To date more than 100 genetic variants are known to be associated with inflammatory bowel disease (IBD). The majority of these have been identified by genome-wide association studies (GWAS). The individual Genetic Research Centers (GRCs) and the collective NIDDK IBD Genetics Consortium have successfully interacted for the last ten years to lead many of these discoveries. However, despite significant progress it is still unknown how the vast majority of these variants lead to IBD. Answering these questions is critical to advancing our knowledge of IBD pathophysiology. The University of Toronto GRC, led by Dr. Mark Silverberg, has made unique and substantial contributions in this field by virtue of its longstanding clinical and genetics expertise in IBD. Since 2002, Dr. Silverberg has established a very large, comprehensive registry of well characterized, longitudinally followed IBD patients at Mount Sinai Hospital in addition to accompanying biospecimens stored at his laboratory at the Samuel Lunenfeld Research Institute in order to facilitate research in IBD. Utilizing these resources, the UTGRC will advance the understanding of IBD pathophysiology in the following ways: (1) To identify gene expression profiles and pathways that will aid in classifying IBD and in revealing those that are mechanistically important in IBD pathophysiology. This will be accomplished by measuring gene expression profiles in the intestinal tissue of those affected and of healthy controls. (2) To evaluate the interaction between host genetic variation and the intestinal microbiome and determine how these changes affect the phenotypic expression of IBD. This will be accomplished by determining the composition of the microbial flora adherent to the intestinal tissue of those affected and of healthy controls. (3) To continue to work in an interactive fashion with the members of the Consortium to complete the discovery of all genetic variation associated with IBD and to advance our knowledge of the functional biology of such genetic variation such that we will effect change in the outcomes of individuals affected by IBD. This will be accomplished by ongoing clinical patient and biospecimen recruitment and by bringing significant clinical and scientific expertise to the Consortium team.

Public Health Relevance

The University of Toronto Genetic Research Center, working within the NIDDK IBD Genetics Consortium, is proposing a series of projects aimed at fully identifying all of the genetic factors that lead to an inherited predisposition to inflammatory bowl disease (IBD). UTGRC will also investigate how patients with these susceptibility factors actually develop IBD by incorporating studies examining how genes are expressed and the composition of the bacteria in the digestive tract. By understanding these processes the aim is to prevent individuals from developing IBD and to improve the quality of life of those individuals currently affected.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
4U01DK062423-12
Application #
8549106
Study Section
Special Emphasis Panel (ZDK1-GRB-G (O3))
Program Officer
Karp, Robert W
Project Start
2002-09-30
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
12
Fiscal Year
2013
Total Cost
$254,642
Indirect Cost
$18,862
Name
MT Sinai Hosp-Samuel Lunenfeld Research Institute
Department
Type
DUNS #
208808949
City
Toronto
State
ON
Country
Canada
Zip Code
M5 3-L9
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Plevy, Scott; Silverberg, Mark S; Lockton, Steve et al. (2013) Combined serological, genetic, and inflammatory markers differentiate non-IBD, Crohn's disease, and ulcerative colitis patients. Inflamm Bowel Dis 19:1139-48
Zhang, W; Hui, K Y; Gusev, A et al. (2013) Extended haplotype association study in Crohn's disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-*B pathway gene, HEATR3. Genes Immun 14:310-6
Lazarev, Mark; Huang, Chengrui; Bitton, Alain et al. (2013) Relationship between proximal Crohn's disease location and disease behavior and surgery: a cross-sectional study of the IBD Genetics Consortium. Am J Gastroenterol 108:106-12
Beaudoin, Mélissa; Goyette, Philippe; Boucher, Gabrielle et al. (2013) Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis. PLoS Genet 9:e1003723
Hu, Pingzhao; Muise, Aleixo M; Xing, Xiang et al. (2013) Association between a multi-locus genetic risk score and inflammatory bowel disease. Bioinform Biol Insights 7:143-52
Kabakchiev, Boyko; Silverberg, Mark S (2013) Expression quantitative trait loci analysis identifies associations between genotype and gene expression in human intestine. Gastroenterology 144:1488-96, 1496.e1-3
Rivas, Manuel A; Beaudoin, Melissa; Gardet, Agnes et al. (2011) Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43:1066-73
Muise, Aleixo M; Walters, Thomas; Xu, Wei et al. (2011) Single nucleotide polymorphisms that increase expression of the guanosine triphosphatase RAC1 are associated with ulcerative colitis. Gastroenterology 141:633-41
Anderson, Carl A; Boucher, Gabrielle; Lees, Charlie W et al. (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43:246-52

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