A polymorphism of the human matrix gamma-carboxyglutamic acid protein promoter alters binding of an activating protein-1 complex and is associated with altered transcription and serum levels

Matrix gamma -carboxyglutamic acid protein (MGP) is a mineral-binding extra cellular matrix protein synthesized by vascular smooth muscle cells (VSMCs) and chondrocytes that is thought to be a key regulator of tissue calcifica tion. In this study, we identified four polymorphisms in the promoter regio n of the human MGP gene. Transfection studies showed that the G-7A and T-13 8C polymorphisms have an important impact on in vitro promoter activity whe n transiently transfected into VSMCs. We found that one of these polymorphi sms (T-138C) is significantly correlated with serum MGP levels in human sub jects. Promoter deletion analysis showed that this polymorphism lies in a r egion of the promoter critical for transcription in VSMCs. This region cont ains a potential activating protein-1 (AP-1) binding element located betwee n -142 and -136. We have demonstrated that the T-138C polymorphism results in altered binding of an AP-1 complex to this region. The -138T allelic var iant binds AP-1 complexes consisting primarily of c-Jun, JunB and its partn ers Fra-1 and Fra-2 in rat VSMC. Furthermore, the -138T variant form of the promoter was induced following phorbol 12-myristate 13-acetate treatment, while the -138C variant was refractive to phorbol 12-myristate 13-acetate t reatment, confirming that AP-1 factors preferentially bind to the -138T var iant. This study therefore suggests that a common polymorphism of the MGP p romoter influences binding of the AP-1 complex, which may lead to altered t ranscription and serum levels. This could have important implications for d iseases such as atherosclerosis and aortic valve stenosis, since it strongl y suggests a genetic basis for regulation of tissue calcification.