Johns Hopkins Crohn's Disease and Ulcerative Colitis Study
Recruitment status was: Recruiting
Inflammatory Bowel Disease
|Study Design:||Observational Model: Case Control
Time Perspective: Prospective
|Official Title:||Johns Hopkins Crohn's Disease and Ulcerative Colitis Study|
|Study Start Date:||July 1996|
Individuals who do not have IBD
Individuals with IBD
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The inflammatory bowel diseases (IBD)—Crohn's disease (CD) and ulcerative colitis (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".
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. First-degree relatives of IBD patients have an 8 to 10 fold increased risk of developing IBD. Therefore, it was hypothesized that IBD is in part the result of mutations and disease polymorphisms in specific susceptibility genes. Furthermore, the complications, site of disease, onset and severity show increased familial concordance. Therefore, these and perhaps other factors in variability of disease expression and course appear to be in part under genetic control. The hypothesis is that familial disease aggregation is the result of IBD susceptibility genes disease risk polymorphisms and mutations. Loci containing these disease genes can be identified by linkage mapping and the disease gene polymorphisms can be determined by showing linkage disequilibrium (LD) with the disease variant greater in affected IBD cases as compared to within family (parental) or unrelated, matched controls. Power analyses show that to have 80% power to only identify IBD susceptibility loci with a relative sibling risk of 1.5 and an error of p = 0.01 and heterogeneity of 0.3 would require a genome screen on approximately 200 affected relative pair pedigrees. It would require several times this number of pedigrees to have power to establish these loci at genome wide levels of significance (Brant and Shugart, Inflamm Bowel Dis, 2004). To have power to establish (at p = 10-7) disease specific risk polymorphisms by LD association analyses—for genotypic relative risks of 2.0 with complex models of inheritance would require 350 to 700 cases and 350 to 700 controls or a similar number of parental/affected offspring "trio" pedigrees (i.e. up to 1400 parents with 700 affected offspring) (Knapp, AJHG, 1999). To establish lower relative risk polymorphisms would require about three times these numbers.
The current protocol was initiated in 1996 to initially collect multiplex pedigrees for linkage studies. The investigators performed the first IBD genome screen in North America in 1998 with DNAs from pedigrees collected from the study combined with those from the Univ. of Chicago and identified multiple loci, and confirmed the IBD1 locus on chromosome 16. In 2003, the investigators published a second genome wide screens that also included a large series
of patients recruited at Johns Hopkins under this protocol identifying and comfirming additional loci. The investigators (and others) have identified 8 confirmed IBD loci (IBD1-8), and there are several additional loci with strong evidence in one or more screens (Brant and Shugart, Inflamm Bowel Dis., 2004). The investigators have recently received funding for a new genome screen performed at the NIH funded Center for Inherited Disease Research (CIDR) genotyping facility, and samples are being submitted at this time. From these multiple loci, three proven disease genes for IBD have been established; the most provocative is the NOD2/CARD15 gene for the IBD1 locus. This gene is an intracellular sensor of bacterial cell wall components and a critical player in the innate immune system known to be important in IBD pathogenesis (Hugot et al and Ogura et al; Nature, 2001). The investigators participated in this discovery (Ogura et al., Nature, 2001).
There are three independent mutations in the NOD2 gene (G908R, R702W, and Cins1007fs) that are consistently increased in white CD patients as compared to healthy controls. These mutations interfere with the gene's ability to sense muramyl dipeptide, the critical bacterial cell wall residue. The investigators added to the protocol in 2001 permission to study isolated cells and biomarkers from larger blood withdrawals from study subjects and the investigators have found evidence for NOD2 gene expression variants. The two other established genetic factors are haplotype associations in the HLA region (IBD3) and the chromosome 5q cytokine cluster (IBD5, leading candidate are functional mutations in the OCTN1/2 genes). The investigators have also identified NFKB1 and MDR1 IBD predisposing polymorphisms.
Despite the exciting discoveries of multiple genes associated with IBD, altogether, these genes account of only a fraction of familial risk. Therefore, the investigators will continue to enroll participants to meet the present goal for recruitment of 2,500 samples composed of IBD pedigrees for linkage and familial LD studies, and singleton cases and controls for case-control LD association studies. The investigators will also work to discover if there is association of the genes with biomarkers from serum (the investigators have examined anti-Saccharomyces cerevisiae antibody and NOD2), and cells from blood and immortalized blood from IBD patients as compared to controls. In addition, the investigators will test biomarkers to evaluate their potential as predictors of disease course and therapeutic outcome.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01169207
|Contact: Patricia Ushry||1(888) firstname.lastname@example.org|
|Contact: Denise Spears, B.A.||(410) email@example.com|
|United States, Maryland|
|Baltimore, Maryland, United States, 21231|
|Contact: Patricia Ushry 888-279-4194 firstname.lastname@example.org|
|Contact: Denise Spears (410) 502-5846 email@example.com|
|Principal Investigator: Steven R Brant, M.D.|
|Principal Investigator:||Steven R Brant, M.D.||Johns Hopkins University|