Coronary Artery Complicated Lesion Area Is Related to Functional Polymorphism of Matrix Metalloproteinase 9 Gene An Autopsy Study Perttu J. Pöllänen, Pekka J. Karhunen, Jussi Mikkelsson, Pekka Laippala, Markus Perola, Antti Penttilä, Kari M. Mattila, Timo Koivula, Terho Lehtimäki Abstract—Matrix metalloproteinase 9 (MMP9) is expressed in human atherosclerotic plaques, and the protein is localized in human coronary atherosclerotic lesions. The MMP9 gene has a C-to-T promoter polymorphism at position -1562, which affects transcription and leads to promoter low-activity (C/C) and high-activity (C/T, T/T) genotypes. To determine whether these genotypes exert an influence on the atherosclerotic lesion area, we investigated their association with different types of coronary lesions in an autopsy cohort of 276 men aged 33 to 69 years. Areas of the coronary wall covered with fatty streaks and fibrotic, calcified, and complicated lesions were measured, and the percentage of coronary narrowing was determined. MMP9 genotypes were determined by polymerase chain reaction and restriction enzyme digestion. In men aged 53 years, the mean area of complicated lesions in 3 coronaries was significantly associated with the MMP9 genotype (P=0.008). Subjects with high promoter activity genotypes had, on average, larger complicated lesion areas than did those with the low-activity genotype. The MMP9 genotype persisted as an independent predictor of complicated lesion area after adjustment for age, body mass index, hypertension, diabetes, and smoking (P=0.012). These data provide evidence that the proposed effect of MMP9 in the process of atherosclerotic lesion development may be modified by the MMP9 genotype. (Arterioscler Thromb Vasc Biol. 2001;21:1446-1450.) Key Words: matrix metalloproteinase 9  coronary artery disease  complicated lesions  genetics  polymorphism T he matrix metalloproteinases (MMPs), among them MMP9 (also known as gelatinase B and 92-kDa type IV collagenase), constitute a family of enzymes required for the degradation of extracellular matrix during embryonic devel- opment, morphogenesis, and tissue remodeling. MMP3 (stromelysin 1), MMP1 (interstitial collagenase), and MMP9 (92-kD gelatinase) are present and enzymatically active in atherosclerotic plaques and are known to be associated with the progression and development of atherosclerotic lesions. 1,2 The MMP family consists of 15 metal-dependent endopep- tidases with activity against most extracellular matrix macromolecules. MMP9 has recently been identified in human atheroscle- rotic lesions. 2,3 It is active against denatured collagens (gel- atin) and type IV, V, and XI collagens in addition to the proteoglycans and elastin also found in atherosclerotic le- sions. 4 MMP9 expression is primarily regulated at the tran- scription level, with the promoter of the gene responding to different growth factors and cytokines. 5 Zhang et al 6 have found a functional MMP9 gene promoter C-to-T polymor- phism at position -1562, which affects gene transcription and yields promoter low-activity (C/C) and high-activity (C/T, T/T) genotypes. 6 They also observed an association between this polymorphism and the severity of angiographi- cally measured atherosclerosis. No data are as yet available on the impact of the MMP9 genotypes at the vessel-wall level in respect to the coronary complicated lesion area and plaque rupture. Nor has it hitherto been sought to establish whether MMP9 genotypes affect coronary artery lesion development or plaque rupture. Therefore, we investigated in an autopsy series of 276 Finnish men included in the Helsinki Sudden Death Study (HSDS) whether the MMP9 promoter low- and high-activity genotype groups are related to the areas of different types of coronary lesions. 7 Methods Subjects The HSDS was designed to investigate lifestyle and genetic factors predisposing to sudden death in Finnish middle-aged men living in Received October 18, 2000; revision accepted May 28, 2001. From the Laboratory of Atherosclerosis Genetics (P.J.P., P.J.K., K.M.M., T.K., T.L.), Department of Clinical Chemistry, Centre for Laboratory Medicine, Tampere University Hospital; the Department of Forensic Medicine (P.J.K., J.M.), Medical School, University of Tampere; and the Tampere School of Public Health (P.L.), University of Tampere and Research Unit, Tampere University Hospital, Tampere, Finland; the Department of Forensic Medicine (A.P.), University of Helsinki, and the Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland; and the Department of Human Genetics (M.P.), University of California, Los Angeles. Correspondence to Terho Lehtimäki, MD, PhD, Laboratory of Atherosclerosis Genetics, Finn Medi 2, Department of Clinical Chemistry, Center for Laboratory Medicine, Tampere University Hospital, PO Box 2000, 33521 Tampere, Finland. E-mail bltele@uta.fi © 2001 American Heart Association, Inc. 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