Promoter polymorphism of the matrix metalloproteinase 3 gene is associated with regurgitation and left ventricular remodelling in mitral valve prolapse patients

Abstract

Background and aims: Mitral valve prolapse (MVP) is common and highly variable in its severity, but the factors underlying this variability are unclear. In this study, we tested the hypothesis that polymorphic variations in Matrix Metalloproteinase (MMP) genes might be predictors of left ventricular (LV) remodelling and severity of regurgitation in MVP. Methods and results: 70 MVP patients and 75 normal subjects were studied. We performed comprehensive echocardiography and analyzed promoter polymorphisms in the MMP-1 and MMP-3 genes. The MMP-3 -1612 5A/6A polymorphism showed strong associations with indices of mitral regurgitation and LV remodelling: Patients with 5A/5A allele had more pronounced remodelling and more severe mitral regurgitation than patients with the 6A/6A or 5A/6A alleles. We then cloned and sequenced 2 kb fragments of MMP-3 promoter from patients with 5A/5A and 6A/6A genotypes and found 4 different sets of promoter haplotypes. Promoter analysis showed that higher promoter activity was related to a more severe phenotype and that the haplotype variants had a more dominant role in determining the activity. Conclusions: Our data identifies the MMP-3 promoter haplotype as a novel marker of an adverse disease course in MVP, suggesting the presence of genetic determinants for the severity of MVP.

Risk of coronary artery stenosis in Iranian type 2 diabetics: is there a role for matrix metalloproteinase-3 gene (-1612 5A/6A) polymorphism?

“…HDL cholesterol was measured as cholesterol after precipitation of apolipoprotein Bcontaining lipoproteins with phosphotungstic-Mg++ (Boehringer Mannheim, Mannheim, Germany). Polymerase chain reaction was performed using primer sequences derived from published data [24].…”

Genetic Basis of Familial Valvular Heart Disease

“…48 It is interesting that in another study of MVP patients, an MMP-3 promoter haplotype-1612 5A/5A polymorphism was associated with severe mitral regurgitation and more pronounced left ventricular remodeling. 49 It is speculated that the MMP-3 promoter 5A/5A polymorphism may result in increased MMP-3 expression in the myocardium, which then accentuates the adaptive response of the myocardium to the volume overload of mitral regurgitation and hence more adverse disease course. 49 This suggests that genetic variation influences the disease course in MVP.…”

“…49 It is speculated that the MMP-3 promoter 5A/5A polymorphism may result in increased MMP-3 expression in the myocardium, which then accentuates the adaptive response of the myocardium to the volume overload of mitral regurgitation and hence more adverse disease course. 49 This suggests that genetic variation influences the disease course in MVP.…”

Associations of rs3918242 and rs2285053 MMP-9 and MMP-2 polymorphisms with the risk, severity, and short- and long-term complications of degenerative mitral valve diseases: a 4.8-year prospective cohort study

“…Our interest is supported by experimental studies on animal models and humans, which have suggested a key role of MMPs in their onset and progression [7][8][9][10][11][12][13][14][15]. However, in literature, there are few data [16,17] showing associations of SNPs in MMP genes with MVD susceptibility. Thus, our study represents the first report that analyzed, in a perspective manner, associations of functional genetic variants in the MMP-2 and MMP-9 genes not only with MVD risk but also with its severity and complications, as well as with long-term outcome after surgical approaches (i.e., mitral valve replacement or plastic surgery).…”

“…Increased systemic and tissue levels of MMPs in cases affected by degenerative sporadic MVDs and with stenosis or regurgitation complications have been also assessed [7][8][9][10][11][12][13][14][15]. In contrast, no exhaustive data about eventual associations between single nucleotide polymorphisms (SNPs) in MMP genes and the risk of degenerative sporadic MVDs are reported until now in literature, since they are a very limited number [16,17]. However, genetic association studies have the potential to identify molecular pathways as early diagnostic biomarkers and targets.…”