Inflammatory bowel disease genetics: candidate gene investigation by genetic association study and expression analysis in ulcerative colitis and Crohn's disease. (360G-Wellcome-078331_Z_05_Z)

Introduction: Inflammatory Bowel Disease (IBD) genetics is an area of rapid scientific progress. Crohn's disease (CD) and ulcerative colitis (UC) comprisethe main and related forms of IBD. Fine mapping of IBD linkage intervals has identified NOD2/CARD15 as a confirmed CD gene, and OCTN1, DLG5 and MDR1 have been recently implicated for CD, UC or both. Several additional strong linkages await resolution, with the prospect of fundamental advance in our understanding of IBD pathogenesis and the heterogeneity within CD and UC.Aim: Working with the world-class facilities and expertise in Cambridge, I aim to perform a systematic large-scale positional candidate gene association study to identify UC and CD susceptibility genes and phenotype-genotype correlations. I will then investigate expression patterns for genes implicatedin the association analysis in intestinal biopsies.Method: Using DNA and clinical data from 2000 UC subjects, I will genotype 768 non-synonymous or tagsingle nucleotide polymorphisms within two strong and replicated regions of linkage. I will then analyse genotypes to identify associated variants, as well as gene-gene and phenotype-genotype correlations. I will also perform replication analyses in an independent panel for CD-associated loci from the UK-wide 500 000 marker Welcome Trust Case Control Consortium study (WTCCC) forwhich the Cambridge group is playing a leading role.Expression patterns of genes identified for both UC and CD will be assessed using quantitative rtPCR,immunohistochemistry and RNA FISH in intestinal biopsies from cases and controls.