Evidence from identical twin studies, familial aggregation, and consistently greater risk in Ashkenazim has shown that the greatest risk for developing Crohn's disease (CD) is genetic. A CD locus on chromosome 16, IBD1, was identified in 1996. IBD1 is the most consistently demonstrated inflammatory bowel disease (IBD) genetic locus, replicated in five out of seven studies. As part of an International IBD Genetics Consortium, we have recently provided definitive evidence for the IBD1 locus. Genotyping of 372 fully informative CD pedigrees randomly selected from 12 international IBD collaborators provided highly significant evidence for IBD1 (Lod 6.41). There was no evidence for IBD1 in 242 UC or mixed pedigrees. IBD1 appears to be particularly relevant in Asheknazim pedigrees. We recently found that stratifying pedigrees by early age at diagnosis and greater disease severity may greatly reduce linkage heterogeneity for IBD1. The overall goal of this application is to identify genetic mutations or polymorphisms responsible for IBD1. This goal will be achieved by the following specific aims: (1) we will identify linkage disequilibrium for IBD1 in Ashkenazim pedigrees. We will genotype markers spaced an average of 100 kb apart in 120 Ashkenazim trios with early-onset, severe CD. (2) For markers where there is evidence for linkage disequilibrium, we will extend evidence for the immediate region by genotyping adjacent markers, additional Ashkenazim CD pedigrees and non-Ashkenazim pedigrees ultimately identifying a minimal IBDI haplotype with maximal evidence of linkage disequilibrium. (3) We will perform mutation/polymorphism analysis on prioritized genes that map within this haplotype, and determine, using linkage disequilibrium analytic methods, which genetic variation is responsible for the genetic risk of Crohn's disease associated with the IBD1, chromosome 16 locus. Defining the IBD1 mutation for CD will be a major step in unraveling the etiology and pathophysiology of this enigmatic disease, improve genetic counseling and make possible novel preventative and therapeutic strategies.
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