The MMP-9 -1562 C/T polymorphism in the presence of metabolic syndrome increases the risk of clinical events in patients with coronary artery disease

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Abstract

© 2014 Opstad et al. Background and Objectives: Elevated levels of matrix metalloproteinase (MMP)-9 have been associated with the metabolic syndrome (MetS) and cardiovascular events. The MMP-9 21562 C/T polymorphism has furthermore been shown as a risk factor for coronary artery disease (CAD). The non-favourable cardiometabolic state in MetS may increase the risk. We aimed to investigate the influence of MMP-9 21562 C/T polymorphism in subjects with CAD and MetS. Methods: Patients (n = 1000) with verified CAD stratified in Mets +/2 (n = 244/756), were analyzed for the MMP-9 21562 C/T polymorphism and related to clinical events after 2 years follow-up. Serum levels of total MMP-9 and tissue inhibitor of matrix metalloproteinases (TIMP)-1were analyzed in all, whereas MMP-9 activity, extracellular matrix metalloproteinase inducer (EMMPRIN), and expression of the two genes were analyzed in a subset of 240 randomly selected patients. Results: Totally, 106 clinical endpoints were recorded. In MetS; the T-allele associated with 5.5 fold increase in event rate (p<0.0001), increased with number of MetS components, a 117% increase in total MMP-9 levels (TT homozygous, p = 0.05), significantly higher total- And endogenous active MMP-9 and TIMP-1 levels (p<0.01 all), and EMMPRIN was inversely correlated with pro- And endogenous active MMP-9 (p<0.05, both). In non-MetS; the T-allele was not associated with new events, nor higher MMP-9 levels. EMMPRIN was significantly correlated with total MMP-9 and TIMP-1 (p<0.01, both) and the two genes were inter-correlated (p<0.001). Conclusion: In CAD patients with MetS, the MMP-9 T-allele increased the risk of clinical events, probably mediated through elevated MMP-9 levels and altered MMP-9 regulation.

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Opstad, T. B., Arnesen, H., Pettersen, A., & Seljeflot, I. (2014). The MMP-9 -1562 C/T polymorphism in the presence of metabolic syndrome increases the risk of clinical events in patients with coronary artery disease. PLoS ONE, 9(9). https://doi.org/10.1371/journal.pone.0106816

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