Journal of Molecular Medicine

, Volume 81, Issue 5, pp 321–326 | Cite as

Haplotypic analysis of the MMP-9 gene in relation to coronary artery disease

  • Angharad R. Morgan
  • Baiping Zhang
  • William Tapper
  • Andrew Collins
  • Shu Ye
Original Article

Abstract

Matrix metalloproteinase-9 (MMP-9) plays an important role in the pathogenesis of atherosclerosis, the pathology underlying the majority of coronary artery disease. We previously identified several polymorphisms in the gene encoding MMP-9. In this study we tested the hypothesis that variation in the matrix metalloproteinase-9 gene influences the development of atherosclerosis. Three common polymorphisms, i.e. −1562C>T, R+279Q and +6C>T, were analysed in 1510 white subjects undergoing coronary angiography. Analyses of individual polymorphisms showed that the frequencies of the C/T and T/T genotypes of the −1562C>T polymorphism were significantly higher in patients with coronary stenosis than in those with a normal angiogram. Logistic regression analyses indicated that individuals carrying the −1562T allele had an approx. 1.5-fold higher risk of developing coronary stenosis (OR 1.49, 95% CI 1.039–2.144), which was equivalent to an over 30% reduction in risk of coronary stenosis in individuals not carrying this allele (OR 0.670, 95% CI 0.467–0.963). The three polymorphisms studied were found to be in strong linkage disequilibrium. Haplotype analyses showed that the C-G-C haplotype (−1562C, +279Q and +6C) was associated with a protective effect against atherosclerosis. Individuals carrying this haplotype were at reduced risk of developing coronary stenosis (OR 0.695, 95% CI 0.530.92). Furthermore, the C-G-C haplotype was associated with less severe coronary atherosclerosis, i.e. carriers of this haplotype were at a lower risk of having coronary stenosis in more than one coronary artery (OR 0.796, 95% CI 0.640.99). These data, together with the previous finding that the −1562T allele has a higher transcriptional activity than the −1562C allele, support the notion that genetic variation with an effect on MMP-9 expression influences the development and progression of atherosclerosis.

Keywords

Matrix metalloproteinase Genetic polymorphism Haplotype Coronary artery disease 

Abbreviations

MMP-9

Matrix metalloproteinase-9

SMC

Smooth muscle cell

References

  1. 1.
    Lusis AJ (2000) Atherosclerosis. Nature 407:233–241CrossRefPubMedGoogle Scholar
  2. 2.
    Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362:801–809PubMedGoogle Scholar
  3. 3.
    Newby AC, Zaltsman AB (1999) Fibrous cap formation or destruction–the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation. Cardiovasc Res 41:345–360CrossRefPubMedGoogle Scholar
  4. 4.
    Zempo N, Kenagy RD, Au YP, Bendeck M, Clowes MM, Reidy MA, AW Clowes (1994) Matrix metalloproteinases of vascular wall cells are increased in balloon-injured rat carotid artery. J Vasc Surg 20:209–217PubMedGoogle Scholar
  5. 5.
    George SJ, Zaltsman AB, Newby AC (1997) Surgical preparative injury and neointima formation increase MMP-9 expression and MMP-2 activation in human saphenous vein. Cardiovasc Res 33:447–459CrossRefPubMedGoogle Scholar
  6. 6.
    Mason DP, Kenagy RD, Hasenstab D, Bowen-Pope DF, Seifert RA, Coats S, Hawkins SM, Clowes AW (1999) Matrix metalloproteinase-9 overexpression enhances vascular smooth muscle cell migration and alters remodeling in the injured rat carotid artery. Circ Res 85:1179–1185PubMedGoogle Scholar
  7. 7.
    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 105:418–423CrossRefPubMedGoogle Scholar
  8. 8.
    Scanlon PJ, Faxon DP, Audet AM, Carabello B, Dehmer GJ, Eagle KA, Legako RD, Leon DF, Murray JA, Nissen SE, Pepine CJ, Watson RM, Ritchie JL, Gibbons RJ, Cheitlin MD, Gardner TJ, Garson A Jr, Russell RO Jr, Ryan TJ, Smith SC Jr (1999) ACC/AHA guidelines for coronary angiography: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Coronary Angiography) developed in collaboration with the Society for Cardiac Angiography and Interventions. Circulation 99:2345–2357PubMedGoogle Scholar
  9. 9.
    Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215-PubMedGoogle Scholar
  10. 10.
    Ye S, Dhillon S, Ke X, Collins AR, Day IN (2001) An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Res 29:E88–E88CrossRefPubMedGoogle Scholar
  11. 11.
    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
  12. 12.
    Shipley JM, Doyle GA, Fliszar CJ, Ye QZ, Johnson LL, Shapiro SD, Welgus HG, Senior RM (1996) The structural basis for the elastolytic activity of the 92-kDa and 72-kDa gelatinases. Role of the fibronectin type II-like repeats. J Biol Chem 271:4335–4341PubMedGoogle Scholar
  13. 13.
    Pollanen PJ, Karhunen PJ, Mikkelsson J, Laippala P, Perola M, Penttila A, Mattila KM, Koivula T, Lehtimaki T (2001) Coronary artery complicated lesion area is related to functional polymorphism of matrix metalloproteinase 9 gene: an autopsy study. Arterioscler Thromb Vasc Biol 21:1446–1450PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Angharad R. Morgan
    • 1
  • Baiping Zhang
    • 1
  • William Tapper
    • 1
  • Andrew Collins
    • 1
  • Shu Ye
    • 1
  1. 1.Human Genetics Division, School of MedicineUniversity of Southampton, Southampton General HospitalSouthamptonUK

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