Crohn's disease (CD) and ulcerative colitis (UC) are two common inflammatory diseases of the gastrointestinal tract, collectively known as the inflammatory bowel diseases (IBD). It is estimated that as many as one million Americans are affected with these debilitating diseases. IBD may occur in people of all ages, but it is primarily a disease that arises in adolescents and young adults. Currently there is no known cure for IBD. Over the last five years, a number of IBD genes (CARD15, IBD5, MYO9B, IL23R, ATG16L1) have been identified, but these do not explain all of the genetic risk to IBD. We have previously reported evidence of linkage to two regions of the genome (located on the short arms of chromosomes 3 and 6) - indicating the presence of additional IBD genes. In the last four years we performed candidate and positional association mapping studies of these two chromosomal regions that have led to the identification of significantly associated alleles or putative genetic risk factors in the targeted regions. In this application, we propose to identify all of the casual alleles in the genes that we have identified and also to identify secondary risk factors for which we have found significant evidence. In the last few years it has also become clear that one of the major challenges in the study of complex genetic traits is to determine how disease genes and their corresponding alleles exert their influence on the biology of health and disease. We therefore aim to employ a limited set of functional approaches that will be commonly applied to a set of IBD risk genes. This systematic pathway analysis will help guide future in-depth functional studies and will provide the beginnings of a common framework by which we can build a model of how these genetic variants influence biological pathways eventually leading to the development of IBD.
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