This Research Plan is submitted in response to the RFA DK-06-504 for continuing the NIDDK Inflammatory Bowel Disease Genetics Consortium (IBDGC). This Master Application, submitted as a Data Coordinating Center application (DCC) from Yale University, describes prior research accomplishments, a prospective research plan, and the operational infrastructure of the entire IBDGC. This DCC application (Principal Investigator, PI: Judy H. Cho, M.D.) has been coordinated with Genetics Research Center (GRC) applications from the Cedars-Sinai Genetics Research Center (CSGRC), the Johns Hopkins Genetics Research Center (JHGRC), the University of Montreal Genetics Research Center (UMGRC), the University of Pittsburgh Genetics Research Center (UPGRC), the University of Toronto Genetics Research Center (UTGRC), and the Yale University Genetics Research Center (YUGRC). The central goal of this Consortium is to identify susceptibility genes contributing to the pathogenesis of IBD. This large challenge is optimally met through a Consortium structure due to synergy in a group with complementary skills, enhanced statistical power, ongoing NIH oversight and optimized quality control. The showpiece of the first funding period has been the identification of IL23R (interleukin-23 receptor) as a major susceptibility gene for IBD, highlighting the significant pathogenic role of genetic variation in IBD. Here, we propose to build on present progress to comprehensively define genetic contributions in IBD.
Three specific aims i nclude: 1) Expansion, Development and Management of Consortium Resources. Increased recruitment of key cohorts, including early-onset cases, will provide improved statistical power. 2) To employ a variety of approaches to identify genetic variation that contributes to IBD susceptibility. We provide a broad algorithm for follow-up of initial association signals. An ulcerative colitis genome-wide association study is proposed. 3) To build a risk model of IBD by understanding genetic influence on variations in phenotypic expressivity, gene pathway, and gene-gene (G x G) and gene-environmental (G x E) interactions. A basic model for identifying genetic predictors of phenotypic variability is provided. Specific stages of workup, optimally utilizing the strengths provided by uniform, well-powered, large Consortium-wide studies with the greater individualization and specialization of approaches achievable with GRC-led studies are described.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK062429-09
Application #
7688654
Study Section
Special Emphasis Panel (ZDK1-GRB-G (M1))
Program Officer
Karp, Robert W
Project Start
2002-09-30
Project End
2012-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
9
Fiscal Year
2009
Total Cost
$1,006,590
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Hinks, Anne; Marion, Miranda C; Cobb, Joanna et al. (2018) Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis. Arthritis Rheumatol 70:957-962
Hui, Ken Y; Fernandez-Hernandez, Heriberto; Hu, Jianzhong et al. (2018) Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. Sci Transl Med 10:
Huang, Hailiang; Fang, Ming; Jostins, Luke et al. (2017) Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature 547:173-178
Hinks, A; Bowes, J; Cobb, J et al. (2017) Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases. Ann Rheum Dis 76:765-772
Yadav, Pankaj; Ellinghaus, David; Rémy, Gaëlle et al. (2017) Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice. Gastroenterology 153:550-565
Misra, Ravi; Arebi, Naila (2017) Re: Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease. Gastroenterology 152:2082-2083
Kopylov, Uri; Boucher, Gabrielle; Waterman, Matti et al. (2016) Genetic Predictors of Benign Course of Ulcerative Colitis-A North American Inflammatory Bowel Disease Genetics Consortium Study. Inflamm Bowel Dis 22:2311-6
Sasaki, Mark M; Skol, Andrew D; Hungate, Eric A et al. (2016) Whole-exome Sequence Analysis Implicates Rare Il17REL Variants in Familial and Sporadic Inflammatory Bowel Disease. Inflamm Bowel Dis 22:20-7
Levine, Adam P; Pontikos, Nikolas; Schiff, Elena R et al. (2016) Genetic Complexity of Crohn's Disease in Two Large Ashkenazi Jewish Families. Gastroenterology 151:698-709
Chuang, Ling-Shiang; Villaverde, Nicole; Hui, Ken Y et al. (2016) A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF. Gastroenterology 151:710-723.e2

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