Identification of the Ulcerative Colitis Gene(s) on Chromosome 2q

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Ulcerative colitis (UC) and Crohn's disease, the two common forms of idiopathic inflammatory bowel disease (IBD), are chronic, relapsing inflammatory disorders of the Gl tract that have a peak age of onset in the second to fourth decades of life. A large body of evidence indicates that IBD is heritable with complex genetics, and the PI's long-term goal is to dissect the complex genetics of IBD. The specific hypothesis underlying the proposed research is that a genetic variant (or genetic variants) conferring susceptibility to UC are located within a 47 megabase region of chromosome 2q. The hypothesis is based on the following preliminary studies: First, this region of chromosome 2q showed the most significant linkage to UC (multipoint lod = 2.19) in a whole genome linkage scan that we and our collaborators performed. Second, two of only three other IBD genome scans that studied a substantial number of UC-affected relative pairs showed nominal evidence for linkage to the same region of chromosome 2q. Third, this region of chromosome 2q showed the most evidence for linkage to UC and was the only genomic region that satisfied criteria for suggestive linkage to UC in a meta-analysis of 10 North American and European IBD genome scans. We believe that the time is ripe to take advantage of data from The International HapMap Project to implement an efficient, systematic linkage disequilibrium (LD) mapping strategy to identify UC-associated genetic variant(s) on chromosome 2q. Our study design, which incorporates two stages of genotyping with joint analysis of the data from both stages, should provide an optimal balance of genotyping efficiency with little loss of power in comparison to a one-stage study design. In the first stage, approximately 8,000 intelligently selected (using HapMap data) SNPs spanning the chromosome 2q linkage region will be genotyped in 500 trios of UC-affected individuals and their parents using Illumina Custom Infinium BeadChips. In the second stage, 768 of the most promising SNPs from Stage I will be genotyped in 500 additional UC cases and 500 unrelated controls using the Illumina GoldenGate Assay platform. Joint LD analyses of the trio and case-control data will be performed. At the end of the project, we expect that we will have identified SNPs that are in LD with UC-predisposing genetic variant(s) on chromosome 2q. [unreadable] [unreadable] [unreadable]