Lay Summary

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

The inflammatory bowel diseases (IBD) are comprised of Crohn’s disease (CD) and ulcerative colitis (UC).  IBD is caused by a complex interplay of genetic, environmental and developmental factors.  IBD cases tend to cluster within families and identical twins tend to both have disease more often than non-identical twins.  The genetic contribution to IBD is complex, with multiple genes contributing to disease (termed multigenic disorders.  Traditionally, the first step in identifying IBD disease genes has been the use of a type of study known as a genetic linkage screen.  In this approach, families with more than one affected member are typed at genetic markers throughout the genome for the purposes of identifying broad chromosomal regions shared more than would normally be expected between two or more affected relative pairs.  We and others initially identified that mutations within the NOD2/CARD15 gene on chromosome 16 initially implicated through a genetic linkage screen contribute to an increased susceptibility of developing CD.  A second well-replicated disease association is with the OCTN1/SCLC22A4 and OCTN2/ SCLC22A5 gene cluster on chromosome 5q, which is clearly associated with CD, and may be associated with UC as well.

A number of genetic linkage studies have been reported over the past several years in IBD implicating a large number of chromosomal regions.  A recent study prioritized the implicated linkage peaks by carefully combining the results of all of the studies.  Using this approach, one of the most important peaks was on chromosome 3q, in a region that was strongly implicated in our genetic linkage study.  This peak may be particularly important in Jewish cases of IBD, as much of our genetic linkage signal in this region derives from Jewish IBD families.  IBD is two to four times more prevalent in the Ashkenazi Jewish population compared to the non-Ashkenazi European ancestry population.  The established gene associations in the NOD2/CARD15 and OCTN gene cluster are unlikely to account for the higher IBD prevalence in Jewish populations.

For multigenic disorders, the feasibility of successfully proceeding from genetic linkage peaks implicating chromosomal regions containing many genes to identifying specific causative mutations within disease genes has increased dramatically with the recent, great strides in the Human Genome Project.  Not only has the entire human genome been sequenced (thus allowing the identification of all human genes), but all relatively common human variants have been identified.  Furthermore, the linkage disequilibrium patterns of these common variants have been described so that the most intelligent selection of genetic variants to type can be performed in order to best capture the genetic structure of the human genome.  For these reasons, we believe that we can find genetic variants within a chromosomal region on chromosome 3q within disease susceptibility genes which significantly increases susceptibility to both CD and UC.