Thrombospondin-4 polymorphism (A387P) predicts cardiovascular risk in postinfarction patients with high HDL cholesterol and C-reactive protein levels.
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.
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. James_Corsetti@urmc.rochester.edu
James P
JP
Corsetti
Dan
D
Ryan
Arthur J
AJ
Moss
Jeanette
J
McCarthy
Ilan
I
Goldenberg
Wojciech
W
Zareba
Charles E
CE
Sparks
D000368:Aged; D001167:Arteritis / Q000235:genetics*; D002097:C-Reactive Protein / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D003327:Coronary Disease / Q000235:genetics*; D004252:DNA Mutational Analysis; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000150:complications*; D011110:Polymorphism, Genetic; D011379:Prognosis; D012008:Recurrence; D012306:Risk; D019699:Thrombospondins / Q000235:genetics*
D008076:Cholesterol, HDL; D019699:Thrombospondins; C101864:thrombospondin 4; D002097:C-Reactive Protein