title: Matrix metalloproteinase3 and 9 gene promoter polymorphisms: joint action of two loci as a risk factor for coronary artery complicated plaques.
abstract: OBJECTIVE
  Matrix metalloproteinases 3 and 9 (MMP3 and MMP9) are present in atherosclerotic plaques and co-operate in the degradation of the fibrous cap of the atheroma, leading to fissuring and ultimately to acute coronary thrombosis. The functional genetic polymorphisms in the promoters of MMP3 and MMP9, which lead to low- and high-transcription activity genotypes, have been shown to be associated with myocardial infarction and angiographically measured atherosclerosis individually, whereas their effects in combination are not yet known. In order to assess the two disease loci simultaneously, we investigated the association of combined low and high promoter activity genotypes with different types of coronary lesions in an autopsy cohort of 300 Caucasian males aged 33-69 years (Helsinki Sudden Death Study).
  
  
  METHODS
  Genotyping at these loci was performed by PCR, restriction enzyme digestion and minisequencing, and areas of the coronary wall covered with atherosclerotic lesions were measured using computer-assisted morphometry.
  
  
  RESULTS
  In analysis of covariance (ANCOVA) with age, body mass index, hypertension, diabetes, smoking and alcohol consumption as covariates, a significant interaction between the MMP3 and MMP9 genotypes was observed on area of complicated lesions (P=0.012). Men with high promoter activity genotypes for both loci had, on average, more than two times larger area of complicated lesions (250%) compared with those men who had low promoter activity genotypes (P=0.008), but these loci showed no association with myocardial infarction.
  
  
  CONCLUSIONS
  The joint action of two susceptibility loci, rather than single MMP genes alone, and the particular combination of MMP3 and MMP9 genotypes present at these loci may contribute to heterogeneity in the presentation of atherosclerosis.
authors.affiliation: Laboratory of Atherosclerosis Genetics, FinnMedi-2, Department of Clinical Chemistry, Centre for Laboratory Medicine, Tampere University Hospital, P.O. Box 2000, 33521 Tampere, Finland.
authors.forename: Perttu J
authors.initials: PJ
authors.lastname: Pöllänen
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.forename: Jussi
authors.initials: J
authors.lastname: Mikkelsson
authors.forename: Erkki
authors.initials: E
authors.lastname: Ilveskoski
authors.forename: Tarja
authors.initials: T
authors.lastname: Kunnas
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.forename: Antti
authors.initials: A
authors.lastname: Penttilä
authors.forename: Kari M
authors.initials: KM
authors.lastname: Mattila
authors.forename: Seppo T
authors.initials: ST
authors.lastname: Nikkari
authors.forename: Kirsi
authors.initials: K
authors.lastname: Syrjäkoski
authors.forename: Pekka J
authors.initials: PJ
authors.lastname: Karhunen
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D003324:Coronary Artery Disease / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D003331:Coronary Vessels / Q000201:enzymology / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors
chemical_list: D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9