Download PDF
Thromb Haemost 2011; 106(06): 1170-1178
DOI: 10.1160/TH11-03-0206
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Thrombospondin-4 polymorphism (A387P) predicts cardiovascular risk in postinfarction patients with high HDL cholesterol and C-reactive protein levels

James P. Corsetti
1   Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
,
Dan Ryan
1   Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
,
Arthur J. Moss
2   Department of Medicine – Cardiology Unit, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
,
Jeanette J. McCarthy
3   Institute for Genomic Sciences and Policy, Center for Genomic Medicine, Duke University, Durham, North Carolina, USA
,
Ilan Goldenberg
2   Department of Medicine – Cardiology Unit, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
,
Wojciech Zareba
2   Department of Medicine – Cardiology Unit, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
,
Charles E. Sparks
1   Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
› Author Affiliations Financial support: This study was supported by the National Institutes of Health, Bethesda, MD, grants HL-48259 and HL-45522.
Further Information

Publication History

Received: 01 April 2011

Accepted after major revision: 04 September 2011

Publication Date:
27 November 2017 (online)

    Permissions and Reprints

Summary

Few studies are available in human populations investigating involvement of vascular inflammation and oxidative stress-related dysfunctional transformation of high-density lipoprotein (HDL) in establishing cardiovascular disease (CVD) risk. To this end, the current work investigated a subgroup of post-infarction patients at high-risk for recurrent events defined by high levels of HDL cholesterol (HDL-C) and concurrently high levels of C-reactive protein (CRP). Thrombospondin-4 (TSP-4), a matricellular protein of vessel walls associated with inflammation, was investigated in terms of CVD risk using multivariable modelling with a well-characterised functional genetic polymorphism of THBS4 (A387P, rs1866389) along with previously demonstrated risk-related functional genetic polymorphisms of CYBA (C242T, rs4673) and CETP (TaqIB, rs708272), and a set of blood markers. Results revealed risk-association for the gain-of-function P-allele of the THBS4 polymorphism (hazard ratio 2.00, 95% confidence interval 1.10–3.65, p=0.024). Additionally, von Willebrand factor was associated with D-dimer levels in the higher-risk P allele patients suggestive of a connection between endothelial dysfunction and thrombogenesis. In conclusion, TSP-4, a matricellular protein involved in regulating vascular inflammation, plays a role in establishing recurrent coronary risk in postinfarction patients with high levels of HDL-C and CRP. Further studies should focus on additional effects of vascular inflammatory processes on anti-atherogenic functionality of HDL particles.

Keywords

Thrombospondin-4 - HDL cholesterol - C-reactive protein - inflammation - oxidative stress
 

  • References

  • 1 Ragbir S, Farmer JA. Dysfunctional high-density lipoprotein and atherosclerosis. Curr Atheroscler Rep 2010; 12: 343-348.
    CrossrefPubMedGoogle Scholar
  • 2 Shao B, Oda M, Oram JF. et al. Myeloperoxidase: an oxidative pathway for generating dysfunctional high-density lipoprotein. Chem Res Toxicol 2010; 23: 447-454.
    CrossrefPubMedGoogle Scholar
  • 3 Ansell BJ, Fonarow GC, Fogelman AM. The paradox of dysfunctional high-density lipoprotein. Curr Opin Lipidol 2007; 18: 427-434.
    CrossrefPubMedGoogle Scholar
  • 4 Kontush A, Chapman MJ. Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacol Rev 2006; 58: 342-374.
    CrossrefPubMedGoogle Scholar
  • 5 Norata GD, Pirillo A, Catapano AL. Modified HDL: biological and physiopathological consequences. Nutr Metabol Cardiovasc Dis 2006; 16: 371-386.
    CrossrefPubMedGoogle Scholar
  • 6 Corsetti JP, Gansevoort RT, Sparks CE. et al. HDL Protection against Primary Cardiac Risk is Lost with Inflammation. Eur J Clin Invest 2010; 40: 483-489.
    CrossrefPubMedGoogle Scholar
  • 7 Corsetti JP, Gansevoort RT, Navis GJ. et al. LPL Polymorphism (D9N) Predicts Cardiovascular Disease Risk Directly and Through Interaction with CETP Polymorphism (TaqIB) in Women with High HDL Cholesterol and CRP. Atherosclerosis 2011; 214: 373-376.
    CrossrefPubMedGoogle Scholar
  • 8 Corsetti JP, Ryan D, Rainwater DL. et al. CETP Polymorphism (TaqIB) Associates with Risk in Postinfarction Patients with High HDL Cholesterol and High CRP Levels. Arterioscler Thromb Vasc Biol 2010; 30: 1657-1664.
    CrossrefPubMedGoogle Scholar
  • 9 Corsetti JP, Ryan D, Moss AJ. et al. NAD(P)H oxidase polymorphism (C242T) and high HDL-C associate with recurrent coronary events in post infarction patients. Atherosclerosis 2007; 196: 461-468.
    PubMedGoogle Scholar
  • 10 Topol EJ, McCarthy J, Gabriel S. et al. Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction. Circulation 2001; 104: 2641-2644.
    CrossrefPubMedGoogle Scholar
  • 11 Stenina OI, Topol EJ, Plow EF. Thrombospondins, their polymorphisms, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2007; 27: 1886-1894.
    CrossrefPubMedGoogle Scholar
  • 12 Frolova E, Pluskota E, Krukovets I. et al. Thrombospondin-4 regulates vascular inflammation and atherogenesis. Circ Res 2010; 107: 1313-1325.
    CrossrefPubMedGoogle Scholar
  • 13 Thompson A, Di Angelantonio E, Sarwar N. et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary Risk. J Am Med Assoc 2008; 299: 2777-2788.
    CrossrefPubMedGoogle Scholar
  • 14 Dullaart RPF, Sluiter W. Common variation in the CETP gene and the implications for cardiovascular disease and its treatment: an updated analysis. Pharmacogenomics 2008; 9: 747-763.
    CrossrefPubMedGoogle Scholar
  • 15 Guzik TJ, West NEJ, Black E. et al. Functional effect of the C242T polymorphism in the NAD(P)H oxidase p22phox gene on vascular superoxide production in atherosclerosis. Circulation 2000; 102: 1744-1747.
    CrossrefPubMedGoogle Scholar
  • 16 Nakano T, Matsunaga S, Nagata A. et al. NAD(P)H oxidase p22phox gene C242T polymorphism and lipoprotein oxidation. Clin Chim Acta 2003; 335: 101-107.
    CrossrefPubMedGoogle Scholar
  • 17 Corsetti JP, Zareba W, Moss AJ. et al. Serum Glucose and Triglyceride Determine High-Risk Subgroups in Non-Diabetic Postinfarction Patients. Atherosclerosis 2005; 183: 293-300.
    CrossrefPubMedGoogle Scholar
  • 18 Corsetti JP, Rainwater DL, Moss AJ. et al. High lipoprotein-associated phospholipase A2 is a risk factor for recurrent coronary events in postinfarction patients. Clin Chem 2006; 52: 1331-1338.
    CrossrefPubMedGoogle Scholar
  • 19 Livak KJ. Allelic discrimination using fluorogenic probes and the 5’ nuclease assay. Genetic Analysis 1999; 14: 143-149.
    CrossrefPubMedGoogle Scholar
  • 20 Goldenberg I, Moss AJ, Block R. et al. Polymorphism in the cholesteryl ester transfer protein gene and the risk of early onset myocardial infarction among cigarette smokers. Ann Noninv Electrocardiol 2007; 12: 364-374.
    CrossrefPubMedGoogle Scholar
  • 21 Gresele P, Momi S, Migliacci R. Endothelium, venous thromboembolism and ischaemic cardiovascular events. Thromb Haemost 2010; 103: 56-61.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Badimon L Storey, Vilahur G. Update on lipids, inflammation and atherothrombosis. Thromb Haemost 2011; 105 (Suppl. 01) (Suppl) S34-S42.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Zareba W, Pancio G, Moss AJ. et al. Increased level of von Willebrand factor is significantly and independently associated with diabetes in postinfarction patients. Thromb Haemost 2001; 86: 791-799.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Koch W, Hoppmann P, de Waha A. et al. Polymorphisms in thrombospondin genes and myocardial infarction: a case-control study and a meta-analysis of available evidence. Hum Mol Gen 2008; 17: 1120-1126.
    CrossrefPubMedGoogle Scholar
  • 25 Stenina OI, Ustinov V, Krukovets I. et al. Polymorphisms A387P in thrombospondin-4 and N700S in thrombospondin-1 perturb calcium binding sites. Faseb J 2005; 19: 1893-1895.
    CrossrefPubMedGoogle Scholar
  • 26 Stenina I O, Byzova TV, Adams JC. et al. Coronary artery disease and the thrombospondin single nucleotide polymorphisms. Int J Biochem Cell Biol 2004; 36: 1013-1030.
    CrossrefPubMedGoogle Scholar
  • 27 Stenina OI, Shailesh YD, Krukovets I. et al. Thrombospondin-4 and its variants expression and differential effects on endothelial cells. Circulation 2003; 108: 1514-1519.
    CrossrefPubMedGoogle Scholar
  • 28 Devaraj S, Singh U, Jialal I. The evolving role of C-reactive protein in atherothrombosis. Clin Chem 2009; 55: 229-238.
    PubMedGoogle Scholar
  • 29 Libby P. The molecular mechanisms of the thrombotic complications of atherosclerosis. J Intern Med 2008; 263: 517-527.
    CrossrefPubMedGoogle Scholar
  • 30 Mineo C, Deguchi H, Griffin JH. et al. Endothelial and antithrombotic actions of HDL. Circ Res 2006; 98: 1352-1364.
    CrossrefPubMedGoogle Scholar
  • 31 Florentin M, Liberopoulos EN, Wierzbicki AS. et al. Multiple actions of high-density lipoprotein. Curr Opin Cardiol 2008; 23: 370-378.
    CrossrefPubMedGoogle Scholar