5th Annual BMRP Investigator Meeting - Abstract
Genes Involved in Epithelial Integrity as Risk Factors for IBD?
Carsten Büning1,a, Janine Buettner1, Heiko Witt2, Verena Haas1, Sabine Bühner1, Andreas Sturm2, Daniel Baumgart2, Tomas Molnar3, Ferenc Nagy3, Janos Lonovics3, Hartmut Schmidt4 and Herbert Lochs1
1Department of Gastroenterology, Hepatology and Endocrinology, Charité, Campus Mitte (Berlin, Germany); 2Department of Gastroenterology and Hepatology, Charité, Campus Virchow (Berlin, Germany); 31st Department of Medicine, Faculty of Medicine, University of Szeged (Hungary) and 4Transplantationshepatologie, Universitätsklinikum Münster (Germany)
A disturbed epithelial barrier function is an important mechanism in the development of Cohn’s disease (CD). This pathogenetic feature is believed to be genetically determinated. We have recently shown that the 3020inC mutation within CARD15 is associated with this disturbed epithelial barrier function but is not sufficient to explain the genetic basis of the increased gastrointestinal permeability in full.
The integrity of the epithelial cell layer within the intestinal barrier is maintained by intercellular junctional complexes composed mainly of tight junctions (TJ). Herein the proteins occludin, claudin-1, claudin-4, and JAM-1 (junction adhesion molecule 1) constitute the backbone strands of the tight junction network. We thus hypothesized that variants in these TJ genes contribute to this barrier dysfunction and might increase susceptibility to CD.
In the first step of our study, we have now sequenced all coding regions including intron/ exon boundaries of the candidate genes in 20 patients with CD where an increased intestinal permeability has been observed by triple-sugar-test analysis. In addition, we analyzed 20 patients with ulcerative colitis (UC), and 20 controls. By this approach, we identified 14 different genetic variants. In the occludin and claudin 1 gene, we identified three single nucleotide polymorphisms, respectively. In the claudin 4 gene, we found two genetic alterations, and in the JAM-1 gene, we identified six variants. Two SNPs were only detected within probands with CD or UC but not in the control group: one of these variants was identified in the exon 1 of claudin 1 (c.108C>T, p.Ala36Ala), the other alteration was found in exon 5 of the JAM-1 gene (c.438G>A, p.Gly146Gly).
We are now investigating these genetic variants in our study population comprising of German and Hungarian IBD patients and controls. In addition, we have started a case control study to investigate genetic variants within myosin IXb recently found to be associated with celiac disease suggestive of a primary intestinal barrier defect. We are also analyzing two other recent mutations identified to be associated with IBD: A non-synonymous SNP (p.Arg381Gln) in the Il23R gene and a SNP encoding a stop codon of TUCAN (CARD8).
In summary, we have found a novel SNP within the claudin-1 gene that has so far been exclusively found in IBD patients. This SNP might be involved in the disturbed epithelial barrier function characteristic for IBD.
aPrincipal Investigator