Crohn's disease (CD) is a chronic, idiopathic inflammatory disease of the gastrointestinal tract, which affects approximately 250,000 Americans. CD has a wide variety in its clinical presentations and complications. Complications include malnutrition, stricture formation, abcesses, fistula formation, gastrointestinal bleeding, eye, skin and joint inflammation, and an increased risk of colorectal cancer. There is substantial evidence that CD is, at least in part, a genetic disease. In twin studies, concordance for monozygotic twins has ranged from 44 to 85%. Overall, approximately 20% of patients with CD have a family history of Crohn's disease or ulcerative colitis. There is no evidence that familial clustering is due to environmental factors. The incidence of CD is consistently most prevalent in Ashkenazi Jews, having a prevalence of 2 to 9 times greater than their non-Jewish neighbors, regardless of geographic location. Inheritance of CD does not fit any simple Mendelian models. Recently, potential susceptibility loci for CD have been identified by genome-wide screens in multiplex families. A French group reported evidence for CD susceptibility loci on chromosome 16, and a group from Oxford, England reported susceptibility loci on chromosomes 3, 7 and 12. Information on disease subtype was not reported for either study. A UCLA study confirmed linkage to the region between chromosome 16q12.1 and 16q12.2 in non-Jews, but found no evidence for linkage in Jews. The purpose of our study is to (1) determine if there is evidence to support linkage in affected relative pairs from the Johns Hopkins Crohn's Disease Family Database to the above putative susceptibility loci; and (2) perform a genome-wide screen to identify additional susceptibility loci. All patients in our study group have been classified on the basis of ethnic descent, intestinal localization of disease, complications and phenotypic presentation. Diagnosis has been confirmed by the study investigators. This study was initiated and continues to be performed with the critical assistance of the OPD-GCRC. At the time of writing this report we have collected blood samples and clinical information on 202 study participants from 84 families. We have begun analyzing microsatellite markers to confirm linkage to the above loci. Our final goal is to obtain samples on 200 families. Through the GCRC we have also performed a limited number of studies necessary to firmly establish a diagnosis of Crohn's disease in relatives of CD probands. About 1/3 of our patients are of Jewish descent. Clinical material obtained with the assistance of the OPD-GCRC has allowed us to obtain a First Award from the Crohn's Colitis Foundation of America for $50,000 for three years, awarded 1/1/97, to identify susceptibility genes in the above putative CD loci. Furthermore, we are in the process of embarking on a genome-wide screen in a collaboration with the University of Chicago. Together we have DNA samples on over 200 affected relative pairs. We will be applying for a joint NIH grant to help support this genome-wide screen.
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