Matrix metalloproteinase-3 (MMP3) and MMP9 genes and risk of myocardial infarction, ischemic stroke, and hemorrhagic stroke.

OBJECTIVE We assessed the association of genetic variation in MMP3 and MMP9 with risk of myocardial infarction and stroke. METHODS A case-control study was conducted among members of Group Health (GH), a large-integrated health care delivery system. Case subjects with incident non-fatal myocardial infarction (n=854), ischemic stroke (n=367), and hemorrhagic stroke (n=66) were identified and validated. A matched control group was selected from among GH members without myocardial infarction or stroke (n=2696). Haplotype-tagging sets of single-nucleotide polymorphisms (SNPs) in MMP3 and MMP9 were genotyped. RESULTS MMP3 haplotype 2 was associated with reduced risk of myocardial infarction (adjusted odds ratio (OR) per copy=0.80, 95% confidence interval 0.66, 0.98) and increased risk of hemorrhagic stroke (OR=1.69, 95% confidence interval 1.05, 2.75). Results for MMP3 haplotype 2 and ischemic stroke resembled those for myocardial infarction but did not achieve statistical significance (OR=0.85, 95% confidence interval 0.64, 1.12). No individual SNP identified MMP3 haplotype 2, and none of the individual MMP3 SNPs were associated with myocardial infarction or stroke. MMP9 haplotypes or SNPs were not associated with myocardial infarction or stroke. CONCLUSIONS MMP3 haplotype may predict both cardiac events and stroke.

[1]  Jianfeng Huang,et al.  Haplotype analysis of the matrix metalloproteinase 3 gene and myocardial infarction in a Chinese Han population , 2004, Thrombosis and Haemostasis.

[2]  G. Rosenberg.  Matrix metalloproteinases in neuroinflammation , 2002, Glia.

[3]  P. Libby,et al.  Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. , 1994, The Journal of clinical investigation.

[4]  A. Gearing,et al.  Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures , 2001, Brain Research.

[5]  Thomas Lumley,et al.  Simple estimates of haplotype relative risks in case‐control data , 2006, Genetic epidemiology.

[6]  Hua-Lin Wu,et al.  Genotype-phenotype association of matrix metalloproteinase-3 polymorphism and its synergistic effect with smoking on the occurrence of acute coronary syndrome. , 2006, The American journal of cardiology.

[7]  Bronwyn A Kingwell,et al.  Matrix Metalloproteinase‐3 Genotype Contributes to Age‐Related Aortic Stiffening Through Modulation of Gene and Protein Expression , 2003, Circulation research.

[8]  S. Cho,et al.  The roles of stromelysin-1 and the gelatinase B gene polymorphism in stable angina. , 2002, Yonsei medical journal.

[9]  S. Cummings,et al.  Use of alendronate and risk of incident atrial fibrillation in women. , 2008, Archives of internal medicine.

[10]  P. Eriksson,et al.  Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction. , 2003, Journal of the American College of Cardiology.

[11]  H. Kuivaniemi,et al.  Genetic analysis of MMP3, MMP9, and PAI-1 in Finnish patients with abdominal aortic or intracranial aneurysms. , 1999, Biochemical and biophysical research communications.

[12]  Bronwyn A. Kingwell,et al.  Matrix Metalloproteinase-9 Genotype Influences Large Artery Stiffness Through Effects on Aortic Gene and Protein Expression , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[13]  A. Henney,et al.  Progression of Coronary Atherosclerosis Is Associated with a Common Genetic Variant of the Human Stromelysin-1 Promoter Which Results in Reduced Gene Expression* , 1996, The Journal of Biological Chemistry.

[14]  P. Donnelly,et al.  A new statistical method for haplotype reconstruction from population data. , 2001, American journal of human genetics.

[15]  L. Matrisian,et al.  Measurement of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Blood and Tissues: Clinical and Experimental Applications , 1999, Annals of the New York Academy of Sciences.

[16]  M. Fornage,et al.  Family-based association study of matrix metalloproteinase-3 and -9 haplotypes with susceptibility to ischemic white matter injury , 2006, Human Genetics.

[17]  S. Ye,et al.  Polymorphisms in Matrix Metalloproteinase-1, -3, -9, and -12 Genes in Relation to Subarachnoid Hemorrhage , 2001, Stroke.

[18]  H. Lijnen,et al.  Stromelysin‐1 (MMP‐3) is critical for intracranial bleeding after t‐PA treatment of stroke in mice , 2007, Journal of thrombosis and haemostasis : JTH.

[19]  William G. Stetler-Stevenson,et al.  Tumor necrosis factor-α-induced gelatinase B causes delayed opening of the blood-brain barrier: an expanded therapeutic window , 1995, Brain Research.

[20]  E. Gaetani,et al.  Proinflammatory Genetic Profiles in Subjects With History of Ischemic Stroke , 2004, Stroke.

[21]  G. Rosenberg.  Rosenberg GA. Matrix metalloproteinases in neuroinflammation. GLIA 2002;39(3):279–291. , 2002 .

[22]  Y. Itoh,et al.  Degradation of cross-linked fibrin by matrix metalloproteinase 3 (stromelysin 1): hydrolysis of the gamma Gly 404-Ala 405 peptide bond. , 1996, Biochemistry.

[23]  P. Amouyel,et al.  Polymorphisms in the promoter regions of MMP-2, MMP-3, MMP-9 and MMP-12 genes as determinants of aneurysmal coronary artery disease. , 2002, Journal of the American College of Cardiology.

[24]  D. Collen,et al.  Modulation of Cell-associated Plasminogen Activation by Stromelysin-1 (MMP-3) , 1999, Thrombosis and Haemostasis.

[25]  T. Lumley,et al.  Association of genetic variations with nonfatal venous thrombosis in postmenopausal women. , 2007, JAMA.

[26]  Alex P. Reiner,et al.  Diuretic Therapy, the α-Adducin Gene Variant, and the Risk of Myocardial Infarction or Stroke in Persons With Treated Hypertension , 2002 .

[27]  Yoshiji Yamada.  Identification of genetic factors and development of genetic risk diagnosis systems for cardiovascular diseases and stroke. , 2006, Circulation journal : official journal of the Japanese Circulation Society.

[28]  L. Liotta,et al.  TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase , 1992, Brain Research.

[29]  P. Declerck,et al.  Inactivation of Plasminogen Activator Inhibitor-1 by Specific Proteolysis with Stromelysin-1 (MMP-3)* , 2000, The Journal of Biological Chemistry.