Scientific Abstract
Proposal No. IBD-0164R
Principal Investigator: Carsten Büning, M.D.
Applicant Organization: Charité, Campus Mitte, Universitätsmedizin Berlin (Germany)
Project Title: Genes involved in epithelial integrity as risk factors for inflammatory bowel disease?
Period of Award: June 1, 2006 – November 30, 2007
An increased gastrointestinal permeability is believed to be an important mechanism in the development and course of Crohn’s disease (CD). Interestingly, this pathogenetic feature also is observed in healthy relatives of CD patients, suggesting that genetic alterations are involved in this phenomenon. However, no mutation yet has been identified to be associated with this disturbed intestinal barrier.
The integrity of the epithelial cell layer within the intestinal barrier is maintained by intercellular junctional complexes composed mainly of tight junctions (TJ). Outstanding progress has been made in order to identify the characteristic structures of the epithelial barrier. Recent studies suggest that the proteins occludin, claudin-1, claudin-4 and JAM-1 (junction adhesion molecule 1) constitute the backbone strands of the tight junction network.
Our hypothesis is that mutations in these tight junction genes (occludin, claudin-1, claudin-4, and JAM-1) increase susceptibility to CD. We also expect that mutations in these candidate genes are associated with a distinct phenotype of CD. In addition, we will analyze recently identified variants within the Myosin IXB gene. These variants are associated with celiac disease and are suggestive of a primary intestinal barrier defect.
In the first step of our study, all coding regions including intronic and promoter regions of the candidate genes occludin, claudin-1, claudin-4, and JAM-1 will be sequenced in CD patients where an increased intestinal permeability has been observed by triple-sugar-test analysis. Relevant single nucleotide polymorphism (SNPs) within the different tight junction genes found by sequencing and the reported myosin IXB gene variants will be investigated in a case control study design in German patients with CD, their healthy relatives, spouses, patients with ulcerative colitis and controls. Data from genotyping will be correlated to results from measurement of gastrointestinal permeability and to clinical characteristics. To test the hypothesis generated within the German samples, a second population of Hungarian IBD patients will be used. In this study group, relevant SNPs also will be investigated and correlated to the phenotype. In both patient populations from Germany and Hungary, data on known CD associated susceptible loci (CARD15, DLG5, OCTN) are available to study potential interactions with the newly identified mutations in our candidate genes.
To our knowledge, this is the first study to analyze genes involved in the regulation of epithelial integrity and their contribution to CD. If our study identifies genetic alterations associated with the impairment of the intestinal barrier, these data would be a rationale basis for the investigation of therapeutic and preventive measures in IBD.