Genetic and environmental influences on the fibrinolytic system: a twin study

 

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Summary

The determination of heritability is a key issue to assess the predictive power of polymorphisms for disease in clinical studies. The aim of this study was to determine the heritability of proteins and activation markers of the fibrinolytic system in a large cohort of healthy twins. Heritability was calculated as 0.76 for thrombin activatable fibrinolysis inhibitor (TAFI), 0.44 for plasminogen activator inhibitor-1 (PAI-1), and 0.43 for tissue plasminogen activator. No significant genetic influence was observed for α₂-antiplasmin-plasmin-complex and D-dimer. Heritability explained by single gene polymorphisms was 25.2% for TAFI 505G>A, 31.5% for 1542C>G, and 50.0% for combination of both. The influence on TAFI levels of 1542C>G (CC→GG, median: −280.5%) was considerably stronger than that of 505G>A (GG→AA, median: +49.3%) and in both cases there seems to be a dose-response relationship. Significant environmental influences on TAFI levels were observed for combined interaction terms (age*sex and bmi*sex). The PAI-1 4G/5G polymorphism explained 56.4% of the calculated heritability. The genetic variables accounting for the 43% heritability of tPA remain unknown. Our data show that the production of several key components of the fibrinolytic system is strongly genetically determined. This genetic influence is accounted for in large part but not completely by a limited number of polymorphisms within the respective genes associated with plasma levels of the gene products.

• References

• 1 College of American Pathologists Consensus Conference XXXVI: Diagnostic Issues in Thrombophilia. Arch Pathol Lab Med 2002; 126 (11) 1277-1433.
  PubMedGoogle Scholar
• 2 Behague I, Poirier O, Nicaud V. et al. Beta fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction. The ECTIM Study. Etude Cas-Temoins surl’Infarctus du Myocarde. Circulation 1996; 93 (03) 440-449.
  CrossrefPubMedGoogle Scholar
• 3 Eriksson P, Kallin B, van ’t Hooft FM. et al. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92 (06) 1851-1855.
  CrossrefPubMedGoogle Scholar
• 4 Ye S, Green FR, Scarabin PY. et al. The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Etude CasTemoins de I’nfarctus du Mycocarde. Thromb Haemost 1995; 74 (03) 837-841.
  Article in Thieme ConnectPubMedGoogle Scholar
• 5 Iacoviello L, Burzotta F, Di Castelnuovo A. et al. The 4G/5G polymorphism of PAI-1 promoter gene and the risk of myocardial infarction: a meta-analysis. Thromb Haemost 1998; 80 (06) 1029-1030.
  Article in Thieme ConnectPubMedGoogle Scholar
• 6 Grant PJ. The genetics of atherothrombotic disorders: a clinician’s view. J Thromb Haemost 2003; 01 (07) 1381-1390.
  CrossrefPubMedGoogle Scholar
• 7 Juhan-Vague I, Morange PE, Aubert H. et al. Plasma thrombin-activatable fibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of Europe. Arterioscler Thromb Vasc Biol 2002; 22 (05) 867-873.
  CrossrefPubMedGoogle Scholar
• 8 Bajzar L. Thrombin activatable fibrinolysis inhibitor and an antifibrinolytic pathway. Arterioscler Thromb Vasc Biol 2000; 20 (12) 2511-2518.
  CrossrefPubMedGoogle Scholar
• 9 Chetaille P, Alessi MC, Kouassi D. et al. Plasma TAFI antigen variations in healthy subjects. Thromb Haemost 2000; 83 (06) 902-905.
  Article in Thieme ConnectPubMedGoogle Scholar
• 10 Boffa MB, Reid TS, Joo E. et al. Characterization of the gene encoding human TAFI (thrombin-activable fibrinolysis inhibitor; plasma procarboxypeptidase B). Biochemistry 1999; 38 (20) 6547-6558.
  CrossrefPubMedGoogle Scholar
• 11 Brouwers GJ, Vos HL, Leebeek FW. et al. A novel, possibly functional, single nucleotide polymorphism in the coding region of the thrombin-activatable fibrinolysis inhibitor (TAFI) gene is also associated with TAFI levels. Blood 2001; 98 (06) 1992-1993.
  CrossrefPubMedGoogle Scholar
• 12 Franco RF, Fagundes MG, Meijers JC. et al. Identification of polymorphisms in the 5’-untranslated region of the TAFI gene: relationship with plasma TAFI levels and risk of venous thrombosis. Haematologica 2001; 86 (05) 510-517.
  PubMedGoogle Scholar
• 13 Henry M, Aubert H, Morange PE. et al. Identification of polymorphisms in the promoter and the 3’ region of the TAFI gene: evidence that plasma TAFI antigen levels are strongly genetically controlled. Blood 2001; 97 (07) 2053-2058.
  CrossrefPubMedGoogle Scholar
• 14 Hohler T, Reuss E, Evers N. et al. Differential genetic determination of immune responsiveness to hepatitis B surface antigen and to hepatitis A virus: a vaccination study in twins. Lancet 2002; 360 9338. 991-995.
  CrossrefPubMedGoogle Scholar
• 15 Caplin E, Rasmussen RPBCW. Light-Cycler Hybridization Probes. Biochemica 1999; 01: 5-8.
  PubMedGoogle Scholar
• 16 Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68 (04) 978-989.
  CrossrefPubMedGoogle Scholar
• 17 Stephens M, Donnelly P. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003 73. 06 1162-1169 Epub 2003 Oct 20.
  PubMedGoogle Scholar
• 18 Vogel F, Motulsky A. Human genetics: problems and approaches. Berlin: Springer; 1997
  Google Scholar
• 19 Jepson A, Banya W, Sisay-Joof F. et al. Quantification of the relative contribution of major histocompatibility complex (MHC) and Non-MHC Genes to human immune responses to foreign antigens. Infection and Immunity 1997; 65: 872-876.
  PubMedGoogle Scholar
• 20 Ariens RA, de Lange M, Snieder H. et al. Activation markers of coagulation and fibrinolysis in twins: heritability of the prethrombotic state. Lancet 2002; 359 9307. 667-671.
  CrossrefPubMedGoogle Scholar
• 21 Tregouet DA, Aubert H, Henry M. et al. Combined segregation-linkage analysis of plasma thrombin activatable fibrinolysis inhibitor (TAFI) antigen levels with TAFI gene polymorphisms. Hum Genet 2001; 109 (02) 191-197.
  CrossrefPubMedGoogle Scholar
• 22 Juhan-Vague I, Renucci JF, Grimaux M. et al. Thrombin-activatable fibrinolysis inhibitor antigen levels and cardiovascular risk factors. Arterioscler Thromb Vasc Biol 2000; 20 (09) 2156-2161.
  CrossrefPubMedGoogle Scholar
• 23 Mansfield MW, Stickland MH, Grant PJ. PAI-1 concentrations in first-degree relatives of patients with non-insulin-dependent diabetes: metabolic and genetic associations. Thromb Haemost 1997; 77 (02) 357-361.
  Article in Thieme ConnectPubMedGoogle Scholar
• 24 Juhan-Vague I, Alessi MC, Vague P. Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis. Diabetologia 1991; 34 (07) 457-462.
  CrossrefPubMedGoogle Scholar
• 25 Francis CW. Plasminogen activator inhibitor-1 levels and polymorphisms. Arch Pathol Lab Med 2002; 126 (11) 1401-1404.
  PubMedGoogle Scholar
• 26 Cesari M, Sartori MT, Patrassi GM. et al. Determinants of plasma levels of plasminogen activator inhibitor-1: A study of normotensive twins. Arterioscler Thromb Vasc Biol 1999; 19 (02) 316-320.
  CrossrefPubMedGoogle Scholar
• 27 de Lange M, Snieder H, Ariens RA. et al. The genetics of haemostasis: a twin study. Lancet 2001; 357 9250. 101-105.
  CrossrefPubMedGoogle Scholar
• 28 Hong Y, Pedersen NL, Egberg N. et al. Moderate genetic influences on plasma levels of plasminogen activator inhibitor-1 and evidence of genetic and environmental influences shared by plasminogen activator inhibitor-1, triglycerides, and body mass index. Arterioscler Thromb Vasc Biol 1997; 17 (11) 2776-2782.
  CrossrefPubMedGoogle Scholar
• 29 Pankow JS, Folsom AR, Province MA. et al. Segregation analysis of plasminogen activator inhibitor-1 and fibrinogen levels in the NHLBI family heart study. Arterioscler Thromb Vasc Biol 1998; 18 (10) 1559-1567.
  CrossrefPubMedGoogle Scholar
• 30 Souto JC, Almasy L, Borrell M. et al. Genetic determinants of hemostasis phenotypes in Spanish families. Circulation 2000; 101 (13) 1546-1551.
  CrossrefPubMedGoogle Scholar
• 31 Degen SJ, Rajput B, Reich E. The human tissue plasminogen activator gene. J Biol Chem 1986; 261 (15) 6972-6985.
  PubMedGoogle Scholar
• 32 Ladenvall P, Nilsson S, Jood K. et al. Genetic variation at the human tissue-type plasminogen activator (tPA) locus: haplotypes and analysis of association to plasma levels of tPA. Eur J Hum Genet 2003; 11 (08) 603-610.
  CrossrefPubMedGoogle Scholar
• 33 Morange PE, Juhan-Vague I, Scarabin PY. et al. Association between TAFI antigen and Ala147Thr polymorphism of the TAFI gene and the angina pectoris incidence. Thromb Haemost 2003; 89 (03) 554-560.
  Article in Thieme ConnectPubMedGoogle Scholar
• 34 Margaglione M, Di Minno G, Grandone E. et al. Abnormally high circulation levels of tissue plasminogen activator and plasminogen activator inhibitor-1 in patients with a history of ischemic stroke. Arterioscler Thromb 1994; 14 (11) 1741-1745.
  CrossrefPubMedGoogle Scholar
• 35 Mansfield MW, Heywood DM, Grant PJ. Circulating levels of factor VII, fibrinogen, and von Willebrand factor and features of insulin resistance in first-degree relatives of patients with NIDDM. Circulation 1996; 94 (09) 2171-2176.
  CrossrefPubMedGoogle Scholar
• 36 Juhan-Vague I, Pyke SD, Alessi MC. et al. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities. Circulation 1996; 94 (09) 2057-2063.
  CrossrefPubMedGoogle Scholar
• 37 Thogersen 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 (21) 2241-2247.
  CrossrefPubMedGoogle Scholar
• 38 Ladenvall P, Johansson L, Jansson JH. et al. Tissue-type plasminogen activator-7,351C/T enhancer polymorphism is associated with a first myocardial infarction. Thromb Haemost 2002; 87 (01) 105-109.
  Article in Thieme ConnectPubMedGoogle Scholar
• 39 Posthuma D, Beem AL, de Geus EJ. et al. Theory and practice in quantitative genetics. Twin Res 2003; (05) 61-76.
  PubMedGoogle Scholar
• 40 Scientific Subcommittees of the Scientific and Standardization Committee. of the International Society on Thrombosis and Haemostasis. 1997 Minutes of Fibrinolysis subcommittee. http://www.med.unc.edu/isth/reports97/Fibrinolysis.html
  PubMedGoogle Scholar
• 41 Eriksson E, Tengborn L, Risberg B. The effect of various anticoagulant/antiplatelet mixtures on determination of plasminogen activator inhibitor, platelet proteins and hemostasis parameters. Thromb Haemost 1989; 01 (03) 11-16.
  PubMedGoogle Scholar