This application is submitted in response to RFA DK-06-504 to continue the efforts of the Inflammatory Bowel Disease Genetics Consortium and our role as a Genetic Research (GRC) with the central goal of identifying susceptibility genes contributing to the pathogenesis of inflammatory bowel disease (IBD). This will be accomplished through the following specific aims.
Specific Aim 1 : Expansion, Development and Management of Consortium Resources. Our GRC will recruit additional IBD cases, controls, and parents with a focus on ulcerative colitis and early onset cases. Extensive clinical data will be collected on recruited subjects and biospecimens (EBV-transformed lymphoblastoid cell lines, DNA, serum, whole blood) will be ascertained and stored at the NIDDK Genetics Repository for use by the Consortium, individual GRCs and outside investigators.
Specific Aim 2 : To employ a variety of approaches to identify genetic variation that contributes to IBD susceptibility. Our GRC will be involved in the follow-up of European ancestry genome-wide association study results. A particular initial focus of our GRC will be on a) integrating the suggestive linkage data and genome-wide association data in the IBD2 linkage region followed by additional association mapping within IBD2, and b) a resequencing, detailed haplotype and additional association study of the IL23R gene region.
Specific Aim 3 : To build a risk model of IBD through understanding genetic influence on variations in phenotypic expressivity, gene pathway analysis, and gene-gene (G x G) and gene-environmental (G x E) interactions. A particular initial focus of our GRC will be on gene-gene interaction analyses and pathway analyses of genes along the IL23R pathway. Our GRC may also take on other projects as genes/genomic regions advance to confirmed evidence for contribution to disease through follow-up of the Consortium's genome-wide association data. IBD is a chronic inflammatory disease of the gastrointestinal tract which primarily affects young people and is characterized by long-term illness and the need for potent medical therapy and substantial surgical therapy. The work of the IBD Genetics Consortium will enable us to identify important predisposing and disease modifying genes contributing to the pathogenesis of IBD which has the promise to: (1) identify persons at risk for disease, (2) predict disease course, (3) aid in selection of treatment, (4) understand pathophysiologic mechanisms such that novel preventive and therapeutic interventions can be developed. Advances in IBD gene identification and methodologic approaches may also be applicable to other complex genetic disorders.
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