title: 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.
  
  
  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.affiliation: Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden. Per.Eriksson@medks.ki.se
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Deguchi
authors.forename: Ann
authors.initials: A
authors.lastname: Samnegård
authors.forename: Pia
authors.initials: P
authors.lastname: Lundman
authors.forename: Susanna
authors.initials: S
authors.lastname: Boquist
authors.forename: Per
authors.initials: P
authors.lastname: Tornvall
authors.forename: Carl-Göran
authors.initials: CG
authors.lastname: Ericsson
authors.forename: Lott
authors.initials: L
authors.lastname: Bergstrand
authors.forename: Lars-Olof
authors.initials: LO
authors.lastname: Hansson
authors.forename: Shu
authors.initials: S
authors.lastname: Ye
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
mesh_terms: D000483:Alleles; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D055316:Cystatin C; D015891:Cystatins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012494:Sampling Studies; D013548:Sweden / Q000453:epidemiology; D014162:Transfection; D020298:U937 Cells
chemical_list: C525030:CST3 protein, human; D055316:Cystatin C; D015891:Cystatins