GENETIC MAPPING STUDIES IN INFLAMMATORY BOWEL DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The idiopathic inflammatory bowel diseases (IBD) are comprised of two major subtypes, Crohn's disease (CD) and ulcerative colitis (UC) and are complex, multigenic disorders. The hypothesis of this study is that specific risk alleles (genetic variants identifiable in genomic DNA) account for the phenotypic expression of IBD. Proof of causation for specific risk alleles is provided by linkage and association studies, and ultimately, functional correlations. We and others have established that Arg702Trp, Gly908Arg, and Leu1007fsinsC in the NOD2/CARD15 gene on chromosome 16 are highly associated with CD 2-4. However, the exact functional mechanisms by which these mutations in NOD2/CARD15 and other genes mediating host response to bacterial peptidoglycan lead to CD are still incompletely defined. Recently, genetic variants within the OCTN1/SLC22A4-OCTN2/SLC22A5 (chromosome 5q) 5, DLG5 (chromosome 10q) 6 and MDR1 (chromosome 7q) 7 genes have been associated with CD and IBD. However, combined meta- 8 and mega-analyses of linkage studies demonstrate relatively modest scores in these regions on chromosomes 5q, 10q and 7q, with other regions demonstrating significantly higher scores. Of special significance is a 5.2 Mb region defined by D3S1262 and D3S2455 on chromosome 3q27-28. Our aim, therefore, is to identify these specific regions and susceptibility genes through Fine-mapping association studies and perform functional analyses to define the mechanisms by which mutations in susceptibility genes lead to IBD. Such studies will provide insight into early steps in the pathogenesis of these diseases and help identify functional variants contributing to IBD susceptibility.