Genetic influences on fibrinogen, tissue plasminogen activatorantigen and von Willebrand factor in males and females

Summary

Differences in genetic influence on death from CHD between males and females have been reported. Haemostatic factors have consistently been associated with risk for coronary heart disease (CHD), but sex differences in genetic architecture have not been studied. This study in middle-aged twins investigates whether there are sex differences in means and in genetic and/ or environmental variance components of haemostatic risk factors for CHD. A total of 93 monozygotic twin pairs (44 male and 49 female) and 116 dizygotic twin pairs (36 male, 40 female and 40 opposite sex) were available for this study. Structural equation modelling was used to estimate the relative influence of genetic and environmental factors on variation in levels of fibrinogen, tissue plasminogen activator (tPA) antigen and von Willebrand factor (vWF). Mean levels of tPA and vWF increased with age. Oral contraceptive pill (OCP) and menopause had significant influences on levels of fibrinogen and tPA. Genetic influences explained 39, 66 and 72% of the variation in levels of fibrinogen, tPA and vWF, respectively. No quantitative or qualitative differences of genetic influences on haemostatic levels were seen between males and females. Haemostatic factors may account fora significant part of the genetic risk for cardiovascular disease. No difference in genetic architecture for levels of fibrinogen, tPA or vWF was observed between males and females.

Keywords

Twins - haemostasis - heritability - sex differences - oral contraceptive pill

• References

• 1 Zdravkovic S, Wienke A, Pedersen NL. et al. Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins. J Intern Med 2002; 252: 247-54.
• 2 Marenberg ME, Risch N, Berkman LF. et al. Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 1994; 330: 1041-6.
• 3 Zdravkovic S, Wienke A, Pedersen NL. et al. Genetic influences on CHD-death and the impact of known risk factors: comparison of two frailty models. Behav Genet 2004; 34: 585-92.
• 4 Sing CF, Moll PP. Genetics of atherosclerosis. Annu Rev Genet 1990; 24: 171-87.
• 5 Schork NJ. Genetically complex cardiovascular traits. Origins, problems, and potential solutions. Hypertension 1997; 29: 145-9.
• 6 Meade TW, Mellows S, Brozovic M. et al. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; 02: 533-7.
• 7 Kannel WB, Wolf PA, Castelli WP. et al. Fibrinogen and risk of cardiovascular disease. The Framingham Study. JAMA 1987; 258: 1183-6.
• 8 Folsom AR, Wu KK, Rosamond WD. et al. Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 1997; 96: 1102-8.
• 9 Thögersen AM, Jansson JH, Boman K. et al. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98: 2241-7.
• 10 Folsom AR, Aleksic N, Park E. et al. Prospective study of fibrinolytic factors and incident coronary heart disease: theAtherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb Vasc Biol 2001; 21: 611-7.
• 11 Ridker PM, Vaughan DE, Stampfer MJ. et al. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-8.
• 12 Lowe GDO, Yarnell JWG, Sweetnam PM. et al. Fibrin D-dimer, tissue plasminogen activator, plasminogen activator inhibitor, and the risk of major ischaemic heart disease in the Caerphilly Study. Thromb Haemost 1998; 79: 129-33.
• 13 Lowe GD, Rumley A, Woodward M. et al. Epidemiology of coagulation factors, inhibitors and activation markers: the Third Glasgow MONICA Survey. I. Illustrative reference ranges by age, sex and hormone use. Br J Haematol 1997; 97: 775-84.
• 14 Kalaria VG, Zareba W, Moss AJ. et al. Gender-related differences in thrombogenic factors predicting recurrent cardiac events in patients after acute myocardial infarction. The THROMBO Investigators. Am J Cardiol 2000; 85: 1401-8.
• 15 Conlan MG, Folsom AR, Finch A. et al. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study. Thromb Haemost 1993; 70: 380-5.
• 16 Mennen LI, Balkau B, Charles MA. et al. Gender differences in the relation between fibrinogen, tissuetype plasminogen activator antigen and markers of insulin resistance: effects of smoking. D.E.S.I.R. Study Group. Data from an Epidemiological Study on Insulin Resistance Syndromes. Thromb Haemost 1999; 82: 1106-11.
• 17 Souto JC, Almasy L, Borrell M. et al. Genetic determinants of hemostasis phenotypes in Spanish families. Circulation 2000; 101: 1546-51.
• 18 de Lange M, Snieder H, Ariëns RA. et al. The genetics of haemostasis: a twin study. Lancet 2001; 357: 101-5.
• 19 Freeman MS, Mansfield MW, Barrett JH. et al. Genetic contribution to circulating levels of hemostatic factors in healthy families with effects of known genetic polymorphisms on heritability. Arterioscler Thromb Vasc Biol 2002; 22: 506-10.
• 20 Snieder H, Boomsma DI, van Doornen LJP. et al. Heritability of respiratory sinus arrhythmia: dependency on task and respiration. Psychophysiology 1997; 34: 317-28.
• 21 Snieder H, Huizink AC, Boomsma DI. et al. Influence of mental stress on fibrinogen, von Willebrand factor and tissue-type plasminogen activator antigen. Fibrinolysis 1996; 10 (Suppl. 02) 137-9.
• 22 Hoegee-de Nobel E, Voskuilen M, Briet E. et al. A monoclonal antibody-based quantitative enzyme immunoassay for the determination of plasma fibrinogen concentrations. Thromb Haemost 1988; 60: 415-8.
• 23 Bos R, Hoegee-de Nobel E, Laterveer R. et al. A one-step enzyme immunoassay for the determination of total tissue-type plasminogen activator (t-PA) antigen in plasma. Blood Coagul Fibrinolysis 1992; 03: 303-7.
• 24 StataCorp Stata Statistical Software. release 7.0. 2001
• 25 Boomsma D, Busjahn A, Peltonen L. Classical twin studies and beyond. Nat Rev Genet 2002; 03: 872-82.
• 26 Neale MC, Boker SM, Xie G. et al. Mx: statistical modeling. 1999. Fifth Edition..
• 27 Wiegratz I, Lee JH, Kutschera E. et al. Effect of four oral contraceptives on hemostatic parameters. Contraception 2004; 70: 97-106.
• 28 Gebara OC, Mittleman MA, Sutherland P. et al. Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study. Circulation 1995; 91: 1952-8.
• 29 Orstavik KH, Magnus P, Reisner H. et al. Factor VIII and factor IX in a twin population. Evidence for a major effect of ABO locus on factor VIII level. Am J Hum Gen 1985; 37: 89-101.
• 30 Snieder H, Harshfield GA, Treiber FA. Heritability of blood pressure and hemodynamics in African- and European-American youth. Hypertension 2003; 41: 1196-201.