Molecular Biology Reports

, Volume 39, Issue 1, pp 555–562 | Cite as

Matrix metalloproteinas-9 functional promoter polymorphism 1562C>T increased risk of early-onset coronary artery disease

  • Massoud Saedi
  • Asad Vaisi-Raygani
  • Shahnaz Khaghani
  • Ahmad Shariftabrizi
  • M. Rezaie
  • Parvin Pasalar
  • Zohreh Rahimi
  • Tayebeh Pourmotabbed


The Matrix metalloproteinas-9 functional promoter polymorphism 1562C>T may be considered an important genetic determinant of early-onset coronary artery disease (ECAD). In this study, association between MMP-9 1562C>T allele with plasma MMP-9 activity, homocysteine and lipid–lipoproteins level and ECAD in Iranian subjects was investigated. This case–control study consisted of 53 ECAD patients (age < 55 years) and unrelated late-onsets CAD (age > 70 years) who angiographically had at least 50% stenosis. MMP-9 1562C>T polymorphism was detected by PCRRFLP, plasma MMP-9 activity, serum lipid and homocysteine levels were determined by gelatin gel zymography, enzyme assay and by HPLC, respectively. The presence of MMP-9 1562C>T allele was found to be associated with ECAD (OR = 3.2, P = 0.001). The ECAD patients with MMP-9 1562C>T allele had higher MMP-9 activity (P = 0.001), LDL-C (P = 0.045), TC (P = 0.02) and homocysteine (P = 0.01) levels than the LCAD subjects. MMP-9 1562C>T allele is a risk factor for ECAD. The carriers of this allele have high levels of MMP-9 activity, LDL-C, TC and homocysteine (P = 0.01), thus, are more likely to develop myocardial infarction and CAD at young age (less than 55 years).


MMP-9 Early coronary artery disease Genetic polymorphism MMP-9 activity Lipid profile Homocysteine 


  1. 1.
    Kharrazi H, Vaisi Raygani A, Sabokroh AR, Pourmotabedd T (2006) Association between apolipoprotein E polymorphism in coronary artery disease patients in Kermanshah, in west of Iran. Clin Biochem 39:613–616PubMedCrossRefGoogle Scholar
  2. 2.
    Vaisi-Raygani A, Tavilani H, Rahimi Z, Zahrai M, Sheikh N, Aminian M, Pourmotaabed T (2009) Serum butyrylcholinesterase activity and phenotype associations with lipid profile in stroke patients. Clin Biochem 42:210–214PubMedCrossRefGoogle Scholar
  3. 3.
    Vaisi-Raygani A, Rahimi Z, Nomani H, Tavilani H, Pourmotaabed T (2007) The presence of apolipoprotein ε4 and ε2 alleles augments the risk of coronary artery disease in Type 2 diabetic patients. Clin Biochem 40:1150–1156bPubMedCrossRefGoogle Scholar
  4. 4.
    Abilleira S, Bevan S, Markus HS (2006) The role of genetic variants of matrix metalloproteinases in coronary and carotid atherosclerosis. J Med Genet 43:897–901PubMedCrossRefGoogle Scholar
  5. 5.
    Vaisi-Raygani A, Rahimi Z, Tavilani H, Pourmotaabed T (2010) Butyrylcholinesterase K variant and the APOE-e4 allele work in synergy to increase the risk of coronary artery disease especially in diabetic patients. Mol Biol Rep 37:2083–2091PubMedCrossRefGoogle Scholar
  6. 6.
    Li Y, Sun DL, Duan YN, Zhang XJ, Wang N, Zhou RM, Chen ZF, Wang SJ (2010) Association of functional polymorphisms in MMPs genes with gastric cardia adenocarcinoma and esophageal squamous cell carcinoma in high incidence region of North China. Mol Biol Rep 37(1):197–205PubMedCrossRefGoogle Scholar
  7. 7.
    Morgan AR, Zhang B, Tapper W, Collins A, Ye S (2003) Haplotypic analysis of the MMP-9 gene in relation to coronary artery disease. J Mol Med 81:321–326PubMedGoogle Scholar
  8. 8.
    Rahimi Z, Vaisi-Raygani A, Pourmotaabed T (2011) Association between apolipoprotein ε4 allele, factor V Leiden, and plasma lipid and lipoprotein levels with sickle cell disease in Southern Iran. Mol Biol Rep 38(2):703–710Google Scholar
  9. 9.
    Zhi H, Wang H, Ren L, Shi Z, Peng H, Cui L, Ma G, Ye X, Feng Y, Shen C, Zhai X, Zhang C, Zen K, Liu N (2010) Functional polymorphisms of matrix metallopeptidase-9 and risk of coronary artery disease in a Chinese population. Mol Biol Rep 37(1):13–20PubMedCrossRefGoogle Scholar
  10. 10.
    Rahimi Z, Felehgari V, Rahimi M, Mozafari H, Yari K, Vaisi-Raygani A, Rezaei M, Malek-Khosravi S, Khazaie H (2011) The frequency of factor V Leiden mutation, ACE gene polymorphism, serum ACE activity and response to ACE inhibitor and angiotensin II receptor antagonist drugs in Iranians type II diabetic patients with microalbuminuria. Mol Biol Rep 38(3):2117–2123Google Scholar
  11. 11.
    Kelly D, Cockerill G, Thompson M, Khan S, Samani NJ, Squire IB (2007) Plasma matrix metalloproteinase-9 and left ventricular remodelling after acute myocardial infarction in man: a prospective cohort study. Eur Heart J 28:711–718PubMedCrossRefGoogle Scholar
  12. 12.
    Li H, Xu H, Liu S (1994) Toll-like receptors 4 induces expression of matrix metalloproteinase-9 in human aortic smooth muscle cells. Mol Biol Rep 38:1419–1423CrossRefGoogle Scholar
  13. 13.
    Gibbons GH, Dzau VJ (1994) The emerging concept of vascular remodelling. N Engl J Med 330:1431–1438PubMedCrossRefGoogle Scholar
  14. 14.
    Ayşegül B, Veysi GH, Muzaffer M, Irfan D, Azra A, Hulyam K (2010) Is a single nucleotide polymorphism a risk factor for lung cancer in the matrix metalloproteinase-2 promoter? Mol Biol Rep 38:1469–1474PubMedCrossRefGoogle Scholar
  15. 15.
    Galis ZS, Khatri JJ (2002) Matrix metalloproteinases in vascular remodeling and atherogenesis. The good, the bad, and the ugly. Circ Res 90:251–262PubMedGoogle Scholar
  16. 16.
    Nanni S, Melandri G, Hanemaaijer R, Cervi V, Tomasi L, Altimari A, Van Lent N, Tricoci P, Bacchi L, Branzi A (2007) Matrix metalloproteinases in premature coronary atherosclerosis: influence of inhibitors, inflammation, and genetic polymorphisms. Transl Res 149(3):137–144PubMedCrossRefGoogle Scholar
  17. 17.
    Loftus IM, Naylor AR, Goodall S (2000) Increased matrix metalloproteinase-9 activity in unstable carotid plaques: a potential role in acute plaque disruption. Stroke 31:40–47PubMedCrossRefGoogle Scholar
  18. 18.
    Zhang B, Ye S, Herrmann SM, Eriksson P, de Maat M, Evans A, Arveiler D, Luc G, Cambien F, Hamsten A, Watkins H, Henney AM (1999) Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation 99:1788–1794PubMedGoogle Scholar
  19. 19.
    Pollanen PJ, Karhunen PJ, Mikkelsson J (2001) Coronary artery complicated lesion area is related to functional polymorphism of matrix metalloproteinase 9 gene: an autopsy study. Arterioscler Thromb Vasc Biol 21:1446–1450PubMedCrossRefGoogle Scholar
  20. 20.
    Zhang B, Henney A, Eriksson P, Hamsten A, Watkins H, Ye S (1999) Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2-13.1. Hum Genet 105:418–423PubMedCrossRefGoogle Scholar
  21. 21.
    Kai H, Ikeda H, Yasukawa H (1998) Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol 32:368–372PubMedCrossRefGoogle Scholar
  22. 22.
    Kim H, Dalal S, Young E (2000) Disruption of the myocardial extracellular matrix leads to cardiac dysfunction. J Clin Invest 106:857–866PubMedCrossRefGoogle Scholar
  23. 23.
    Sambrook J, Russell DW (2001) Preparation and analysis of Eukaryotic genomic DNA. In: Argentine J, Irwin N (eds) Molecular cloning: a laboratory manual, vol 1. Cold spring Harbor Laboratory Press, Cold Spring Harbor (protocol 6.1)Google Scholar
  24. 24.
    Kleiner D, Stetler-Stevenson W (1994) Quantitative zymography: detection of picogram quantities of gelatinases. Anal Biochem 218:325–329PubMedCrossRefGoogle Scholar
  25. 25.
    Cho A, Reidy MA (2002) Matrix metalloproteinase-9 is necessary for the regulation of smooth muscle cell replication and migration after arterial injury. Circ Res 91:845–851PubMedCrossRefGoogle Scholar
  26. 26.
    Ferrand PE, Parry S, Sammel M (2002) A polymorphism in the matrix metalloproteinase-9 promoter is associated with increased risk of preterm premature rupture of membranes in Africans Americans. Mol Hum Reprod 8(5):494–501PubMedCrossRefGoogle Scholar
  27. 27.
    Ubbink JB, Hayward Vermaak WJ, Bissbort S (1991) Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum. J Chromatogr 565:441–446PubMedCrossRefGoogle Scholar
  28. 28.
    Vaisi-Raygani A, Rahimi Z, Entezami H, Kharrazi H, Bahrhemand F, Tavilani H, Rezaei M, Kiani A, Nomanpour B, Pourmotabbed T (2008) Butyrylcholinesterase K variants increase the risk of coronary artery disease in the population of western Iran. Scand J Clin Lab Invest 68(2):123–129PubMedCrossRefGoogle Scholar
  29. 29.
    Blankenberg S, Rupprecht HJ, Poirier O, Bickel C, Smieja M, Hafner G, Meyer J, Cambien F, Tiret L, AtheroGene Investigators (2003) Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 107:1579–1585PubMedCrossRefGoogle Scholar
  30. 30.
    Medley TL, Cole TJ, Dart AM, Gatzka CD, Kingwell BA (2004) Matrix metallaproteinase-9 genotype influences large artery stiffness through effects on aortic gene and protein expression. Arterioscler Thromb Vasc Biol 24:1479–1484PubMedCrossRefGoogle Scholar
  31. 31.
    Sundstrom J, Evans JC, Benjamin EJ, Levy D, Larson MG, Sawyer DB, Siwik DA, Colucci WS, Sutherland P, Wilson PWF, Vasan RS (2004) Relations of plasma matrix metalloproteinase-9 to clinical cardiovascular risk factors and echocardiographic left ventricular measures: the Framingham Heart Study. Circulation 109(23):2850–2856PubMedCrossRefGoogle Scholar
  32. 32.
    Ranucci M, Ballotta A, Frigiola A, Boncilli A, Brozzi S, Costa E, Mehta RH (2009) Preoperative homocysteine levels and morbidity and mortality following cardiac surgery. Eur Heart J 30:995–1004PubMedCrossRefGoogle Scholar
  33. 33.
    Pasali D, Marinkovi N, Grskovi B, Ferencak G, Bernat R, Stavljeni-Rukavina A (2009) C-reactive protein gene polymorphisms affect plasma CRP and homocysteine concentrations in subjects with and without angiographically confirmed coronary artery disease. Mol Biol Rep 36(4):775–780CrossRefGoogle Scholar
  34. 34.
    Madani H, Rahimi Z, Manavi-Shad M, Mozafari H, Akramipour R, Vaisi-Raygani A, Rezaei M, Malek-Khosravi S, Shakiba E, Parsian A (2011) Plasma lipids and lipoproteins in children and young adults with major β-thalassemia from western Iran: influence of genotype. Mol Biol Rep 38(4):2573–2578Google Scholar
  35. 35.
    Ashok Kumar M, Subhashini NG, SaiBabu R, Ramesh A, Cherian KM, Emmanuel C (2010) Genetic variants on apolipoprotein gene cluster influence triglycerides with a risk of coronary artery disease among Indians. Mol Biol Rep 37(1):521–527CrossRefGoogle Scholar
  36. 36.
    Liang S, Pan M, Geng HH, Chen H, Gu LQ, Qin XT, Qian JJ, Zhu JH, Liu CF (2009) Apolipoprotein E polymorphism in normal Han Chinese population: frequency and effect on lipid parameters. Mol Biol Rep 36(6):1251–1256PubMedCrossRefGoogle Scholar
  37. 37.
    Robertson L, Grip L, Mattsson Hulte L, Hulthe J, Wiklund O (2007) Release of protein as well as activity of MMP-9 from unstable atherosclerotic plaques during percutaneous coronary intervention. J Internal Medici 262:659–667CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Massoud Saedi
    • 1
  • Asad Vaisi-Raygani
    • 1
    • 2
    • 3
  • Shahnaz Khaghani
    • 1
  • Ahmad Shariftabrizi
    • 1
  • M. Rezaie
    • 1
  • Parvin Pasalar
    • 1
  • Zohreh Rahimi
    • 3
  • Tayebeh Pourmotabbed
    • 1
    • 4
  1. 1.Department of Clinical BiochemistryTehran University of Medical SciencesTehranIran
  2. 2.Fertility Infertility Research CenterKermanshah University of Medical SciencesKermanshahIran
  3. 3.Department of Clinical BiochemistryKermanshah University of Medical SciencesKermanshahIran
  4. 4.Department of Molecular SciencesUniversity of Tennessee Health Science CenterMemphisUSA

Personalised recommendations