Genetic and molecular determinants in inflammatory bowel disease

Abstract: Inflammatory Bowel Disease, IBD, are polygenic disorders that present itself to the clinician as a sum of interacting events arising from multiple factors of genetic, immunological and environmental origin, resulting in a chronic relapsing inflammation that manifests itself in two major forms, ulcerative colitis (UC) and Crohn Ls disease (CD). Shortage of reliable biomarkers for correct diagnosis and thus appropriate treatment regime is still a major problem for the clinically active physician. The disclosure of CARD 15/NOD2 as a susceptibility gene for CD, represents, therefore, an important observation towards a better understanding of the pathogenesis of IBD and its integrated diagnosis. The objective of my thesis was to further our understanding of the patho-physiology of IBD. In paper I, the contribution of CARD15/NOD2 polymorphisms in explaining concordance of Crohn Ls disease in monozygotic twins was evaluated. Although total allele frequency of these mutations was higher in concordant twin pairs compared to discordant pairs, statistical significance was not observed. Thus, other CARD15/NOD2 polymorphisms or additional genes are likely to contribute to the disease. In paper II, we assessed polymorphisms in the CARD15/NOD2 gene and in the TNF ¿ promoter, in order to explain variation in individual disease phenotypes. The results indicate that certain CARD15/TNF ¿ allelic combinations can affect TNF ¿ gene expression, which potentially can contribute to interindividual variation in susceptibility to, and manifestation of, IBD. One trade mark of IBD is disruption of the intestinal barrier homeostasis. In paper III, we performed a population genetic study and evaluated whether the ABC transporter cystic fibrosis transmembrane conductance regulator (CFTR), known to be a recognition receptor for bacteria, could be a putative candidate gene in IBD. While the ¢F508 CFTR heterozygosity is markedly underrepresented in Crohn Ls disease patients from Italy and Sweden, stratification for disease location revealed an absence of ¢F508 carriers among Scottish CD patients with right-sided colitis. Our data are in line with the possibility that a mutated CFTR may exhibit a protective role in CD. In some instances, IBD may progress to colorectal cancer. It was therefore of great interest to learn that the bile acid ursodeoxycholic acid (UDCA) was reported to reduce preneoplastic lesions in IBD patients. In paper IV, microarray analysis was performed on a colon epithelial cell line stimulated with UDCA to identify target genes. A cluster of UDCA regulated genes was identified and one gene, the NSAID-activated gene-1 (NAG-1), a divergent member of the TGF À superfamily is of particular interest. Complementary experimental data support that NAG-1 may take part in the UDCA mediated antiproliferative effect. In conclusion, my work adds new information of our understanding of IBD and may help along to develop better and accurate diagnosis, and in improving treatment regimens of IBD. related preneoplastic lesions.