The gender-specific role of polymorphisms from the fibrinolytic, renin-angiotensin, and bradykinin systems in determining plasma t-PA and PAI-1 levels.
Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thus risk for arterial thrombosis. We report here results from a genetic analysis of plasma t-PA and PAI-1 levels in a large population-based sample from the PREVEND study in Groningen, the Netherlands (n = 2,527). We measured polymorphisms from genes of the fibrinolytic system, the renin-angiotensin system (RAS), and the bradykinin system. We found that males had higher levels of natural-log transformed t-PA, and PAI-1 (P < 0.01) compared to females. When stratifying females by menopausal status, PAI-1 levels were only significantly different between pre-menopausal females and males (p < 0.001). Furthermore, we found that age, body mass index, and waist-to-hip ratio were significant predictors of t-PA and PAI-1 in both females and males, and that the regression relationships between these factors and plasma t-PA and PAI-1 were dependent on gender. In addition, we found that the PAI-1 4G/5G polymorphism was a significant predictor of PAI-1 levels in both females and males, that the angiotensin II type I receptor A1166C was a significant predictor of t-PA and PAI-1 levels in females, and that the bradykinin receptor B2 58CT polymorphism was a significant predictor of t-PA levels in females. In conclusion, this large population-based study showed that t-PA and PAI-1 levels are determined by several demographic and genetic factors involved in the fibrinolytic, RAS and bradykinin system. In addition, the results support the idea that the biology of t-PA and PAI-1 is different between females and males.
Asselbergs
Folkert W
FW
Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands.
Williams
Scott M
SM
Hebert
Patricia R
PR
Coffey
Christopher S
CS
Hillege
Hans L
HL
Navis
Gerjan
G
Vaughan
Douglas E
DE
van Gilst
Wiek H
WH
Moore
Jason H
JH
D000328:Adult; D000367:Age Factors; D000368:Aged; D000808:Angiotensinogen / Q000235:genetics; D015992:Body Mass Index; D005260:Female; D005342:Fibrinolysis / Q000235:genetics*; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D043782:Receptor, Bradykinin B2 / Q000235:genetics*; D012044:Regression Analysis; D012084:Renin-Angiotensin System / Q000235:genetics*; D012737:Sex Factors; D010959:Tissue Plasminogen Activator / Q000097:blood*; D049629:Waist-Hip Ratio
D017395:Plasminogen Activator Inhibitor 1; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; C051321:SERPINE1 protein, human; D000808:Angiotensinogen; D007703:Peptidyl-Dipeptidase A; D010959:Tissue Plasminogen Activator