A common tag nucleotide variant in MMP7 promoter increases risk for hypertension via enhanced interactions with CREB transcription factor

Abstract

MMP7 (Matrilysin), a potent extracellular matrix degrading enzyme with wide substrate specificity, is emerging as a new regulator of cardiovascular diseases including coronary artery disease and atherosclerosis. However, potential contributions of MMP7 genetic variations to hypertension remain unknown. In this study, we first probed for the association of a tag single nucleotide polymorphism (SNP) in the MMP7 gene promoter (-181A/G; rs11568818) with hypertension in an urban south Indian population (n=1517). The heterozygous A/G genotype showed a strong association with hypertension as compared to the A/A wild-type genotype (OR=1.641, 95% CI=1.276-2.109; p=1x10-4); AG genotype carriers also displayed significantly higher diastolic blood pressure and mean arterial pressure than AA genotype subjects. The study was replicated in a north Indian population (n=977) as well (OR=1.520, 95% CI =1.106-2.090; p=0.01). Transient transfection experiments using MMP7 promoter-luciferase reporter constructs revealed that the variant -181G allele conferred greater promoter activity than the -181A allele. Computational prediction and structure-based conformational and molecular dynamics simulation studies suggested higher binding affinity for the transcription factor CREB to the -181G promoter. In corroboration, over-expression/down-regulation of CREB and chromatin immunoprecipitation experiments provided convincing evidence for stronger binding of CREB with the -181G promoter. Further, the -181G promoter also displayed an enhanced response to hypoxia and epinephrine-treatment. The higher promoter activity of -181G allele also translated to increased MMP7 protein levels. Indeed, MMP7-181A/G heterozygous individuals displayed elevated plasma MMP7 levels which positively correlated with blood pressure. In conclusion, the MMP7 A-181G promoter SNP increased expression of MMP7 under pathophysiological (such as hypoxic stress and catecholamine excess) conditions via increased interactions with the transcription factor CREB and enhanced the risk for hypertension in its carriers.