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, Crohn's disease (CD) and ulcerative colitis (UC), are chronic, frequently disabling diseases of the gastrointestinal tract. CD and UC have an estimated combined prevalence of 0.2% to 0.3% in the United States, and are two to eight times more prevalent in Jewish Americans of Central or Eastern European descent (Ashkenazi Jews) as compared to non-Jewish Americans. CD may involve any part of the gastrointestinal tract, but most often the colon and terminal ileum. Bowel inflammation is discontinuous, transmural, and may contain granulomas. CD is also associated with bowel stenoses and intestinal and perianal fistulas. UC, by contrast, involves continuous, non-granulomatous inflammation of the colon and rectum, limited to the mucosal layers. Fistulas are not observed. Colonic disease that cannot be clearly identified as CD or UC is designated 'indeterminate colitis.' The etiology of CD and UC is unknown. There is strong evidence from twin studies and familial aggregation that CD and UC are in large part genetic, and follow a complex, non-Mendelian mode of inheritance. International efforts to identify the genes that result in the observed genetic susceptibility to IBD have identified and confirmed susceptibility loci on chromosomes 12 and 16cen. We have previously reported replicating in our patient cohort, the chromosome 16 locus, IBD1, that was first identified by Hugot et al., in a French population in 1996 (see Brant et al, Gastroenterology, 1998). In December 2000, we reported that younger age- at-diagnosis and more severe disease markedly decreased genetic heterogeneity for the IBD1 locus (Brant et al., Gastroenterology, 2000). In a collaboration with investigators from University of Chicago, University of Michigan and University or Pittsburgh, a candidate gene, NOD2, which mapped to the IBD1 locus was tested for mutations in Crohn's disease families. Three mutations were identified that were highly associated mutations (see Ogura et al., Nature, 2001). The most prominent mutation is a frame shift mutation, Leu1007fsInsC/3020, an insertion of a single cytosine nucleotide at position 3020 of the DNA coding region. This region codes for a motif known as a leucine-rich-region (LRR) and is believed to be of specific import to the Nod2 protein's interaction with the nuclear transcription factor NF-Kb. Results such as these further our understanding of the disease process as well as provide clues about the underlying molecular mechanisms that when hampered, contributes to the chronic inflammation of the intestinal tract. We are also in the process of defining the clinical characteristics of NOD2 mutations. Intriguingly, NOD2 mutations are found in a minority of patients with Crohn's disease and are not risk factors for ulcerative colitis. Our previous results from our 10 cM genome-wide screen on 297 CD, UC or mixed relative pairs from 174 families multiplex for IBD (Cho et al, PNAS, 1998) provided strong evidence of linkage on three novel loci: 1p, 3q and 4q. Furthermore, there is additional evidence supporting potential IBD susceptibility genes on other chromosomes, 3p and 7q. These data are an impetus for the continual pursuit of other disease-causing genes. To this end, the overall objective of this protocol is to continue to ascertain database information and blood samples from individuals with IBD, their affected and unaffected relatives and control individuals to continue to identify additional genes and defining additional IBD loci.
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