The VITA Project: Prothrombin G20210A Mutation and Venous Thromboembolism in the General Population

Alberto Tosetto; Edoardo Missiaglia; Maurizio Frezzato; Francesco Rodeghiero

doi:10.1055/s-0037-1614842

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1999; 82(05): 1395-1398
DOI: 10.1055/s-0037-1614842

Rapid Communications

Schattauer GmbH

The VITA Project: Prothrombin G20210A Mutation and Venous Thromboembolism in the General Population

Alberto Tosetto

¹From the Hemophilia and Thrombosis Center, Department of Hematology, S. Bortolo Hospital, Vicenza, Italy

,

Edoardo Missiaglia

¹From the Hemophilia and Thrombosis Center, Department of Hematology, S. Bortolo Hospital, Vicenza, Italy

,

Maurizio Frezzato

¹From the Hemophilia and Thrombosis Center, Department of Hematology, S. Bortolo Hospital, Vicenza, Italy

,

Francesco Rodeghiero

¹From the Hemophilia and Thrombosis Center, Department of Hematology, S. Bortolo Hospital, Vicenza, Italy

› Author Affiliations

Abstract

Summary

Recently a new identified genetic variant in the 3’-untranslated region of the prothrombin gene (G20210A allele) associated with increased plasma prothrombin levels has been linked to an increased risk of venous thromboembolism (VTE). Most of our knowledge on the G20210A allele as a risk factor for VTE derives from a population-based case-control study and from studies on selected series of VTE patients. To determine the importance of the G20210A allele as a causative risk factor for VTE in the general population, we analyzed the cross-sectional data of the Vicenza Thrombophilia and Atherosclerosis (VITA) Project. One hundred sixteen cases of VTE, ascertained in a random fashion within the general population aged 18-65, were age and sex-matched with 232 healthy subjects. Heterozygosity for the G20210A allele was present in 4.3% of VTE cases and in 3.4% of controls, indicating a marginal increase of VTE risk in carriers of the allele (odds ratio: 1.26; 95% CI 0.4-3.9). However, the VTE risk was substantially higher in subjects with idiopathic VTE before age 45 or with recurrent, idiopathic VTE (odds ratio: 2.8; 95% CI 0.6-13.8) or in subjects with a family history of VTE (odds ratio: 7.6; 95% CI 1.8-32.8). Accordingly, our results suggest that the G20210A allele associates with VTE only in selected cases, and that screening for this genetic variant is not warranted for all patients with VTE.

Keywords

Prothrombin - venous thromboembolism - thrombophilia - epidemiological studies - genetics

Full Text

References

References
1 Poort SR, Rosendaal FR, Reitsma PH, Bertina R. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
2 Rosendaal FR, Doggen CJ, Zivelin A, Arruda VA, Aiach M, Siscovick DS. et al. Geographic distribution of the 20210G to A prothrombin variant. Thromb Haemost 1998; 79: 706-8 Abstract.
3 Hillarp A, Zoller B, Svensson PJ, Dahlback B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost 1997; 78: 990-2.
4 Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3’-untranslated region of the prothrombin gene. Br J Haematol 1997; 98: 907-9.
5 Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CR. The prothrombin gene G20210A variant: prevalence in a U.K. anticoagulant clinic population. Br J Haematol 1997; 98: 353-5.
6 Margaglione M, Brancaccio V, Giuliani N, D’Andrea G, Cappucci G, Iannaccone L. et al. Increased risk for venous thrombosis in carriers of the prothrombin G → A20210 gene variant. Ann Int. Med 1998; 129: 89-93.
7 Arruda VA, Annichino-Bizzacchi JM, Goncalves MS, Costa F. Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease. Thromb Haemost 1997; 78: 1430-3.
8 De Stefano V, Chiusolo P, Paciaroni K, Casorelli I, Di Mario A, Rossi E. et al. Prevalence of the Factor II G20210A mutation in symptomatic patients with inherited thrombophilia. Thromb Haemos. 1998; 80: 342-3.
9 Rodeghiero F, Tosetto A. The epidemiology of inherited thrombophilia: the VITA Project. Thromb Haemost 1997; 78: 636-40.
10 Tosetto A, Missiaglia E, Gatto E, Rodeghiero F. The Vita Project: phenotypic resistance to activated protein C and FV Leiden mutation in the general population. Thromb Haemost 1997; 78: 859-63.
11 Rodeghiero F, Tosetto A. The VITA Project: Population-based distribution of protein C, antithrombin III, heparin cofactor II and plasminogen. Relationship with physiological variables and establishment of reference ranges. Thromb Haemost 1996; 76: 226-33.
12 Frezzato M, Tosetto A, Rodeghiero F. Validated questionnaire for the identification of previous personal or familial venous thromboembolism. Am J Epidemiol 1996; 143: 1257-65.
13 Tosetto A, Frezzato M, Rodeghiero F. Family history and inherited thrombophilia. Br J Haematol 1995; 89: 227-8.
14 Bertina RM, van der Marel-Nieuwkoop W, Loeliger EA. Spectrophotometric assays of prothrombin in plasma of patients using oral anticoagulants. Thromb Haemost 1979; 42: 1296-305 Abstract.
15 Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic research. Belmont, Calif: Lifetime Learning Publ.; 1982
16 Hsieh CC. The effect of non-differential outcome misclassification on estimates of the attributable and prevented fraction. Stat Med 1991; 10: 361-73.
17 Copeland KT, Checkoway H, McMichael AJ, Holbrook RH. Bias due to misclassification in the estimation of relative risk. Am J Epidemiol 1977; 105: 488-95.
18 Stata Statistical Software: Release 5.0. StataCorp.; 1997
19 Rosendaal FR, Vos HL, Poort S, Bertina RM. Prothrombin 20210A variant and age at thrombosis. Thromb Haemost 1998; 79: 444.
20 Howard T, Marusa M, Boisza J, Young A, Sequeira J, Channel C. et al. The prothrombin gene 3’-untranslated region mutation is frequently associated with Factor V Leiden in thrombophilic patients and shows ethnic-specific variation in allele frequency. Blood 1998; 91: 1092 Abstract.
21 Tosetto A, Missiaglia E, Martinelli I, De Stefano V, Rodeghiero F. Additional genetic risk factors for venous thromboembolism in carriers of FV Leiden. Br J Haematol 1998; 103: 871-6.
22 Ferraresi P, Marchetti G, Legnani C, Cavallari E, Castoldi E, Mascoli F. et al. The heterozygous 20210 G/A prothrombin genotype is associated with early venous thrombosis in inherited thrombophilias and is not increased in frequency in arterial disease. Arterioscler Thromb Vasc Biol 1997; 17: 2418-22.
23 Makris M, Preston FE, Beauchamp NJ, Cooper PC, Daly ME, Hampton KK. et al. Co-inheritance of the 20210A allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia. Thromb Haemost 1997; 78: 1426-9.
24 Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannucci PM. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med 1998; 338: 1793-7.