Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

作者：Isabelle Cleynen, Gabrielle Boucher, Luke Jostins, L. Philip Schumm, Sebastian Zeißig, Tariq Ahmad, Vibeke Charlotte Andersen, Jane Mary Andrews, Vito Annese, Stephan Brand, Steven R. Brant, Judy H. Cho, Mark J. Daly, Marla C. Dubinsky, Richard H. Duerr, Lynnette Robyn Ferguson, André Franke, Richard Blair Gearry, Philippe Goyette, Hakon H. Hakonarson, Jonas Halfvarson, Johannes R. Hov, H Huang, Nicholas Alexander Kennedy, Limas Kupčinskas, Ian C. Lawrance, James Christopher Lee, Jack Satsangi, S Schreiber, Emilie Théâtre, Andrea E. van der Meulen‐de Jong, Rinse Karel Weersma, David C. Wilson, Miles Parkes, Severine A.R.A. Vermeire, John David Rioux, John C. Mansfield, Mark S. Silverberg, Graham L Radford‐Smith, Dermot P.B. McGovern, Jeffrey C. Barrett, Charlie W. Lees · 发表于：The Lancet · 年份：2015 · DOI：10.1016/s0140-6736(15)00465-1 · 被引用次数：791 · 研究领域：Inflammatory Bowel Disease、Liver Diseases and Immunity、Rheumatoid Arthritis Research and Therapies

BACKGROUND: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. METHODS: This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. FINDINGS: After quality control, the primary analysis included 29,838 patients (16,902 ...