The inflammatory bowel diseases (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), are complex, multigenic disorders. A central epidemiologic feature of IBD is its several-fold increased prevalence in individuals of Ashkenazi Jewish ancestry. Associated variants in the NOD2/CARD15 gene do not account for the increased CD prevalence among the Ashkenazim and implicated variants in the OCTN gene cluster and MDR1 are not significantly associated in Ashkenazim CD. These unexpected findings demonstrate that mechanisms of disease pathogenesis are fundamentally different in Jewish and non-Jewish CD. Support for significant linkage evidence on chromosome 3q27-28 is provided by a meta-analysis of all linkage studies in IBD. In our large IBD cohort and in the Ashkenazim subset, the most significant evidence for linkage is observed in this region. Identifying CD-associated risk alleles, given the markedly higher disease prevalence in Jewish populations, will provide significant insight into mechanisms of disease. I. To perform a comprehensive SNP-based case-control association study in Ashkenazi Jewish CD between 186,600,000 and 191,700,000 on chromosome 3q. A case-control study genotyping tagging SNPs in the region in 300 Ashkenazim CD and 300 Ashkenazi controls is proposed. Single and multipoint analyses will be performed to test identify markers and genes meriting replication efforts. II. To test SNPs demonstrating the most significant evidence for CD association in independent Ashkenazi and non-Ashkenazi European ancestry CD cohorts. To ascertain 100 independent Jewish UC cases. Replication cohorts will include independent Jewish CD cases and Jewish controls, non-Ashkenazim European ancestry CD cases and controls. Comparative patterns of disease association and linkage disequilibrium in Ashkenazim and non-Ashkenazim European ancestry cases and controls will be defined. Ascertainment of 100 additional independent Jewish UC cases will allow for well-powered association studies in functional, disease-associated SNPs. III. To identify functional variants contributing to IBD susceptibility on chromosome 3q27-28. To comprehensively define the nature of IBD association for these functional variants. Markers will be developed and typed in replicated regions of association to assess which genes contribute to the replicated association. Sequence conservation analyses between species are highly effective in identifying conserved functional motifs (e.g. microRNA targets). Resequencing will be performed in CD patients in those regions most likely to contain functional alterations. Genotype-dependent alterations in gene activity and expression will be defined using primary cells. Genotyping of all putative functional SNPs in the region will be performed in Jewish and non-Jewish CD and UC to comprehensively define the nature of IBD association contributed by functional variants in this region. ? ? ?
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