The gender-specific role of polymorphisms from the fibrinolytic, renin-angiotensin, and bradykinin systems in determining plasma t-PA and PAI-1 levels

Summary

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 wasa 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.

Keywords

Epidemiological studies - thrombosis - risk factors - plasminogen - sex

• References

• 1 Tracy RP, Bovill EG. Thrombosis and cardiovascular risk in the elderly. Arch Pathol Lab Med 1992; 116: 1307-12.
• 2 Ridker PM. et al. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-8.
• 3 Jansson JH. et al. Predictive value of tissue plasminogen activator mass concentration on long-term mortality in patients with coronary artery disease. A 7-year follow-up. Circulation 1993; 88: 2030-4.
• 4 Folsom AR. et al. Prospective study of fibrinolytic factors and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb Vasc Biol 2001; 21: 611-7.
• 5 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-7.
• 6 Scarabin PY. et al. Associations of fibrinogen, factor VII and PAI-1 with baseline findings among 10,500 male participants in a prospective study of myocardial infarction--the PRIME Study. Prospective Epidemiological Study of Myocardial Infarction. Thromb Haemost 1998; 80: 749-56.
• 7 Yarnell JW. et al. Lifestyle and hemostatic risk factors for ischemic heart disease : the Caerphilly Study. Arterioscler Thromb Vasc Biol 2000; 20: 271-9.
• 8 Pankow JS. et al. Segregation analysis of plasminogen activator inhibitor-1 and fibrinogen levels in the NHLBI family heart study. Arterioscler Thromb Vasc Biol 1998; 18: 1559-67.
• 9 Verschuur M. et al. The plasminogen activator inhibitor-1 (PAI-1) promoter haplotype is related to PAI-1 plasma concentrations in lean individuals. Atherosclerosis 2005; 181: 275-84.
• 10 Ridker PM. et al. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the reninangiotensin system and fibrinolytic function. Circulation 1993; 87: 1969-73.
• 11 Pretorius M. et al. Angiotensin-converting enzyme inhibition increases human vascular tissue-type plasminogen activator release through endogenous bradykinin. Circulation 2003; 107: 579-85.
• 12 Mansfield MW. et al. Environmental and genetic factors in relation to elevated circulating levels of plasminogen activator inhibitor-1 in Caucasian patients with non-insulin-dependent diabetes mellitus. Thromb Haemost 1995; 74: 842-7.
• 13 Juhan-Vague I. et al. Involvement of the hemostatic system in the insulin resistance syndrome. A study of 1500 patients with angina pectoris. The ECAT Angina Pectoris Study Group. Arterioscler Thromb 1993; 13: 1865-73.
• 14 Toft I. et al. Gender differences in the relationships between plasma plasminogen activator inhibitor-1 activity and factors linked to the insulin resistance syndrome in essential hypertension. Arterioscler Thromb Vasc Biol 1997; 17: 553-9.
• 15 Hillege HL. et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 2002; 106: 1777-82.
• 16 Rothman KJ. No adjustments are needed for multiple comparisons. Epidemiology 1990; 01: 43-6.
• 17 Tofler GH. et al. Relation of the prothrombotic state to increasing age (from the Framingham Offspring Study). Am J Cardiol 2005; 96: 1280-3.
• 18 Rosito GA. et al. Association between obesity and a prothrombotic state: the Framingham Offspring Study. Thromb Haemost 2004; 91: 683-9.
• 19 Sing CF. et al. Genes, environment, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2003; 23: 1190-6.
• 20 Moore JH. Quantitative trait linkage analysis. In: Genetic Analysis of Complex Disease. New York: Wiley-Liss, Inc; 2006
• 21 Peetz D. et al. Genetic and environmental influences on the fibrinolytic system: a twin study. Thromb Haemost 2004; 92: 344-51.
• 22 Best LG. et al. Genetic determination of acute phase reactant levels: the strong heart study. Hum Hered 2004; 58: 112-6.
• 23 Margaglione M. et al. Plasminogen activator inhibitor-1 (PAI-1) antigen plasma levels in subjects attending a metabolic ward: relation to polymorphisms of PAI-1 and angiontensin converting enzyme (ACE) genes. Arterioscler Thromb Vasc Biol 1997; 17: 2082-7.
• 24 Moore JH. et al. A comparison of combinatorial partitioning and linear regression for the detection of epistatic effects of the ACE I/D and PAI-1 4G/5G polymorphisms on plasma PAI-1 levels. Clin Genet 2002; 62: 74-9.
• 25 Moore JH. et al. The relationship between plasma t-PA and PAI-1 levels is dependent on epistatic effects of the ACE I/D and PAI-1 4G/5G polymorphisms. Clin Genet 2002; 62: 53-9.
• 26 Bairey CNMerz. et al. Insights from the NHLBISponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part II: gender differences in presentation, diagnosis, and outcome with regard to genderbased pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease. J Am Coll Cardiol 2006; 47: S21-S29.
• 27 Shaw LJ. et al. Insights from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J Am Coll Cardiol 2006; 47: S4-S20.
• 28 Verhave JC. et al. Cardiovascular risk factors are differently associated with urinary albumin excretion in men and women. J Am Soc Nephrol 2003; 14: 1330-5.
• 29 Gebara OC. et al. Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study. Circulation 1995; 91: 1952-8.
• 30 Stangl V. et al. Coronary atherogenic risk factors in women. Eur Heart J 2002; 23: 1738-52.
• 31 Stevenson JC. et al. Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atherosclerosis 1993; 98: 83-90.
• 32 Brown NJ. et al. Comparative effects of estrogen and angiotensin-converting enzyme inhibition on plasminogen activator inhibitor-1 in healthy postmenopausal women. Circulation 2002; 105: 304-9.
• 33 Hoetzer GL. et al. Acute and chronic effects of oestrogen on endothelial tissue-type plasminogen activator release in postmenopausal women. J Physiol 2003; 551: 721-8.