Studies by the genome scan approach have identified over 10 chromosomal regions containing putative loci predisposing to IBD. The identified IBD1 gene (NOD2) can only explain a small percent of Crohn's disease (CD) patients and does not contribute to ulcerative colitis (UC). Thus, other genes that contribute to IBD susceptibility exist and need to be identified. Compared to the NOD2 gene, the remaining loci contribute a lower susceptibility to IBD as indicated by weaker linkage evidence and less consistency across populations/studies. To identify such genes with modest effects, association studies based on linkage disequilibrium (LD) are the method of choice. However, in the Caucasian population the extent and usefulness of LD is limited by population history. Therefore, we herein propose an alternative strategy to map the IBD genes by taking advantage of an admixed population in Puerto Rico - mapping by admixture linkage disequilibrium (MALD). The goal of this study is to identify IBD susceptibility genes by narrowing selected chromosome regions showing sufficient evidence for linkage, then performing fine mapping using both case-control and the family based approaches. Specifically, the investigators will establish a panel of clinically characterized Puerto Rican IBD patients (300UC, 300CD, 300control) and families (400 trios); narrow selected chromosomal regions containing putative loci for IBD using MALD with population specific markers; evaluate potential interaction/confounding effect with NOD2 and serological antibodies (ANCA, ASCA, I2); and fine map the susceptibility genes with dense markers across the narrowed region and within candidate genes. By covering important chromosomal regions, using an admixed population in which LD has been sustained at longer chromosome segments; genotyping sufficient population specific markers; controlling for spurious association; evaluating interaction effects with other factors, and employing a two-stage mapping strategy, this proposal maximizes the opportunity to refine the chromosomal regions that contain susceptibility genes for IBD, thus enhancing the opportunity to identify the actual genes that contribute to the development of IBD.
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