1. HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants.
- Author
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Heap GA, Weedon MN, Bewshea CM, Singh A, Chen M, Satchwell JB, Vivian JP, So K, Dubois PC, Andrews JM, Annese V, Bampton P, Barnardo M, Bell S, Cole A, Connor SJ, Creed T, Cummings FR, D'Amato M, Daneshmend TK, Fedorak RN, Florin TH, Gaya DR, Greig E, Halfvarson J, Hart A, Irving PM, Jones G, Karban A, Lawrance IC, Lee JC, Lees C, Lev-Tzion R, Lindsay JO, Mansfield J, Mawdsley J, Mazhar Z, Parkes M, Parnell K, Orchard TR, Radford-Smith G, Russell RK, Reffitt D, Satsangi J, Silverberg MS, Sturniolo GC, Tremelling M, Tsianos EV, van Heel DA, Walsh A, Watermeyer G, Weersma RK, Zeissig S, Rossjohn J, Holden AL, and Ahmad T
- Subjects
- Azathioprine adverse effects, Azathioprine chemistry, Azathioprine metabolism, Gene Frequency, Genome-Wide Association Study, Genotype, HLA-DQ alpha-Chains chemistry, HLA-DQ alpha-Chains metabolism, HLA-DRB1 Chains chemistry, HLA-DRB1 Chains metabolism, Haplotypes, Humans, Immunosuppressive Agents adverse effects, Immunosuppressive Agents chemistry, Immunosuppressive Agents metabolism, Inflammatory Bowel Diseases drug therapy, Mercaptopurine adverse effects, Mercaptopurine chemistry, Mercaptopurine metabolism, Models, Molecular, Molecular Structure, Pancreatitis chemically induced, Protein Binding, Protein Structure, Tertiary, Risk Factors, Genetic Predisposition to Disease genetics, HLA-DQ alpha-Chains genetics, HLA-DRB1 Chains genetics, Pancreatitis genetics, Polymorphism, Single Nucleotide
- 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.
- Published
- 2014
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