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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:551.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Per Eriksson; Hiroyuki Deguchi; Ann Samnegård; Pia Lundman; Susanna Boquist; Per Tornvall; Carl-Göran Ericsson; Lott Bergstrand; Lars-Olof Hansson; Shu Ye; Anders Hamsten

From the Atherosclerosis Research Unit, King Gustaf V Research Institute (P.E., H.D., A.S., A.H.) and the Cardiology Unit (S.B., P.T.), Department of Medicine, and the Division of Clinical Chemistry and Blood Coagulation (L.-O.H.), Department of Surgery, Karolinska Institute, Karolinska Hospital, Stockholm; the Cardiology Unit (A.S., P.L., C.-G.E.), Department of Medicine, and the Department of Radiology (L.B.), Karolinska Institute, Danderyd Hospital, Danderyd, Sweden; and the Human Genetics Division (S.Y.), Southampton University Medical School, Southampton, UK.

Correspondence to Dr Per Eriksson, King Gustaf V Research Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail Per.Eriksson{at}medks.ki.se

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.

Key Words: cystatin C • genetics • coronary artery disease • promoter • remodeling

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