Lay Summary

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 an inflammatory bowel disease that causes ill health in 0.5% of people in the Western world.  We believe that the development of this form of inflammation of the gut is the result of a combination of genetic factors and factors in the environment, including normal gut bacteria.  The genetic factors that contribute to this disease have been widely studied, and a number of areas of the human genome have been highlighted.  However, it was only in 2001 that the first disease gene, known as NOD2 or CARD15, was identified.  Common differences in this gene are associated with disease in about one-third of patients, and we have recently shown that this is particularly true for those patients with disease in the ileum, a specific region of the gut.  This genetic evidence confirms our clinical suspicion that CD is not single disorder, but a family of closely related diseases that demonstrate similar symptoms and signs that are a result of different genetic abnormalities. 

The aim of this study is to identify which genes are responsible for the variant of CD that affects the large bowel.  We plan to use a combination of approaches:  first, we will identify which genes are activated in the blood and colon during the early stages of a disease flare.  To do this, we will study patients whose colon has been taken out of circuit by a “defunctioning ileostomy.”   This treatment is used because diverting the feces from the large bowel may result in improvement in inflammation in that area.  In previous studies performed by ourselves and by colleagues in Belgium, we have shown that we can reactivate disease in a limited manner by controlled contact with an individual’s own feces.  In this study, we will biopsy the colon and take blood from patients before and after contact with feces.  These samples will be studied to identify which genes are activated during the course of disease.  To make sure that we are not identifying genes that normally activate in this situation, we will compare results from patients who have had a “defunctioning ileostomy” for CD with those who have had the same treatment for cancer.  We will then sequence these genes to see if they harbor common variations that may influence the gene’s function.  Finally, we will use our large group of 1500 CD patients to test if these gene variants are associated with specific kinds of disease pattern.