Human evidence that the Cystatin C Gene is implicated in focal progression of Coronary Artery Disease
Eriksson, Per, Deguchi, Hiroyuki, Samnegard, Ann, Lundman, Pia, Boquist, Susanna, Tornvall, Per, Ericsson, Carl-Goran, Bergstrand, Lott, Hansson, Lars-Olof, Ye, Shu and Hamsten, Anders (2004) Human evidence that the Cystatin C Gene is implicated in focal progression of Coronary Artery Disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 24, (3), 551-557. (doi:10.1161/01.ATV.0000117180.57731.36).
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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.
|Keywords:||cystatin c, genetics, coronary artery disease, promoter, remodeling|
|Subjects:||R Medicine > R Medicine (General)
Q Science > QP Physiology
Q Science > QH Natural history > QH426 Genetics
|Divisions:||University Structure - Pre August 2011 > School of Medicine > Human Genetics
|Date Deposited:||04 Apr 2006|
|Last Modified:||27 Mar 2014 18:13|
|Contact Email Address:||Shu.Ye@soton.ac.uk|
|RDF:||RDF+N-Triples, RDF+N3, RDF+XML, Browse.|
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