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

P. Eriksson, H. Deguchi, A. Samnegard, P. Lundman, S. Boquist, P. Tornvall, C.-G. Ericsson, L. Bergstrand, L.-O. Hansson, S. Ye, A. Hamsten
2004 Arteriosclerosis, Thrombosis and Vascular Biology  
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
more » ... 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 random 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;24:1-7.)
doi:10.1161/01.atv.0000117180.57731.36 pmid:14726415 fatcat:zgvijbvufbadri2u6zxrc5b66a