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


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.


CONCLUSIONS
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.
Department of Medicine and Aging, 'G. d'Annunzio' University, Chieti, Italy. ppatrignani@unich.it
Paola
P
Patrignani
Concetta
C
Di Febbo
Stefania
S
Tacconelli
Karen
K
Douville
Maria D
MD
Guglielmi
Ryan J
RJ
Horvath
Min
M
Ding
Kent
K
Sierra
Jeremiah
J
Stitham
Scott
S
Gleim
Giovanna
G
Baccante
Valeria
V
Moretta
Luigia
L
Di Francesco
Marta L
ML
Capone
Ettore
E
Porreca
John
J
Hwa
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000032:analysis*; D005260:Female; D008040:Genetic Linkage; D005820:Genetic Testing; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000097:blood; D015539:Platelet Activation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D044006:Receptors, Epoprostenol / Q000235:genetics*; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine; D017539:Tunica Intima / Q000473:pathology*; D020246:Venous Thrombosis / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000652:urine
D015415:Biomarkers; D019007:P-Selectin; D044006:Receptors, Epoprostenol; D013929:Thromboxane B2; C049235:11-dehydro-thromboxane B2