The aim of this project is to identify major susceptibility genes involved in the pathogenesis of inflammatory bowel disease (IBD). IBD involves chronic recurring inflammation of the intestines and is a major cause of morbidity in children and young adults. The etiology is unknown. Development of better therapies is dependent on understanding the earliest stages of disease pathogenesis. Genetic approaches offer a powerful means of identifying genetic variations within genes which underlie diseases susceptibility. A genome-wide linkage search for IBD susceptibility genes demonstrated the greatest evidence for linkage at chromosome 1p36. The concomitant inheritance of risk alleles at chromosomes 1 and 16 increases the overall risk for IBD. Linkage and linkage disequilibrium is observed in a genetic isolate with a high prevalence of IBD, the American Chaldeans over a region which precisely overlaps the region of linkage in the outbred populations. A central hypothesis is that the IBD susceptibility gene in the Chaldean population at chromosome 1p36 is the same susceptibility gene accounting for the observed linkage in outbred populations. Localization of the disease gene has been refined to a 2 cM region. The major aim of this project is to identify the IBD disease gene and specific risk alleles contributing to the evidence for linkage at chromosome 1p36. It is predicted that risk alleles for IBD will be high in frequency and therefore common to different populations (Chaldeans, Ashkenazim, non-Ashkenazim Caucasians). Specific risk alleles for IBD will identified through: a) Construction of a sequence- ready, PAC(P1 artificial chromosome)-based contig spanning the region of interest. b) Characterizing, through random sequencing, single nucleotide polymorphisms (SNPs) and expressed sequence tags in the region. c) Typing SNPs in Chaldeans and outbred, multiply affected families throughout the region. As refinement is localized, alleles in linkage disequilibrium with disease alleles are predicted to have progressively higher frequencies in enriched subsets most likely to inherit specific risk alleles. Once risk alleles are identified in multiplex families, characterization of the nature and broad significance of specific risk alleles for IBD in a variety of populations will be performed.
