Abstract 3460: Promoter Polymorphism of Matrix Metalloproteinase 3 Gene Predicts Regurgitation and Left Ventricular Remodeling in Mitral Valve Prolapse Patients
Mitral valve prolapse (MVP) is common and highly variable in severity, but the factors underlying this variability are unclear. We hypothesized that polymorphic variations in genes whose products determine contractility and remodeling may be predictors of left ventricular (LV) remodeling and regurgitation in MVP. We therefore screened 12 polymorphisms in 10 genes known to be related to these processes (α and β adrenergic receptors, matrix metallopro-teinases (MMP), elastin, tumor necrosis factor, aldosterone synthase and angiotensin converting enzyme) in a total of 70 MVP patients and 75 controls. All patients had a regurgitant fraction > 40% and LV mass ranged from 114 to 527 g. A common single nucleotide polymorphism (SNP) in the proximal promoter region of the MMP3 gene which has either five or six consecutive adenosine bases (5A/6A) showed strong associations with indices of LV remodeling and regurgitation: Patients homozygous for the 5A allele (n=16) had larger LV mass (314 ± 26 g vs 245 ± 12 g; P<0.05), left atrial volume (106 ± 8 ml vs 85 ± 5 ml; P<0.05), mitral annulus (39.4 ± 0.7 mm vs 36.9 ± 0.5 mm; P<0.01), and higher regurgitation volume (169 ± 10 ml vs 127 ± 7 ml; P<0.05) than patients with 6A/6A or 5A/6A (n=54) alleles. Multiple regression analysis showed that the effect was independent of other covariants such as blood pressure, age, and body surface area. To begin studying the mechanism, we cloned and sequenced a 2kb fragment of MMP3 promoter from patients with 5A/5A and 6A/6A genotypes. Four additional SNPs were found within the fragment constituting 4 sets of promoter haplotypes. To test whether the haplotype determines promoter activity, we generated promoter-luciferase constructs and assessed their activity in fibroblast and myoblast cells. We found that lower MMP3 promoter activity was related to more severe MVP phenotype and that the combination of several SNPs was the determinant factor of promoter activity. This is in line with data in heart failure in which the activity of specific MMPs may be either increased or decreased. In conclusion, our data identifies SNPs in the promoter of MMP3 gene as a novel marker of an adverse disease course in MVP and to our knowledge are the first data to suggest the presence of genetic determinants for the severity of MVP.