Scientific Abstract

Proposal No.   IBD-0055
Principal Investigator:  Derek P. Jewell, BM, BCh, DPhil
Applicant Organization:  University of Oxford (United Kingdom)
Project Title: Identification of the susceptibility gene for colonic Crohn's disease by targeted positional cloning and microarray expression studies
Period of Award:  March 1, 2003 - February 29, 2004

Crohn’s disease (CD) is characterized by an inappropriate response of the mucosal immune system to unidentified antigens.  Epidemiological and molecular evidence implicate genetic factors in determining both susceptibility and phenotype of disease.  These data suggest that CD is not a single disease, but a group of heterogeneous disorders, with distinct molecularly defined clinical characteristics.  In 2001, the first CD gene (NOD2/CARD15) was identified on chromosome 16.  Recent studies have shown that NOD2/CARD15 disease-causing mutations are present in up to 30% of all patients and are associated with small intestinal disease.  A number of other regions of the human genome are believed to harbor CD susceptibility genes including loci on chromosomes 1, 5, 6, 12, 14, 16, and 19.

The aim of this study is to identify genes determining susceptibility to colonic CD by combining positional information with data on gene expression.  We will use the human ileostomy model of Crohn’s disease to determine changes in gene expression in both peripheral blood mononuclear cells and colonic mucosal tissue following reactivation of disease by a five day in vivo fecal challenge.  Subjects will be drawn from an ethnically and clinical homogenous, well-described group of patients defined both by genotype and phenotype.  Control subjects who have had a loop ileostomy for rectal cancer will also be studied pre and post fecal challenge.  Gene expression will be studied using a customized oligonucleotide array.  This will permit the interrogation of 9,500 genes chosen because they lie within replicated CD linkage areas.  These expression studies will generate a short-list of candidate genes that will then be screened for novel polymorphisms by direct sequencing.  Informative candidate polymorphisms will be further studied in large scale case-control association studies, again drawn from our well-defined patient cohort.