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Title: Matrix Metalloproteinase-3 (Stromelysin-1) gene promoter polymorphism in relation to predisposition to inflammatory bowel disease (IBD)
Author: Prothero, Joanna
ISNI:       0000 0001 3502 4000
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2006
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The two main forms of inflammatory bowel diseases (IBD): Crohn's Disease (CD) and Ulcerative Colitis (UC) are chronic, lifetime, inflammatory disorders. The aetiology and the pathogenesis of IBD remain largely unknown, but evidence has implicated excessive responses to antigens present in the normal bacterial microflora. Matrix metalloproteinases (MMPs) are a group of matrix degrading enzymes which are important in the pathophysiology ofIBD. MMP-3 is a key effector molecule in remodelling tissues during intestinal injury and is upregulated in CD and UC compared to control groups. The main cellular source ofMMP-3 is subepithelial myofibroblasts. A naturally-occurring polymorphism in the MMP-3 promoter may be important in which one allele has a run of five adenosines (SA) while the other has six adenosines (6A). In atherosclerosis, the SA allele is associated with conditions of increased extracellular matrix degradation, whereas the 6A allele is associated with conditions of matrix accumulation. We hypothesise that the SA/6A polymorphism has the ability to regulate the production ofMMP-3 in IBD. The aims of this study were to investigate MMP-3 production between individuals with different MMP-3 SA/6A genotypes; and to compare the association of the MMP-3 SA/6A genotype with susceptibility to CD and UC. Myofibroblast cell lines were isolated from CD, UC patients and control subjects. The phenotype of these cells lines were characterised with immunohistochemistry. Cell lines were stimulated with TNF-a or IL-1P and the production ofMMP-3 was measured by western blotting and ELISA. The diseased and control groups were genotyped for the SA/6A polymorphism using whole blood assay. The production ofMMP-3 by myofibroblasts isolated from individuals with different MMP-3 SA/6A genotypes was investigated. A study on MMP-3 SA/6A genotype in German and British families and sporadic cases was setup. Cell lines from CD, UC and control patients were myofibroblast-enriched populations of cells. Cell lines responded to stimulation with TNF-a by a dose-dependent rise in MMP-3 production. The SA/6A polymorphism was analysed in 468 German sporadic inflammatory disease trios and 270 British and German multiplex IBD families using the transmission disequilibrium test (TDT). There was an overtransmission of the SA allele to affected offspring (p=0.0012). There was an interaction between the MMP-3 gene SA/6A polymorphism and the Caspase Activating Recruitment Domain (CARD) IS gene, a well established gene for CD, such that overtransmission of the SA allele was a significant in CARD1S carriers (p=0.00S4) but not in non-carriers. In the CARD1S carriers, overtransmission of the SA allele was associated with stenosis (p=0.0027), fistulising disease (p=0.0007), previous surgical resection (p=0.0023), disease of the ileum (p=O.OOOl), and disease of the right colon (p=O.OOlS) in CD. The relationship of functional polymorphisms in promoters of the MMP-1,-3, -9 and -12 genes with IBD was also investigated in children and adults, and age-matched controls, described in the Appendices. No significant association was found between these polymorphisms and CD or UC, though the power of these studies was reduced by small sample numbers. In conclusion, the MMP3 SA/6A polymorphism appears to be a genetic factor in CD.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available