The inflammatory bowel diseases (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), are complex, multigenic disorders. A central epidemiologic feature of IBD is its several-fold increased prevalence in individuals of Ashkenazi Jewish ancestry. Associated variants in the NOD2/CARD15 gene do not account for the increased CD prevalence among the Ashkenazim and implicated variants in the OCTN gene cluster and MDR1 are not significantly associated in Ashkenazim CD. These unexpected findings demonstrate that mechanisms of disease pathogenesis are fundamentally different in Jewish and non-Jewish CD. Support for significant linkage evidence on chromosome 3q27-28 is provided by a meta-analysis of all linkage studies in IBD. In our large IBD cohort and in the Ashkenazim subset, the most significant evidence for linkage is observed in this region. Identifying CD-associated risk alleles, given the markedly higher disease prevalence in Jewish populations, will provide significant insight into mechanisms of disease. I. To perform a comprehensive SNP-based case-control association study in Ashkenazi Jewish CD between 186,600,000 and 191,700,000 on chromosome 3q. A case-control study genotyping tagging SNPs in the region in 300 Ashkenazim CD and 300 Ashkenazi controls is proposed. Single and multipoint analyses will be performed to test identify markers and genes meriting replication efforts. II. To test SNPs demonstrating the most significant evidence for CD association in independent Ashkenazi and non-Ashkenazi European ancestry CD cohorts. To ascertain 100 independent Jewish UC cases. Replication cohorts will include independent Jewish CD cases and Jewish controls, non-Ashkenazim European ancestry CD cases and controls. Comparative patterns of disease association and linkage disequilibrium in Ashkenazim and non-Ashkenazim European ancestry cases and controls will be defined. Ascertainment of 100 additional independent Jewish UC cases will allow for well-powered association studies in functional, disease-associated SNPs. III. To identify functional variants contributing to IBD susceptibility on chromosome 3q27-28. To comprehensively define the nature of IBD association for these functional variants. Markers will be developed and typed in replicated regions of association to assess which genes contribute to the replicated association. Sequence conservation analyses between species are highly effective in identifying conserved functional motifs (e.g. microRNA targets). Resequencing will be performed in CD patients in those regions most likely to contain functional alterations. Genotype-dependent alterations in gene activity and expression will be defined using primary cells. Genotyping of all putative functional SNPs in the region will be performed in Jewish and non-Jewish CD and UC to comprehensively define the nature of IBD association contributed by functional variants in this region. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK072373-03
Application #
7487293
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Karp, Robert W
Project Start
2006-09-25
Project End
2010-08-31
Budget Start
2008-09-01
Budget End
2010-08-31
Support Year
3
Fiscal Year
2008
Total Cost
$275,602
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Chen, Min; Cho, Judy; Zhao, Hongyu (2011) Incorporating biological pathways via a Markov random field model in genome-wide association studies. PLoS Genet 7:e1001353
Chen, Min; Cho, Judy; Zhao, Hongyu (2011) Detecting epistatic SNPs associated with complex diseases via a Bayesian classification tree search method. Ann Hum Genet 75:112-21
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Ballard, David; Abraham, Clara; Cho, Judy et al. (2010) Pathway analysis comparison using Crohn's disease genome wide association studies. BMC Med Genomics 3:25
Ballard, David H; Cho, Judy; Zhao, Hongyu (2010) Comparisons of multi-marker association methods to detect association between a candidate region and disease. Genet Epidemiol 34:201-12
Silverberg, Mark S; Cho, Judy H; Rioux, John D et al. (2009) Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet 41:216-20
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Abraham, Clara; Cho, Judy (2009) Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflamm Bowel Dis 15:1090-100
Bhat, Mamatha; Nguyen, Geoffrey C; Pare, Pierre et al. (2009) Phenotypic and genotypic characteristics of inflammatory bowel disease in French Canadians: comparison with a large North American repository. Am J Gastroenterol 104:2233-40

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