Genotype association of C(-735)T polymorphism of the MMP-2 gene with the risk of carotid atherosclerosis-vulnerable plaque in the Han Chinese population

Abstract

The aim of the current study was to explore the possible association of the polymorphism of C(-735)T in MMP-2 with the vulnerable plaque risk in ultrasound-confirmed carotid atherosclerosis cases. Serum MMP-2 levels were measured to investigate the relationship between the MMP-2 level and the genetic variability. The MMP-2 polymorphism was detected by PCR-RFLP in the 243 cases with stable plaque and 221 cases with vulnerable plaque. Serum MMP-2 levels were measured with ELISA. The results showed that MMP-2 was significantly higher in the cases with vulnerable plaque than in the cases with stable plaque. A statistical difference was found between the genotype distributions in the vulnerable plaque cases and that in the stable cases. T-allele frequency was also found to be over-represented in the stable plaque cases than in the vulnerable plaque cases, which might partially explain the observed difference in the serum MMP-2 levels in the different plaque cases. The current results also suggested that MMP-2 was a risk factor in the cases with vulnerable plaques, whereas TT genotype and T allele might be protective factors in the cases with vulnerable plaques.

Keywords

carotid atherosclerosis genetic polymorphism matrix metalloproteinase-2 vulnerable plaque

References

Galis ZS , Khatri JJ Matrix metalloproteinase in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 2002; 90: 251-262.

Li Z. , Li L. , Zielke HR , et al. Increased expression of 72-kd type IV collagenase (MMP-2) in human aortic atherosclerotic lesions. Am J Pathol 1996; 148: 121-128.

Yu C. , Zhou Y. , Miao X. , Xiong P. , Tan W. , Lin D. Functional haplotypes in the promoter of matrix metalloproteinase-2 predict risk of the occurrence and metastasis of esophageal cancer. Cancer Res 2004; 64: 7622-7628.

Mathiesen EB , Bønaa KH , Joakimsen O. Echolucent plaques are associated with high risk of ischemic cerebrovascular events in carotid stenosis: the Tromsø study. Circulation 2001; 103: 2171-2175.

Naghavi M. , Libby P. , Falk E. , et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 2003; 108; 1664-1672.

Derosa G. , D’Angelo A. , Ciccarelli L. , et al. Matrix metalloproteinase-2,-9, and tissue inhibitor of metalloproteinase-1 in patients with hypertension. Endothelium 2006; 13: 227-231.

Huhtala P. , Chow LT , Tryggvason K. Structure of the human type IV collagenase gene. J Biol Chem 1990; 265: 11,077- 11,082.

Egeblad M. , Werb Z. New functions for the matrixmetalloproteinases in cancer progression. Nat Rev Cancer 2002; 2: 161-174.

Ehringer WD , Wang OL , Haq A. , Miller FN Bradykinin and alpha-thrombin increase human umbilical vein endothelial macromolecular permeability by different mechanisms. Inflammation 2000; 24: 175-193.

10.

Heo JH , Lucero J. , Abumiya T. , Koziol JA , Copeland BR , del Zoppo GJ Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. Cereb Blood Flow Metab 1999; 19: 624-633.

11.

Thrailkill KM , Bunn RC , Moreau CS , et al. Matrix metalloproteinase-2 dysregulation in type 1 diabetes. Diabetes Care 2007; 30: 2321-2326.

12.

Momi S. , Falcinelli E. , Giannini S. , et al. Loss of matrix metalloproteinase 2 in platelets reduces arterial thrombosis in vivo. J Exp Med 2009; 206: 2365-2379.

13.

Fatar M. , Stroick M. , Steffens M. , et al. Single-nucleotide polymorphisms of mmp-2 gene in stroke subtypes . Cerebrovasc Dis 2008; 26: 113-119.

14.

Kang S. , Zhao X. , Xing H. , et al. Polymorphisms in the matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 and the risk of human adenomyosis. Environ Mol Mutagen 2008; 49: 226-231.

15.

Vask A. , Goldbergová M. , Izakovicová Hollá L. , et al. A haplotype constituted of four MMP-2 promoter polymorphisms is associated with coronary triple-vessel disease. Matrix Biol 2004; 22: 585-591.

16.

Zhou Y. , Yu C. , Miao X. , et al. Functional haplotypes in the promoter of matrix metalloproteinase-2 and lung cancer susceptibility. Carcinogenesis 2005; 26: 1117-1121.

17.

Huang X. , Jin X. , Zhu M. , Lin X. , Zhang D. , Ye Z. The relationship between the polymorphism of the MMP-3 gene and the vulnerability of carotid atherosclerosis in Chinese Han population. Chinese J Neurol 2009; 42: 233-236.

18.

Armstrong C. , Abilleira S. , Sitzer M. , Markus HS , Bevan S. Polymorphisms in MMP family and TIMP genes and carotid artery intima-media thickness. Stroke 2007; 38: 2895-2899.