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 (-82G/C and -78T/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 (N=237) undergoing routine coronary angiography. CONCLUSIONS: These results provide human evidence for an important role of cystatin C in coronary artery disease.
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 humanatherosclerosis 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 (-82G/C and -78T/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 (N=237) undergoing routine coronary angiography. CONCLUSIONS: These results provide human evidence for an important role of cystatin C in coronary artery disease.
Authors: A Gyllenberg; F Piehl; L Alfredsson; J Hillert; I L Bomfim; L Padyukov; M Orho-Melander; E Lindholm; M Landin-Olsson; Å Lernmark; T Olsson; I Kockum Journal: Genes Immun Date: 2014-01-16 Impact factor: 2.676
Authors: David M Maahs; Janet K Snell-Bergeon; John E Hokanson; Gregory L Kinney; Tomas Berl; Marian Rewers; Lorraine G Ogden Journal: Diabetes Technol Ther Date: 2010-01 Impact factor: 6.118
Authors: Meda E Pavkov; William C Knowler; Robert L Hanson; Desmond E Williams; Kevin V Lemley; Bryan D Myers; Robert G Nelson Journal: Am J Kidney Dis Date: 2013-01-21 Impact factor: 8.860
Authors: Andrew Moran; Ronit Katz; Nicolas L Smith; Linda F Fried; Mark J Sarnak; Stephen L Seliger; Bruce Psaty; David S Siscovick; John S Gottdiener; Michael G Shlipak Journal: J Card Fail Date: 2008-02 Impact factor: 5.712