Investigation of genetic susceptibility to inflammatory bowel disease. (360G-Wellcome-081808_Z_06_Z)

The inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) are chronic disorders that are associated with severe inflammation of parts of the gastrointestinal tract. The underlying causes are unresolved, but may involve chronic bacterial infection and a dysregulated immune response. Epidemiological studies indicate that both genetic and environmental factors contribute to pathogenesis, and the NOD2/CARD15 gene has been identified as a susceptibility gene for CD. The W ellcome Trust has funded a genome-wide case control association study to identify susceptibility loci for common diseases, including CD. A major goal of this proposal is to develop the leads from that study by fine mapping and identification of the associated susceptibility genes and causal variants. The case control data will also enhance our current work to define the genes and causal variants at the CD susceptibility loci on chromosome 5q31 and 6p21. Follow-up of ongoing genome-wide and a gen e-based scans for susceptibility genes for UC will also be undertaken. Two further key goals are to examine the effect of causal variants on gene function in cells from patients of defined genotype, and to investigate their contribution to disease risk and to disease behaviour.