The gender-specific role of polymorphisms from the fibrinolytic, renin-angiotensin, and bradykinin systems in determining plasma t-PA and PAI-1 levels
Folkert W. Asselbergs1, Scott M. Williams2, Patricia R. Hebert3, Christopher S. Coffey4, Hans L. Hillege1, Gerjan Navis5, Douglas E. Vaughan2, Wiek H. van Gilst1,6, Jason H. Moore7
1Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands; 2Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical School, Nashville, Tennessee, USA; 3Section of Cardiovascular Medici
Risk Factors, epidemiological studies, thrombosis, sex, plasminogen
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 reninangiotensin 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.