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.
Subject(s)
Genetic Predisposition to Disease/genetics , HLA-DQ alpha-Chains/genetics , HLA-DRB1 Chains/genetics , Pancreatitis/genetics , Polymorphism, Single Nucleotide , 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 FactorsABSTRACT
The diverse and complex community of microorganisms that has co-evolved with the human gut is vital to intestinal functioning, and disturbances in the microbiota and its relationship with the host immune system have been linked to inflammatory bowel diseases, including Crohn's disease and ulcerative colitis. This has suggested several treatment options, including antibiotics, probiotics and faecal transplantation. The human microbiome project has been established to enable comprehensive characterisation of the human microbiota and in the coming years, knowledge in this area is expected to continue to expand.
