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071 RECENT ADVANCES IN THE GENETICS OF INFLAMMATORY BOWEL DISEASES C Labbé1,2, P Goyette1, P DeJager3, C Lefebvre1, C Reinhard1, M Silverberg4, H Steinhart4, G Aumais5, EJ Bernard6, A Bitton7, A Cohen8, C Deslandres9, S Forget10, D Franchimont11, D Gaudet12, G Jobin5, R Lahaie13, D Langelier14, P Paré15, G Wild11, V Annese16, JD Rioux1,2,3 Over the last decade there has been an explosion of analytical and technological developments that have driven the scientific advances genetics and genomics as it relates to identifying critical biological pathways in disease and normal homeostasis. The Laboratory for Genetics and Genomic Medicine of Inflammation (www.inflammgen.org), located at the Montreal Heart Institute, focuses primarily on common inflammatory diseases such as Crohn's Disease (CD) and ulcerative colitis (UC). We are employing genome-wide, region-specific, and biological pathway approaches to identify genetic variants contributing to disease risk and phenotypic expression. These approaches are only possible when large cohorts of well-phenotyped patients and well-matched controls (family or population based), such as that created by the Quebec IBD Genetics Consortium; a university hospital based network of gastroenterologists and geneticists.
1Montreal Heart Institute, Montreal, Quebec; 2Université de Montréal, Montreal, Quebec; 3The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; 4Mount Sinai Hospital, Toronto, Ontario; 5Hôpital Maisonneuve Rosemont, Montreal, Quebec; 6CHUM - Hôpital Hôtel Dieu, Quebec City, Quebec; 7MUHC - Royal Victoria Hospital; 8Jewish General Hospital; 9Hôpital Sainte-Justine; 10MUHC - Montreal Children's Hospital; 11MUHC - Montreal General Hospital, Montreal, Quebec; 12Centre hospitalier de Chicoutimi, Chicoutimi; 13CHUM - Hôpital Saint-Luc, Montreal, Quebec; 14Centre hospitalier universitaire de Sherbrooke, Montreal, Quebec; 15Hôpital Saint-Sacrement, Quebec City, Quebec; 16CSS-IRCCS, S Giovanni Rotondo, Italy
These genetic approaches have led to the recent identification of genetic risk factors such as TLR4 and MYO9B. Specifically, our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD identified a haplotype of the TLR4 gene conferring risk to develop IBD (P=0.00017) and Crohn's disease (P=0.000035) but not ulcerative colitis. MYO9B, a gene first identified as conferring susceptibility to celiac disease, was found to be primarily associated with ulcerative colitis (P=1.9 x 10-6). In addition, we have performed additional work on the IBD5 CD risk haplotype, as well as the extended major histocompatibility complex (MHC), and together these results continue to support the fact that there are multiple mechanisms involved in the pathogenesis of IBD.