. [2].
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.affiliation: 1] IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK. [2] Precision Medicine Exeter, University of Exeter, Exeter, UK.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Bewshea
authors.affiliation: IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK.
authors.forename: Abhey
authors.initials: A
authors.lastname: Singh
authors.affiliation: Oxford Transplant Centre, Oxford University Hospital National Health Service (NHS) Trust, Oxford, UK.
authors.forename: Mian
authors.initials: M
authors.lastname: Chen
authors.affiliation: Oxford Transplant Centre, Oxford University Hospital National Health Service (NHS) Trust, Oxford, UK.
authors.forename: Jack B
authors.initials: JB
authors.lastname: Satchwell
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Julian P
authors.initials: JP
authors.lastname: Vivian
authors.affiliation: IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK.
authors.forename: Kenji
authors.initials: K
authors.lastname: So
authors.affiliation: Department of Gastroenterology, King's College Hospital, London, UK.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Dubois
authors.affiliation: IBD Service, Department of Gastroenterology and University of Adelaide at Royal Adelaide Hospital, Adelaide, South Australia, Australia.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Andrews
authors.affiliation: Division of Gastroenterology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy.
authors.forename: Vito
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authors.lastname: Annese
authors.affiliation: Flinders Medical Centre, Flinders University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Bampton
authors.affiliation: Oxford Transplant Centre, Oxford University Hospital National Health Service (NHS) Trust, Oxford, UK.
authors.forename: Martin
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authors.lastname: Barnardo
authors.affiliation: Department of Gastroenterology, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Sally
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authors.lastname: Bell
authors.affiliation: Gastroenterology and Hepatology, Royal Derby Hospital, Derby, UK.
authors.forename: Andy
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authors.lastname: Cole
authors.affiliation: Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Connor
authors.affiliation: Joint Clinical Research Unit, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
authors.forename: Tom
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authors.lastname: Creed
authors.affiliation: Department of Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Fraser R
authors.initials: FR
authors.lastname: Cummings
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden.
authors.forename: Mauro
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authors.lastname: D'Amato
authors.affiliation: IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK.
authors.forename: Tawfique K
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authors.lastname: Daneshmend
authors.affiliation: Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Fedorak
authors.affiliation: The University of Queensland School of Medicine, South Brisbane, Queensland, Australia.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Florin
authors.affiliation: Gastroenterology Unit, Glasgow Royal Infirmary, Glasgow, UK.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Gaya
authors.affiliation: Department of Gastroenterology, Taunton and Somerset NHS Foundation Trust, Taunton, UK.
authors.forename: Emma
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authors.lastname: Greig
authors.affiliation: Division of Gastroenterology, Örebro University Hospital and School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Halfvarson
authors.affiliation: Department of Medicine, St. Mark's Hospital and Academic Institute, North West London Hospitals NHS Trust, London, UK.
authors.forename: Alisa
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authors.lastname: Hart
authors.affiliation: Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
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authors.initials: PM
authors.lastname: Irving
authors.affiliation: Department of Gastroenterology, Western General Hospital, Edinburgh, UK.
authors.forename: Gareth
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authors.lastname: Jones
authors.affiliation: Department of Gastroenterology, Rambam Medical Center, Haifa, Israel.
authors.forename: Amir
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authors.lastname: Karban
authors.affiliation: Centre for Inflammatory Bowel Diseases, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Lawrance
authors.affiliation: Department of Gastroenterology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
authors.forename: James C
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Department of Gastroenterology, Western General Hospital, Edinburgh, UK.
authors.forename: Charlie
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authors.lastname: Lees
authors.affiliation: Paediatric Gastroenterology and Nutrition Unit, Shaare Zedek Medical Centre, Jerusalem, Israel.
authors.forename: Raffi
authors.initials: R
authors.lastname: Lev-Tzion
authors.affiliation: Department of Gastroenterology, Barts and The London NHS Trust, London, UK.
authors.forename: James O
authors.initials: JO
authors.lastname: Lindsay
authors.affiliation: Department of Gastroenterology, Newcastle University Hospitals NHS Trust, Newcastle, UK.
authors.forename: John
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authors.lastname: Mansfield
authors.affiliation: Department of Gastroenterology, West Middlesex University Hospital NHS Trust, Isleworth, UK.
authors.forename: Joel
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authors.lastname: Mawdsley
authors.affiliation: Department of Gastroenterology, Basildon and Thurrock Hospital NHS Trust, Basildon, UK.
authors.forename: Zia
authors.initials: Z
authors.lastname: Mazhar
authors.affiliation: Department of Gastroenterology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
authors.forename: Miles
authors.initials: M
authors.lastname: Parkes
authors.affiliation: Precision Medicine Exeter, University of Exeter, Exeter, UK.
authors.forename: Kirstie
authors.initials: K
authors.lastname: Parnell
authors.affiliation: Department of Medicine, Imperial College Healthcare NHS, London, UK.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Orchard
authors.affiliation: 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.
authors.forename: Graham
authors.initials: G
authors.lastname: Radford-Smith
authors.affiliation: Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, UK.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Russell
authors.affiliation: Department of Gastroenterology, Lewisham and Greenwich NHS Trust, London, UK.
authors.forename: David
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authors.lastname: Reffitt
authors.affiliation: Department of Gastroenterology, Western General Hospital, Edinburgh, UK.
authors.forename: Jack
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authors.lastname: Satsangi
authors.affiliation: Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
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authors.initials: MS
authors.lastname: Silverberg
authors.affiliation: Gastroenterologia, Univerita di Padova, Padova, Italy.
authors.forename: Giacomo C
authors.initials: GC
authors.lastname: Sturniolo
authors.affiliation: Department of Gastroenterology, Norfolk and Norwich Hospital NHS Trust, Norwich, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Tremelling
authors.affiliation: 1st Division of Internal Medicine and Division of Gastroenterology, Faculty of Medicine, University of Ioannina, Ioannina, Greece.
authors.forename: Epameinondas V
authors.initials: EV
authors.lastname: Tsianos
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: David A
authors.identifier: 0000000206372265
authors.initials: DA
authors.lastname: van Heel
authors.affiliation: Department of Gastroenterology, St. Vincent's Hospital, Sydney, New South Wales, Australia.
authors.forename: Alissa
authors.initials: A
authors.lastname: Walsh
authors.affiliation: Gastrointestinal Clinic, Groote Schuur Hospital, Cape Town, South Africa.
authors.forename: Gill
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authors.lastname: Watermeyer
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen and the University of Groningen, Groningen, the Netherlands.
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.affiliation: Department of Internal Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zeissig
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Jamie
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authors.lastname: Rossjohn
authors.affiliation: The International Serious Adverse Events Consortium, Chicago, Illinois, USA.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Holden
authors.affiliation: 1] IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK. [2] Precision Medicine Exeter, University of Exeter, Exeter, UK.
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mesh_terms: D001379:Azathioprine / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D059848:HLA-DQ alpha-Chains / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D059811:HLA-DRB1 Chains / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy; D015122:Mercaptopurine / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012307:Risk Factors
chemical_list: D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D059811:HLA-DRB1 Chains; D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D001379:Azathioprine