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Genetic and molecular determinants in inflammatory bowel disease

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posted on 2024-09-02, 20:12 authored by Francesca Bresso

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 pathophysiology 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 TNFα promoter, in order to explain variation in individual disease phenotypes. The results indicate that certain CARD15/TNFα allelic combinations can affect TNFα gene expression, which potentially can contribute to inter-individual 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 ΔF508 CFTR heterozygosity is markedly underrepresented in Crohn Ls disease patients from Italy and Sweden, stratification for disease location revealed an absence of ΔF508 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 TGFβ superfamily is of particular interest. Complementary experimental data support that NAG-1 may take part in the UDCA mediated anti-proliferative 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.

List of scientific papers

I. Halfvarson J, Bresso F, D'Amato M, Jarnerot G, Pettersson S, Tysk C (2005). CARD15/NOD2 polymorphisms do not explain concordance of Crohn's disease in Swedish monozygotic twins. Dig Liver Dis. 37(10): 768-72.
https://doi.org/10.1016/j.dld.2005.05.005

II. Linderson Y, Bresso F, Buentke E, Pettersson S, D'Amato M (2005). Functional interaction of CARD15/NOD2 and Crohn's disease-associated TNFalpha polymorphisms. Int J Colorectal Dis. 20(4): 305-11.
https://doi.org/10.1007/s00384-004-0732-z

III. Bresso F, Askling J, Astegiano M, Demarchi B, Sapone N, Rizzetto M, Gionchetti P, Lammers KM, de Leone A, Riegler G, Nimmo ER, Drummond H, Noble C, Torkvist L, Ekbom A, Zucchelli M, Löfberg R, Satsangi J, Pettersson S, D'Amato M (2006). A potential role for the common cystic fibrosis ÄF508 mutation in Crohn's disease. [Accepted]
https://doi.org/10.1002/ibd.20067

IV. Bresso F, Edlundh-Rose E, D'Amato M, Are A, Grecius G, Linden A, Sjöqvist U, Lundeberg J, Arulampalam V, Löfberg R, Pettersson S (2006). Ursodeoxycholic acid (UDCA) mediated cell cycle arrest of adenocarcinoma cells likely operates through induction of NAG-1. [Manuscript]

History

Defence date

2006-12-12

Department

  • Department of Microbiology, Tumor and Cell Biology

Publication year

2006

Thesis type

  • Doctoral thesis

ISBN-10

91-7140-982-3

Number of supporting papers

4

Language

  • eng

Original publication date

2006-11-21

Author name in thesis

Bresso, Francesca

Original department name

Department of Microbiology, Tumor and Cell Biology

Place of publication

Stockholm

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