Human Evidence That the Cystatin C Gene Is Implicated in Focal Progression of Coronary Artery Disease

Abstract

Objective-Overexpression of elastolytic cysteine and aspartic proteases, known as cathepsins, is implicated in atherogenesis. The potential significance of imbalance in expression between cathepsins and their inhibitor cystatin C in cardiovascular disease has been highlighted by the demonstration of cystatin C deficiency in human atherosclerosis and abdominal aortic aneurysms. Methods and Results-We identified and characterized physiologically relevant polymorphisms in the promoter region of the cystatin C gene that influence cystatin C production and used these polymorphisms as a tool to examine the significance of cystatin C in coronary atherosclerosis in vivo in humans. Seven polymorphisms, all in strong-linkage disequilibrium, were identified in the cystatin C gene, of which 2 promoter polymorphisms (Ϫ82G/C and Ϫ78T/G) were functional in vitro in electromobility shift and transient transfection assays. Genotyping of 1105 individuals (237 survivors of a first myocardial infarction before age 60 and 2 independent groups comprising a total of 868 healthy individuals) revealed that the plasma cystatin C concentration was significantly lower in carriers of the mutant haplotype. Furthermore, the mutant haplotype was associated with a higher average number of stenoses per coronary artery segment in unselected postinfarction patients (Nϭ237) undergoing routine coronary angiography. Conclusions-These results provide human evidence for an important role of cystatin C in coronary artery disease.(Arterioscler Thromb Vasc Biol. 2004;24:551-557.)

Use of Serum Cystatin C in Assessment of Early Deterioration of Renal Function in Type 2 Diabetic Industrial Workers in Port Harcourt, Nigeria

“…Even if non-renal influences, including polymorphisms in the promoter and exon 1 of the cystatin C gene [30,31], make cystatin C not completely reliable as a measure of renal function, most studies have found cystatin C to be a better marker of GFR than creatinine. In a recent meta-analysis [9], approximations of GFR performed with cystatin C compared with creatinine had higher correlation coefficients (0.816vs 0.742;P<0.001) and ROC-AUC (0.926 vs 0.837; P < 0.001).…”

Cystatin C: current position and future prospects

“…Apolipoprotein E (ApoE)-/-mice in which the CysC gene has been incapacitated (Cyst-/-) develop aneurysmal lesions and rupture of the limiting internal elastic lamina compared to ApoE-/-, Cystq/q mice (212,213). These studies on animal models are supported by occasional human genetic data (214,215). Patients with mutations in the CysC promoter gene have low circulating CysC concentrations (214,215).…”

“…Patients with mutations in the CysC promoter gene have low circulating CysC concentrations (214,215). The same mutations are associated with a higher number of coronary artery stenoses in a sub-group of patients (ns237) undergoing coronary angiography during an infarction, although they had no influence on the severity of the stenoses (214). These genotypes also do not influence patient survival at 3 years (215).…”

Cardiovascular Biomarkers in Chronic Kidney Disease

“…Its increased plasma concentrations have been found to predict the presence and severity of CVD in mild renal impairment, hence it could be an early marker of vascular risk (16). It has been suggested that cystatin C may directly contribute to atherogenesis by affecting arterial extracellular matrix remodeling (17).…”