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

Thromb Haemost. 2011 Dec;106(6):1170-8. doi: 10.1160/TH11-03-0206. Epub 2011 Oct 20.

Abstract

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 post-infarction 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Arteritis / genetics*
  • C-Reactive Protein / metabolism
  • Cholesterol, HDL / blood
  • Coronary Disease / genetics*
  • DNA Mutational Analysis
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Middle Aged
  • Myocardial Infarction / complications*
  • Polymorphism, Genetic
  • Prognosis
  • Recurrence
  • Risk
  • Thrombospondins / genetics*

Substances

  • Cholesterol, HDL
  • Thrombospondins
  • thrombospondin 4
  • C-Reactive Protein