The role of matrix metalloproteinases in atherosclerosis in the young: Genetic association studies and functional analyses of promoter polymorphisms

The role of extracellular matrix degrading enzymes and their inhibitors was investigated at early stages of atherosclerosis by genetic association studies since they have previously been shown to exhibit increased expression. Matrix metalloproteinases (MMPs), the major extracellular matrix degrading enzymes, are involved in transition from early to intermediate stages of disease which is accompanied by tissue remodeling.; The study material was the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) collection, which is a unique resource for studying early pathological changes in atherosclerosis. Genomic DNA was isolated from 995 livers and used for genotyping. Polymorphisms in the promoters of MMP1, MMP3, MMP9 and PAI-1 genes were tested for genetic association with the PDAY collection. In black females fibrous plaque lesions were significant associated with MMP1 genotypes by ordinary regression (p = 0.037) and MMP3 genotypes by chi-square test (p = 0.039). However, the analysis of other subgroups failed to reveal any significantly association, either because they were truly insignificant or because the association remained undetectable with the PDAY collection.; Three newly identified sequence variants among the twelve variants were regarded as polymorphisms. They were A to C at nt −955 in MMP2, and 11A/12A at nt −291 (MMP13v1) and A to G at nt −77 (MMP13v2) in MMP13. The A allele in MMP13v2 is located in the 5′ -end of the PEA-3 consensus sequence. The PDAY collection was used to test for association with these three polymorphisms. The MMP13v2 was highly significantly associated with fibrous plaque lesions in black males (ordinary regression; p = 0.0014).; Functional importance was investigated for the new MMP13 polymorphisms. Transfection assay showed a 2-fold higher expression for the A allele in MMP13v2 than the G allele (p = 0.030). Gel-shift assay also suggested that the binding capacity of transcription factors might be affected by the MMP13v2. The results provided evidence for a difference between the two alleles in MMP13v2 in the transcriptional activity through binding of transcription factors.