Coeliac disease candidate genes:: No association with functional polymorphisms in matrix metalloproteinase 1 and 3 gene promoters

Background: Coeliac disease is polygenic with a large genetic component. Matrix metalloproteinase-1 (MMP-1) and MMP-3 degrade extracellular matrix; expression levels are increased in the coeliac lesion where tissue damage is observed. Polymorphisms associated with elevated expression (MMP-3 -1171 allele 5A: MMP-1-1607 2G), at 11q22.2, a region repeatedly showing evidence of linkage in coeliac disease, are associated with other chronic inflammatory disorders which may share a common molecular pathology. We tested for an association between these candidate gene polymorphisms and coeliac disease. Methods: Two independent collections of 225 and 102 combined (Norwegian and Swedish) simplex families, and 160 independent healthy controls from the Norwegian Bone Marrow Donor Registry were used. Each individual was genotyped by PCR and fragment length analysis on an automated sequencer. The transmission/disequilibrium test was applied. Odds ratios were calculated employing probands or affected sibs where available, as cases versus independent controls. Results: MMP-1 allele 2G did not show evidence of association in any tests undertaken. Neither did we find evidence for association of MMP-3 allele 5A, except among the combined family data: a non-significant tendency toward reduced risk was observed among males carrying MMP-3 allele 5A (40.2% transmission, P-c = 0.2). Further testing to clarify this observation did not reveal a significant association (odds ratio = 0.67 (95% confidence interval: 0.42-1.07), P = 0.08). Conclusions: We did not find significant evidence to support an association of MMP-3 allele 5A or MMP-1 allele 2G with coeliac disease in Norwegian and Swedish populations.