Scientific Abstract

Proposal No.  IBD-0133R
Principal Investigator:  Judy H. Cho, M.D.
Applicant Organization:  The University of Chicago (Illinois, U.S.A.)
Project Title:  Identification of inflammatory bowel disease susceptibility gene(s) on chromosome 3q
Period of Award:  December 1, 2004 – May 31, 2006

Crohn’s disease (CD) and ulcerative colitis (UC) are related chronic inflammatory disorders of the intestines caused by a combination of genetic, developmental and environmental factors.  We and others have established that three major coding region polymorphisms within the NOD2/CARD15 gene are highly associated with CD.  While these findings represent a crucial advance, it is clear that the NOD2/CARD15 mutations are neither necessary nor sufficient for disease expression. 

We present data from our large North-American linkage screen demonstrating that the largest peak overall was in the chromosome 3q27-28 region, a region demonstrating suggestive evidence for linkage in our initial linkage analysis.  Importantly, the linkage evidence on chromosome 3q27-28 is observed most significantly in Jewish inflammatory bowel disease (IBD) families, and represents the most significant region of linkage evidence in Jewish cohorts.  We also present data from a meta-analysis combining linkage data from 1253 IBD affected relative pairs implicating the chromosome 3q region.  Because the Ashkenazi Jewish population represents a genetically more homogeneous subgroup, and because the prevalence of IBD is higher in this cohort, we hypothesize that significant IBD susceptibility gene(s) reside in this region, and the aim of this proposal is to identify genetic associations, and ultimately identify risk alleles in IBD patients on chromosomes 3q27-28.

A strategy for initial SNP genotyping over a 5 Mb region around D3S2398 in an initial cohort of 200 Jewish trios (affected child plus both parents) plus 80 nuclear families (affected sibling pair plus both parents) is proposed.  Single and multipoint analyses based on linkage disequilibrium (LD) patterns will be performed with integration of covariate data (disease location, age of onset, NOD2/CARD15 genotype status) through risk parameters.  Selected markers will be tested in replication cohorts (Jewish case-control, non-Ashkenazi Caucasian trios). 

Regions demonstrating significant replication will undergo further SNP discovery to identify all variants, especially rare ones often missing in current public databases.  Recent technical advances in high-throughput custom genotyping of known variants and resequencing approaches to comprehensively identify rare variants have occurred, and together with novel analytic LD approaches, use of these new, cutting edge technologies dramatically increases the feasibility of successfully mapping IBD risk alleles in the chromosome 3q27-28 region.
 
The identification of associated haplotypes on chromosome 3q27-28 will provide additional insight into ethnic differences in complex multigenic disorders.  Finally, perhaps for no other complex disorder is the potential for genetic approaches to fundamentally advance present paradigms of disease pathogenesis as significant as in IBD.  The identification of risk alleles for IBD has already, and will continue to provide new ideas and directions in our understanding, treatment and prevention of the disorders presently classified as Crohn’s disease and ulcerative colitis.