Differential association between human prostacyclin receptor polymorphisms and the development of venous thrombosis and intimal hyperplasia: a clinical biomarker study

Pharmacogenet Genomics. 2008 Jul;18(7):611-20. doi: 10.1097/FPC.0b013e328301a774.

Abstract

Objective and methods: The role of prostacyclin in the development of venous thrombosis and vascular dysfunction in humans is unclear. In patients with deep vein thrombosis (DVT, n=34) and controls (matched for age, sex, indexes of systemic inflammation and metabolic status, n=20), we studied (i) differences on systemic markers of vascular disease and platelet activation and (ii) the influence of prostacyclin receptor gene (PTGIR) polymorphisms.

Main results: Enhanced levels of urinary 11-dehydro-thromboxane (TX)B2 and plasma [soluble(s)] P-selectin, mostly platelet derived, were detected in DVT patients, whereas plasma von Willebrand factor levels and intima-media thickness of the common carotid arteries were not significantly different. In all patients' cohorts, we identified five PTGIR polymorphisms (three nonsynonymous: P226T, R212C, V196L; two synonymous: V53V, S328S). In the four individuals carriers of R212C polymorphism (three in DVT, one in controls), intima-media thickness values were significantly (P=0.0043) higher than those detected in individuals of all cohorts [1.68+/-0.38, 1.55 (1.4-2.2) vs. 1.05+/-0.33, 1.08 (0.01-1.68) mm, respectively, mean+/-SD, median (range)]. Moreover, enhanced sP-selectin and 11-dehydro-TXB2, in DVT versus controls, were statistically significant only in carriers of both synonymous PTGIR polymorphisms V53V/S328S. Only the PTGIR mutant R212C was dysfunctional when examined in an in vitro overexpression system.

Conclusion: Our results suggest a propensity of enhanced platelet activation in DVT patients with PTGIR polymorphisms V53V/S328S. Moreover, we identified a dysfunctional PTGIR polymorphism (R212C) associated with intimal hyperplasia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers / analysis*
  • Female
  • Genetic Linkage
  • Genetic Testing
  • Humans
  • Hyperplasia / genetics
  • Male
  • Middle Aged
  • P-Selectin / blood
  • Platelet Activation / genetics
  • Polymorphism, Single Nucleotide*
  • Receptors, Epoprostenol / genetics*
  • Thromboxane B2 / analogs & derivatives
  • Thromboxane B2 / urine
  • Tunica Intima / pathology*
  • Venous Thrombosis / blood
  • Venous Thrombosis / genetics*
  • Venous Thrombosis / pathology
  • Venous Thrombosis / urine

Substances

  • Biomarkers
  • P-Selectin
  • Receptors, Epoprostenol
  • Thromboxane B2
  • 11-dehydro-thromboxane B2