Atherosclerosis 180 (2005) 73–78 Matrix metalloproteinase 3 and 9 gene promoter polymorphisms: joint action of two loci as a risk factor for coronary artery complicated plaques Perttu J. P ¨ oll¨ anen a , Terho Lehtim¨ aki a,c,∗ , Jussi Mikkelsson a,d , Erkki Ilveskoski a,d , Tarja Kunnas a,e , Markus Perola g , Antti Penttil¨ a f , Kari M. Mattila a , Seppo T. Nikkari a,e , Kirsi Syrj¨ akoski b , Pekka J. Karhunen a,c,d a Laboratory of Atherosclerosis Genetics, FinnMedi-2, Department of Clinical Chemistry, Centre for Laboratory Medicine, Tampere University Hospital, P.O. Box 2000, 33521 Tampere, Finland b Laboratory of Cancer Genetics, Department of Clinical Chemistry, Centre for Laboratory Medicine, Tampere University Hospital, Tampere, Finland c Department of Clinical Chemistry, Medical School, University of Tampere, Finland d Department of Forensic Medicine, Medical School, University of Tampere, Finland e Department of Medical Biochemistry, Medical School, University of Tampere, Finland f Department of Forensic Medicine, University of Helsinki, Finland g Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland Received 2 June 2004; received in revised form 5 October 2004; accepted 20 October 2004 Available online 18 December 2004 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. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Atherosclerosis; Metalloproteinases; Apoptosis The matrix metalloproteinases (MMPs), among them MMP3 (stromelysin-1) and MMP9 (92-KDa gelatinase), are a family of enzymes present and enzymatically active in atherosclerotic plaques [1,2]. MMP expression is regu- ∗ Corresponding author. Tel.: +358 3 3117 4066; fax: +358 3 3117 4168. E-mail address: terho.lehtimaki@uta.fi (T. Lehtim¨ aki). lated primarily at the transcription level, the promoters of the genes responding to various growth factors and cy- tokines [3–5]. Increasing evidence indicates that a set of markers in the promoters of MMPs, the single nucleotide polymorphisms, alter the transcriptional activity of MMPs and contribute to susceptibility to coronary heart disease [3–5]. 0021-9150/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2004.10.041