The −33T → C Polymorphism in Intron 7 of the TFPI Gene Influences the Risk of Venous Thromboembolism, Independently of the Factor V Leiden and Prothrombin Mutations

Summary

We have previously identified, in intron 7 of the TFPI gene, a T to C single-base polymorphism (−33T→C) which is strongly associated with total circulating TFPI antigen levels. Here we examined the influence of this polymorphism on the risk of venous thromboembolism. The polymorphism was identified in the PATHROS study population (330 cases with venous thromboembolism and 826 controls). The CC genotype was found in 6.4% of cases and 10.2% of controls (age-adjusted odds ratio 0.6; 95% CI 0.3–0.9; p = 0.03). This protective effect persisted after adjustment for oral contraception and the factor V Leiden and prothrombin gene polymorphisms. In 171 controls and 49 cases in whom blood was taken at least three months after the thrombotic event, the CC genotype was associated with significantly higher total TFPI levels than the TT genotype. These results suggest that the CC genotype of the TFPI intron 7 polymorphism is an independent protective factor for venous thromboembolism, an effect probably mediated by increased TFPI levels.

Keywords

TFPI - venous thrombosis - genetic risk factors

^* The first two authors contributed equally to this work

• References

• 1 Lane DA, Grant PJ. Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood 2000; 95: 1517-32.
• 2 Bajaj MS, Bajaj SP. Tissue factor pathway inhibitor: Potential therapeutic applications. Thromb Haemost 1997; 78: 471-7.
• 3 Holst J, Lindblad B, Bergqvist D, Nordfang O, Ostergaard PB, Petersen JL, Nielsen G, Hedner U. Antithrombotic properties of a truncated recombinant Tissue Factor Pathway Inhibitor in an experimental venous thrombosis model. Thromb Haemost 1994; 71: 214-9.
• 4 Kaiser B, Fareed J. Recombinant full-length tissue factor pathway inhibitor (TFPI) prevents thrombus formation and rethrombosis after lysis in a rabbit model of jugular vein thrombosis. Thromb Haemost 1996; 76: 615-20.
• 5 Huang ZF, Higuchi D, Lasky N, Broze GJ. Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice. Blood 1997; 90: 944-51.
• 6 Ariens RAS, Alberio G, Moia M, Mannucci PM. Low levels of heparin-releasable tissue factor pathway inhibitor in young patients with thrombosis. Thromb Haemost 1999; 81: 203-7.
• 7 Amini-Nekoo A, Futers TS, Moia M, Mannucci PM, Grant PJ, Ariens RAS. Analysis of the tissue factor pathway inhibitor gene and antigen levels in relation to venous thrombosis. Br J Haematol 2001; 113: 537-43.
• 8 Kleesiek K, Schmidt M, Gotting C, Brinkmann T, Prohaska W. A first mutation in the human Tissue Factor Pathway Inhibitor gene encoding [P151L] TFPI. Blood 1998; 92: 3976-7.
• 9 Miyata T, Sakata T, Kumeda K, Uchida K, Tsushima M, Fujimura H, Kawasaki T, Kato H. C-399T polymorphism in the promoter region of human tissue factor pathway inhibitor (TFPI) gene does not change the plasma TFPI antigen level and does not cause venous thrombosis. Thromb Haemost 1998; 80: 345-6.
• 10 Moatti D, Seknadji P, Galand C, Poirier O, Fumeron F, Desprez S, Garbarz M, Dhermy D, Arveiler D, Evans A, Luc G, Ruidavets JB, Ollivier V, Hakim J, Aumont MC, De Prost D. Polymorphisms of the tissue factor pathway inhibitor (TFPI) gene in patients with acute coronary syndromes and in healthy subjects: impact of the V264M substitution on plasma levels of TFPI. Arterioscler Thromb Vasc Biol 1999; 19: 862-9.
• 11 Moatti D, Haidar B, Fumeron F, Gauci L, Boudvillain O, Seknadji P, Ollivier V, Aumont MC, De Prost D. A new T-287C polymorphism in the 5’ regulatory region of the tissue factor pathway inhibitor gene. Association study of the T-287C and C-399T polymorphisms with coronary artery disease and plasma TFPI levels. Thromb Haemost 2000; 84: 244-9.
• 12 Moatti D, Meirhaeghe A, Ollivier V, Bauters A, Amouyel P, De Prost D. Polymorphisms of the tissue factor pathway inhibitor gene and the risk of restenosis after coronary angioplasty. Blood Coag Fibrinol 2001; 12: 317-23.
• 13 Arnaud E, Nicaud V, Poirier O, Rendu F, Alhenc-Gelas M, Fiessinger JN, Aiach M. Protective effect of a thrombin receptor (protease-activated receptor 1) gene polymorphism toward venous thromboembolism. Arterioscler Thromb Vasc Biol 2000; 20: 585-92.
• 14 Arnaud E, Barbalat V, Nicaud V, Cambien F, Evans A, Morrison C, Arveiler D, Luc G, Ruidavets JB, Emmerich J, Fiessinger JN, Aiach M. Polymorphisms in the 5’ regulatory region of the tissue factor gene and the risk of myocardial infarction and venous thromboembolism – The ECTIM and PATHROS studies. Arterioscler Thromb Vasc Biol 2000; 20: 892-8.
• 15 Alhenc-Gelas M, Arnaud E, Nicaud V, Aubry M-L, Fiessinger JN, Aiach M, Emmerich J. Venous thromboembolic disease and the prothrombin, methylene tetrahydrofolate reductase and factor V genes. Thromb Haemost 1999; 81: 506-10.
• 16 Tyagi S, Bratu DP, Kramer FR. Multicolor molecular beacons for allele discrimination. Nat Biotechnol 1998; 16: 49-53.
• 17 Morange PE, Renucci JF, Charles MA, Aillaud MF, Giraud F, Grimaux M, Juhan-Vague I. Plasma levels of free and total TFPI, relationship with cardiovascular risk factors and endothelial cell markers. Thromb Haemost 2001; 85: 999-1003.
• 18 Giensendorf BAJ, Vet JAM, Tyagi S, Mensink EJMG, Tribels FJM, Blom HJ. Molecular beacons : a new approach for semiautomated mutation analysis. Clin Chem 1998; 44: 482-6.
• 19 Smit ML, Giesendorf BAJ, Vet JAM, Trijbels FJM, Blom HJ. Semiautomated DNA mutation analysis using a robotic workstation and molecular beacons. Clin Chem 2001; 47: 739-44.
• 20 Neumann FJ, Zohlnhofer D, Fakhoury L, Ott I, Gawaz M, Schomig A. Effect of glycoprotein IIb/IIIa receptor blockade on platelet-leukocyte interaction and surface expression of the leukocyte integrin Mac-1 in acute myocardial infarction. J Am Coll Cardiol 1999; 34: 1420-6.
• 21 Paciaroni K, Rossi E, Bazzan M, Ireland H, Destefano V. Prevalence of the C536T mutation in the tissue factor pathway inhibitor (TFPI) gene among patients with venous thromboembolic disease. Thromb Haemost 2001; 85: 938-9.
• 22 Gonzalez-Conejero R, Lozano ML, Corral J, Martinez C, Vicente V. The TFPI 536C T mutation is not associated with increased risk of venous or arterial thrombosis. Thromb Haemost 2000; 83: 787-8.
• 23 Arnaud E, Moatti D, Emmerich J, Aiach M, De Prost D. No link between the TFPI V264M mutation and venous thromboembolic disease. Thromb Haemost 1999; 82: 159-60.
• 24 Lindahl AK. Tissue factor pathway inhibitor in health and disease. Trend Cardiovasc Med 1995; 05: 167-71.