Skip to main content
SpringerLink
Log in

Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls

  • META-ANALYSIS
  • Published:
European Journal of Epidemiology Aims and scope Submit manuscript

Abstract

Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case–control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95 % confidence intervals [CI]: 0.98–1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR = 4.22; 95 % CI: 3.35–5.32; and OR = 2.79;95 % CI: 2.25–3.46, respectively), in double heterozygotes (OR = 3.42; 95 %CI 1.64-7.13), and in homozygous FVL or PT20210A (OR = 11.45; 95 %CI: 6.79-19.29; and OR: 6.74 (CI 95 % 2.19–20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤ 45 years (p value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. White RH. The epidemiology of venous thromboembolism MD. Circulation. 2003;107:I-4–8.

    Article  Google Scholar 

  2. Snow V, Qaseem A, Barry P, Hornbake ER, Rodnick JE, Tobolic T, Ireland B, Segal JB, Bass EB, Weiss KB, Green L, Owens DK. American College of Physicians, American Academy of Family Physicians Panel on Deep Venous. Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2007;146(3):204–10.

    Article  PubMed  Google Scholar 

  3. White RH, Keenan CR. Effects of race and ethnicity on the incidence of venous thromboembolism. Thromb Res. 2009;123(Suppl. 4):S11–7.

    Article  PubMed  CAS  Google Scholar 

  4. Gohil R, Peck G, Sharma P. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemostas. 2009;102:360–70.

    CAS  Google Scholar 

  5. Learning about Factor V Leiden thrombophilia. National Human Genome Research Institute. 2011. http://www.genome.gov/15015167#Q5. Accessed September 20th 2012.

  6. Varga EA, Moll S. Prothrombin 20210 Mutation (Factor II Mutation). Circulation. 2004;110:e15–8.

    Article  PubMed  Google Scholar 

  7. Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2001;151(9):862–7.

    Article  Google Scholar 

  8. Brouwer JL, Veeger NJ, Kluin-Nelemans HC, van der Meer J. The pathogenesis of venous thromboembolism: evidence for multiple interrelated causes. Ann Intern Med. 2006;145:807–15.

    Article  PubMed  Google Scholar 

  9. Emmerich J, Rosendaal FR, Cattaneo M, Margaglione M, De Stefano V, Cumming T, Arruda V, Hillarp A, Reny JL. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism–pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism. Thromb Haemost. 2001;86:809–16.

    PubMed  CAS  Google Scholar 

  10. International Statistical Classification of Diseases and Related Health Problems 10th Revision. 2010. http://apps.who.int/classifications/icd10/browse/2010/en. Accessed September 20th 2012.

  11. Bezemer ID, van der Meer FJ, Eikenboom JC, Rosendaal FR, Doggen CJ. The value of family history as a risk indicator for venous thrombosis. Arch Intern Med. 2009;169(6):610–5.

    Article  PubMed  Google Scholar 

  12. Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Intern Med. 1999;159(12):1289–98.

    Article  PubMed  CAS  Google Scholar 

  13. Graham IM, Daly LE, Refsum HM, Robinson K, Brattström LE, Ueland PM, Palma-Reis RJ, Boers GH, Sheahan RG, Israelsson B, Uiterwaal CS, Meleady R, McMaster D, Verhoef P, Witteman J, Rubba P, Bellet H, Wautrecht JC, de Valk HW, Sales Lúis AC, Parrot-Rouland FM, Tan KS, Higgins I, Garcon D, Andria G, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA. 1997;277(22):1775–81.

    Article  PubMed  CAS  Google Scholar 

  14. Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss. Fertil Steril 2008; 89:1603.

    Google Scholar 

  15. Schwahn B, Rozen R. Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences. Am J Pharmacogenomics. 2001;1(3):189–201.

    Article  PubMed  CAS  Google Scholar 

  16. Akar N, Akar E, Akcay R, Avcu F, Yalcin A, Cin S. Effect of methylenetetrahydrofolate reductase 677 C-T, 1298 A-C, and 1317 T-C on factor V 1691 mutation in Turkish deep vein thrombosis patients. Thromb Res. 2000;97:163–7.

    Article  PubMed  CAS  Google Scholar 

  17. Almawi WY, Tamim H, Kreidy R, Timson G, Rahal E, Nabulsi M, Finan RR, Irani-Hakime N. A case control study on the contribution of factor V-Leiden, prothrombin G20210A, and MTHFR C677T mutations to the genetic susceptibility of deep venous thrombosis. Thromb Thrombolysis. 2005;19(3):189–96.

    Article  CAS  Google Scholar 

  18. Angchaisuksiri P, Pingsuthiwong S, Sura T, Aryuchai K, Busabaratana M, Atichartakarn V. Prevalence of the C677T methylenetetra- hydrofolate reductase mutation in Thai patients with deep vein thrombosis. Acta Haematol. 2000;103(4):191–6.

    Article  PubMed  CAS  Google Scholar 

  19. Aznar J, Vayá A, Estellés A, Mira Y, Seguí R, Villa P, Ferrando F, Falcó C, Corella D, España F. Risk of venous thrombosis in carriers of the prothrombin G20210A variant and factor V Leiden and their interaction with oral contraceptives. Haematologica. 2000;85(12):1271–6.

    PubMed  CAS  Google Scholar 

  20. Bedencic M, Bozic M, Peternel P, Stegnar M. Major and potential prothrombotic genotypes in patients with venous thrombosis and in healthy subjects from Slovenia. Pathophysiol Haemost Thromb. 2007;36(2):58–63.

    Article  Google Scholar 

  21. Cantu C, Alonso E, Jara A, Martínez L, Ríos C, Fernández Mde L, Garcia I, Barinagarrementeria F. Hyperhomocysteinemia, low folate and vitamin B12 concentrations, and methylene tetrahydrofolate reductase mutation in cerebral venous thrombosis. Stroke. 2004;35(8):1790–4.

    Article  PubMed  CAS  Google Scholar 

  22. Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS, Sidney S, Rosendaal FR. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292(13):1573–80.

    Article  PubMed  CAS  Google Scholar 

  23. De Stefano V, Rossi E, Paciaroni K, D’Orazio A, Cina G, Marchitelli E, Pepe R, Leone G. Different circumstances of the first venous thromboembolism among younger or older heterozygous carriers of the G20210A polymorphism in the prothrombin gene. Haematologica. 2003;88(1):61–6.

    PubMed  Google Scholar 

  24. Díaz DE, Tuesta AM, Ribó MD, Belinchón O, Marchena PJ, Bruscas MJ, Val E, Cortés A, Nieto JA. Low levels of vitamin B12 and venous thromboembolic disease in elderly men. J Intern Med. 2005;258(3):244–9.

    Article  Google Scholar 

  25. Ducros V, Barro C, Yver J, Pernod G, Polack B, Carpentier P, Desruets MD, Bosson JL. Should plasma homocysteine be used as a biomarker of venous thromboembolism? A case–control study. Clin Appl Thromb Hemost. 2009;15(5):517–22.

    Article  PubMed  CAS  Google Scholar 

  26. Fernández-Miranda C, Coto A, Martínez J, Gómez P, Gómez de la Cámara A. Effect of hyperhomocysteinemia and methylenetetrahydrofolate reductase 677C - > T mutation in venous thromboembolism risk of young adults. Med Clin (Barc). 2005;124(14):532–4.

    Article  Google Scholar 

  27. Folsom AR, Cushman M, Tsai MY, Aleksic N, Heckbert SR, Boland LL, Tsai AW, Yanez ND, Rosamond WD. A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. Blood. 2002;99(8):2720–5.

    Article  PubMed  CAS  Google Scholar 

  28. Folsom AR. Update on factor V Leiden association with venous thromboembolism in the LITE Study. Blood. 2007;109(3):1336–7.

    Article  PubMed  CAS  Google Scholar 

  29. Frederiksen J, Juul K, Grande P, Jensen GB, Schroeder TV, Tybjaerg-Hansen A, Nordestgaard BG. Methylenetetrahydrofolate reductase polymorphism (C677T), hyperhomocysteinemia, and risk of ischemic cardiovascular disease and venous thromboembolism: prospective and case-control studies from the Copenhagen City Heart Study. Blood. 2004;104(10):3046–51.

    Article  PubMed  CAS  Google Scholar 

  30. Gemmati D, Previati M, Serino ML, Moratelli S, Guerra S, Capitani S, Forini E, Ballerini G, Scapoli GL. Low folate levels and thermolabile methylenetetrahydrofolate reductase as primary determinant of mild hyperhomocystinemia in normal and thromboembolic subjects. Arterioscler Thrombvasc Biol. 1999;19:1761–7.

    Article  CAS  Google Scholar 

  31. Gemmati D, Serino ML, Trivellato C, Fiorini S, Scapoli GL. C677T substitution in the methylenetetrahydrofolate reductase gene as a risk factor for venous thrombosis and arterial disease in selected patients. Haematologica. 1999;84:824–8.

    PubMed  CAS  Google Scholar 

  32. Ivanov P, Komsa-Penkova R, Kovacheva K, Ivanov Y, Stoyanova A, Ivanov I, Pavlov P, Glogovska P, Nojarov V. Impact of thrombophilic genetic factors on pulmonary embolism: early onset and recurrent incidences. Lung. 2008;186(1):27–36.

    Article  PubMed  CAS  Google Scholar 

  33. Keijzer MB, den Heijer M, Blom HJ, Bos GM, Willems HP, Gerrits WB, Rosendaal FR. Interaction between hyperhomocysteinemia, mutated methylenetetrahydrofolatereductase (MTHFR) and inherited thrombophilic factors in recurrent venous thrombosis. Thromb Haemost. 2002;88(5):723–8.

    PubMed  CAS  Google Scholar 

  34. Le Cam-Duchez V, Bagan-Triquenot A, Ménard JF, Mihout B, Borg JY. Association of the protein C promoter CG haplotype and the factor II G20210A mutation is a risk factor for cerebral venous thrombosis. Blood Coagul Fibrinolysis. 2005;16(7):495–500.

    Article  PubMed  Google Scholar 

  35. Lichy C, Dong-Si T, Reuner K, Genius J, Rickmann H, Hampe T, Dolan T, Stoll F, Grau A. Risk of cerebral venous thrombosis and novel gene polymorphisms of the coagulation and fibrinolytic systems. J Neurol. 2006;253(3):316–20.

    Article  PubMed  CAS  Google Scholar 

  36. Martinelli I, Battaglioli T, Pedotti P, Cattaneo M, Mannucci PM. Hyperhomocysteinemia in cerebral vein thrombosis. Blood. 2003;102(4):1363–6.

    Article  PubMed  CAS  Google Scholar 

  37. Nizankowska-Mogilnicka E, Adamek L, Grzanka P, Domagala TB, Sanak M, Krzanowski M, Szczeklik A. Genetic polymorphisms associated with acute pulmonary embolism and deep venous thrombosis. Eur Respir J. 2003;21(1):25–30.

    Article  PubMed  CAS  Google Scholar 

  38. Ogunyemi D, Cuellar F, Ku W, Arkel Y. Association between inherited thrombophilias, antiphospholipid antibodies, and lipoprotein A levels and venous thromboembolism in pregnancy. Am J Perinatol. 2003;20(1):17–24.

    Article  PubMed  Google Scholar 

  39. Oguzulgen IK, Yilmaz E, Demirtas S, Erkekol FO, Ekim N, Demir N, Numanoglu N, Ozel D, Ulu A, Akar. The role of plasminogen activator inhibitor-1 polymorphism, factor-V-Leiden, and prothrombin-20210 mutations in pulmonary thromboembolism. Clin Appl Thromb Hemost 2009;15(1):73–7. Epub 2007 Dec 26.

  40. Okumus G, Kiyan E, Arseven O, Tabak L, Diz-Kucukkaya R, Unlucerci Y, Abaci N, Unaltuna NE, Issever H. ereditary thrombophilic risk factors and venous thromboembolism in Istanbul, Turkey: the role in different clinical manifestations of venous thromboembolism. Clin Appl Thromb Hemost. 2008;14(2):168–73. Epub 2007 Sep 25.

    Google Scholar 

  41. Penco S, Grossi E, Cheng S, Intraligi M, Maurelli G, Patrosso MC, Marocchi A, Buscema M. Assessment of the role of genetic polymorphism in venous thrombosis through artificial neural networks. Ann Hum Genet. 2005;69(Pt 6):693–706.

    Article  PubMed  CAS  Google Scholar 

  42. Shmeleva VM, Kapustin SI, Papayan LP, Sobczyńska-Malefora A, Harrington DJ, Savidge GF. Prevalence of hyperhomocysteinemia andù the MTHFR C677T polymorphism in patients with arterial and venous thrombosis from North Western Russia. Thromb Res. 2003;111(6):351–6.

    Article  PubMed  CAS  Google Scholar 

  43. Straczek C, Oger E. Yon de Jonage-Canonico MB, Plu-Bureau G, Conard J, Meyer G, Alhenc-Gelas M, Lévesque H, Trillot N, Barrellier MT, Wahl D, Emmerich J, Scarabin PY; Estrogen and Thromboembolism Risk (ESTHER) Study Group. Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation. 2005;112(22):3495–500.

    Article  PubMed  CAS  Google Scholar 

  44. Torres JD, Cardona H, Alvarez L, Cardona-Maya W, Castañeda SA, Quintero-Rivera F, Cadavid A, Bedoya G, Tobón L. Inherited thrombophilia is associated with deep vein thrombosis in a Colombian population. Am J Hematol. 2006;81(12):933–7.

    Article  PubMed  CAS  Google Scholar 

  45. Vayá A, Mira Y, Mateo J, Falco C, Villa P, Estelles A, Corella D, Fontcuberta J, Aznar J. Prothrombin G20210A mutation and oral contraceptive use increase upper-extremity deep vein thrombotic risk. Thromb Haemost. 2003;89(3):452–7.

    PubMed  Google Scholar 

  46. Alhenc-Gelas M, Arnaud E, Nicaud V, Aubry ML, Fiessinger JN, Aiach M, Emmerich J. Venous thromboembolic disease and the prothrombin, methylene tetrahydrofolate reductase and factor V genes. Thromb Haemost. 1999;81(4):506–10.

    PubMed  CAS  Google Scholar 

  47. Alhenc-Gelas M, Nicaud V, Gandrille S, van Dreden P, Amiral J, Aubry ML, Fiessinger JN, Emmerich J, Aiach M. The factor V gene A4070G mutation and the risk of venous thrombosis. Thromb Haemost. 1999;81:193–7.

    PubMed  CAS  Google Scholar 

  48. Arruda VR, von Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF. The mutation Ala677– > Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis. Thromb Haemost. 1997;77:818–21.

    PubMed  CAS  Google Scholar 

  49. Avdonin PV, Kirienko AI, Kozhevnikova LM, Shostak NA, Babadaeva NM, Leont’ev SG, Petukhov EB, Kubatiev AA, Savel’ev VS. C677T mutation in methylentetrahydrofolatereductase gene in patients with venous thromboses from the central region of Russia correlates with a high risk of pulmonary artery thromboembolism. Ter Arkh. 2006;78:70–6.

    PubMed  CAS  Google Scholar 

  50. Balta G, Gurgey A. Methylenetetrahydrofolate reductase (MTHFR) C677T mutation in Turkish patients with thrombosis. Turk J Pediatr. 1999;41:197–9.

    PubMed  CAS  Google Scholar 

  51. Barcellona D, Fenu L, Cauli C, Pisu G, Marongiu F. Allele 4G of gene PAI-1 associated with prothrombin mutation G20210A increases the risk for venous thrombosis. Thromb Haemost. 2003;90:1061–4.

    PubMed  CAS  Google Scholar 

  52. Benson JM, Ellingsen D, El-Jamil M, Jenkins M, Miller CH, Dilley A, Evatt BL, Hooper WC. Factor V Leiden and factor V R2 allele: high-throughput analysis and association with venous thromboembolism. Thromb Haemost. 2001;86:1188–92.

    PubMed  CAS  Google Scholar 

  53. Bouaziz-Borgi L, Almawi WY, Mtiraoui N, Nsiri B, Keleshian SH, Kreidy R, Louzir B, Hezard N, Mahjoub T. Distinct association of factor V-Leiden and prothrombin G20210A mutations with deep venous thrombosis in Tunisia and Lebanon. Am J Hematol. 2006;81:641–3.

    Article  PubMed  CAS  Google Scholar 

  54. Boyanovsky B, Russeva M, Ganev V, Penev M, Baleva M. Prevalence of factor V Leiden and prothrombin 20210 A variant in Bulgarian patients with pulmonary thromboembolism and deep venous thrombosis. Blood Coagul Fibrinolysis. 2001;12:639–42.

    Article  PubMed  CAS  Google Scholar 

  55. Brown K, Luddington R, Baglin T. A common polymorphism in the tumour necrosis factor-alpha gene associated with high TNF levels is not a risk factor for venous thromboembolism. Br J Haematol. 1998;101(3):480–2.

    Article  PubMed  CAS  Google Scholar 

  56. Brown K, Luddington R, Taylor SA, Lillicrap DP, Baglin TP. Risk of venous thromboembolism associated with the common hereditary haemochromatosis Hfe gene (C282Y) mutation. Br J Haematol. 1999;105:95–7.

    Article  PubMed  CAS  Google Scholar 

  57. 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(4):907–9.

    Article  PubMed  CAS  Google Scholar 

  58. Cappucci G, Margaglione M, Ames PR. Comparative prevalence of antiphospholipid antibodies and thrombophilic genotypes in consecutive patients with venous thrombosis. Blood Coagul Fibrinolysis. 2001;12:659–65.

    Article  PubMed  CAS  Google Scholar 

  59. Cattaneo M, Chantarangkul V, Taioli E, Santos JH, Tagliabue L. The G20210A mutation of the prothrombin gene in patients with previous first episodes of deep-vein thrombosis: prevalence and association with factor V G1691A, methylenetetrahydrofolate reductase C677T and plasma prothrombin levels. Thromb Res. 1999;93:1–8.

    Article  PubMed  CAS  Google Scholar 

  60. Cattaneo M, Tsai MY, Bucciarelli P, Taioli E, Zighetti ML, Bignell M, Mannucci PM. A common mutation in the methylenetetrahydrofolate reductase gene (C677T) increases the risk for deep-vein thrombosis in patients with mutant factor V (factor V:Q506). Arterioscler Thromb Vasc Biol. 1997;17:1662–6.

    Article  PubMed  CAS  Google Scholar 

  61. Chan DK, Hu G, Tao H, Owens D, Vun CM, Woo J, Chong BH. A comparison of polymorphism in the 3′-untranslated region of the prothrombin gene between Chinese and Caucasians in Australia. Br J Haematol. 2000;111:1253–5.

    Article  PubMed  CAS  Google Scholar 

  62. Coen D, Zadro R, Honović L, Banfić L, Stavljenić Rukavina A. Prevalence and association of the factor V Leiden and prothrombin G20210A in healthy subjects and patients with venous thromboembolism. Croat Med J. 2001;42:488–92.

    PubMed  CAS  Google Scholar 

  63. Colaizzo D, Amitrano L, Iannaccone L, Vergura P, Cappucci F, Grandone E, Guardascione MA, Margaglione M. Gain-of-function gene mutations and venous thromboembolism: distinct roles in different clinical settings. J Med Genet. 2007;44:412–6.

    Article  PubMed  CAS  Google Scholar 

  64. Corral J, González-Conejero R, Soria JM, González-Porras JR, Pérez-Ceballos E, Lecumberri R, Roldán V, Souto JC, Miñano A, Hernández-Espinosa D, Alberca I, Fontcuberta J, Vicente V. A nonsense polymorphism in the protein Z-dependent protease inhibitor increases the risk for venous thrombosis. Blood. 2006;108:177–83.

    Article  PubMed  CAS  Google Scholar 

  65. Couturaud F, Oger E, Abalain JH, Chenu E, Guias B, Floch HH, Mercier B, Mottier D, Leroyer C. Methylenetetrahydrofolate reductase C677T genotype and venous thromboembolic disease. Respiration. 2000;67:657–61.

    Article  PubMed  CAS  Google Scholar 

  66. de Franchis R, Fermo I, Mazzola G, Sebastio G, Di Minno G, Coppola A, Andria G, D’Angelo A. Contribution of the cystathionine beta-synthase gene (844ins68) polymorphism to the risk of early-onset venous and arterial occlusive disease and of fasting hyperhomocysteinemia. Thromb Haemost. 2000;84:576–82.

    PubMed  Google Scholar 

  67. de Moerloose P, Reber G, Perrier A, Perneger T, Bounameaux H. Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thromboembolism. Br J Haematol. 2000;110:125–9.

    Article  PubMed  Google Scholar 

  68. de Paula Sabino A, Guimarães DA, Ribeiro DD, Paiva SG, Sant’Ana Dusse LM, das Graças Carvalho M, Fernandes AP. Increased Factor V Leiden frequency is associated with venous thrombotic events among young Brazilian patients. J Thromb Thrombolysis. 2007;24:261–6.

    Article  PubMed  CAS  Google Scholar 

  69. Dilley A, Austin H, Hooper WC, Lally C, Ribeiro MJ, Wenger NK, Silva V, Rawlins P, Evatt B. Relation of three genetic traits to venous thrombosis in an African-American population. Am J Epidemiol. 1998;147:30–5.

    Article  PubMed  CAS  Google Scholar 

  70. Dölek B, Eraslan S, Eroğlu S, Kesim BE, Ulutin T, Yalçiner A, Laleli YR, Gözükirmizi N. Molecular analysis of factor V Leiden, factor V Hong Kong, factor II G20210A, methylenetetrahydrofolate reductase C677T, and A1298C mutations related to Turkish thrombosis patients. Clin Appl Thromb Hemost. 2007;13:435–8.

    Article  PubMed  CAS  Google Scholar 

  71. Dowling NF, Austin H, Dilley A, Whitsett C, Evatt BL, Hooper WC. The epidemiology of venous thromboembolism in Caucasians and African-Americans: the GATE Study. J Thromb Haemost. 2003;1:80–7.

    Article  PubMed  CAS  Google Scholar 

  72. Faioni EM, Castaman G, Asti D, Lussana F, Rodeghiero F. Association of factor V deficiency with factor V HR2. Haematologica. 2004;89:195–200.

    PubMed  CAS  Google Scholar 

  73. Ferraresi P, Marchetti G, Legnani C, Cavallari E, Castoldi E, Mascoli F, Ardissino D, Palareti G, Bernardi F. The heterozygous 20210 G/A prothrombin genotype is associated with early venous thrombosis in inherited thrombophilias and is not increased in frequency in artery disease. Arterioscler Thromb Vasc Biol. 1997;17:2418–22.

    Article  PubMed  CAS  Google Scholar 

  74. Francès F, Portolès O, Gabriel F, Corella D, Sorlí JV, Sabater A, Alfonso JL, Guillén M. Factor V Leiden (G1691A) and prothrombin-G20210A alleles among patients with deep venous thrombosis and in the general population from Spain. Rev Med Chil. 2006;134:13–20.

    Article  PubMed  Google Scholar 

  75. Franco RF, Fagundes MG, Meijers JC, Reitsma PH, Lourenço D, Morelli V, Maffei FH, Ferrari IC, Piccinato CE, Silva WA Jr, Zago MA. Identification of polymorphisms in the 5′-untranslated region of the TAFI gene: relationship with plasma TAFI levels and risk of venous thrombosis. Haematologica. 2001;86:510–7.

    PubMed  CAS  Google Scholar 

  76. Franco RF, Morelli V, Lourenço D, Maffei FH, Tavella MH, Piccinato CE, Thomazini IA, Zago MA. A second mutation in the methylenetetrahydrofolate reductase gene and the risk of venous thrombotic disease. Br J Haematol. 1999;105:556–9.

    Article  PubMed  CAS  Google Scholar 

  77. García-Gala JM, Alvarez V, Pinto CR, Soto I, Urgellés MF, Menéndez MJ, Carracedo C, López-Larrea C, Coto E. Factor V Leiden (R506Q) and risk of venous thromboembolism: a case-control study based on the Spanish population. Clin Genet. 1997;52:206–10.

    Article  PubMed  Google Scholar 

  78. Gaustadnes M, Rüdiger N, Møller J, Rasmussen K, Bjerregaard Larsen T, Ingerslev J. Thrombophilic predisposition in stroke and venous thromboembolism in Danish patients. Blood Coagul Fibrinolysis. 1999;10:251–9.

    Article  PubMed  CAS  Google Scholar 

  79. González Ordóñez AJ, Fernández Alvarez CR, Rodríguez JM, García EC, Alvarez MV. Genetic polymorphism of methylenetetrahydrofolate reductase and venous thromboembolism: a case-control study. Haematologica. 1999;84:190–1.

    PubMed  Google Scholar 

  80. González-Conejero R, Lozano ML, Corral J, Martínez C, Vicente V. The TFPI 536C– > T mutation is not associated with increased risk for venous or arterial thrombosis. Thromb Haemost. 2000;83:787–8.

    PubMed  Google Scholar 

  81. Grossmann R, Schwender S, Geisen U, Schambeck C, Merati G, Walter U. CBS 844ins68, MTHFR TT677 and EPCR 4031ins23 genotypes in patients with deep-vein thrombosis. Thromb Res. 2002;107:13–5.

    Article  PubMed  CAS  Google Scholar 

  82. Hainaut P, Jaumotte C, Verhelst D, Wallemacq P, Gala JL, Lavenne E, Heusterspreute M, Zech F, Moriau M. Hyperhomocysteinemia and venous thromboembolism: a risk factor more prevalent in the elderly and in idiopathic cases. Thromb Res. 2002;106:121–5.

    Article  PubMed  CAS  Google Scholar 

  83. Hanson NQ, Aras O, Yang F, Tsai MY. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular disease. Clin Chem. 2001;47:661–6.

    PubMed  CAS  Google Scholar 

  84. Hessner MJ, Luhm RA, Pearson SL, Endean DJ, Friedman KD, Montgomery RR. Prevalence of prothrombin G20210A, factor V G1691A (Leiden), and methylenetetrahydrofolate reductase (MTHFR) C677T in seven different populations determined by multiplex allele-specific PCR. Thromb Haemost. 1999;81(5):733–8.

    PubMed  CAS  Google Scholar 

  85. Hoppe B, Tolou F, Radtke H, Kiesewetter H, Dörner T, Salama A. Marburg I polymorphism of factor VII-activating protease is associated with idiopathic venous thromboembolism. Blood. 2005;105:1549–51.

    Article  PubMed  CAS  Google Scholar 

  86. Ioannou HV, Mitsis M, Eleftheriou A, Matsagas M, Nousias V, Rigopoulos C, Vartholomatos G, Kappas AM. The prevalence of factor V Leiden as a risk factor for venous thromboembolism in the population of North-Western Greece. Int Angiol. 2000;19:314–8.

    PubMed  CAS  Google Scholar 

  87. Isotalo PA, Donnelly JG. Prevalence of methylenetetrahydrofolate reductase mutations in patients with venous thrombosis. Mol Diagn. 2000;5:59–66.

    PubMed  CAS  Google Scholar 

  88. Jackson A, Brown K, Langdown J, Luddington R, Baglin T. Effect of the angiotensin-converting enzyme gene deletion polymorphism on the risk of venous thromboembolism. Br J Haematol. 2000;111:562–4.

    Article  PubMed  CAS  Google Scholar 

  89. Junker R, Koch HG, Auberger K, Münchow N, Ehrenforth S, Nowak-Göttl U. Prothrombin G20210A gene mutation and further prothrombotic risk factors in childhood thrombophilia. Arterioscler Thromb Vasc Biol. 1999;19:2568–72.

    Article  PubMed  CAS  Google Scholar 

  90. Kapur RK, Mills LA, Spitzer SG, Hultin MB. A prothrombin gene mutation is significantly associated with venous thrombosis. Arterioscler Thromb Vasc Biol. 1997;17(11):2875–9.

    Article  PubMed  CAS  Google Scholar 

  91. Kluijtmans LA, den Heijer M, Reitsma PH, Heil SG, Blom HJ, Rosendaal FR. Thermolabile methylenetetrahydrofolate reductase and factor V Leiden in the risk of deep-vein thrombosis. Thromb Haemost. 1998;79:254–8.

    PubMed  CAS  Google Scholar 

  92. Koch HG, Nabel P, Junker R, Auberger K, Schobess R, Homberger A, Linnebank M, Nowak-Göttl U. The 677T genotype of the common MTHFR thermolabile variant and fasting homocysteine in childhood venous thrombosis. Eur J Pediatr. 1999;158(Suppl 3):S113–6.

    Article  PubMed  CAS  Google Scholar 

  93. Köppel H, Renner W, Gugl A, Cichocki L, Gasser R, Wascher TC, Pilger E. The angiotensin-converting-enzyme insertion/deletion polymorphism is not related to venous thrombosis. Thromb Haemost. 2004;91(1):76–9.

    PubMed  Google Scholar 

  94. Kostka H, Kuhlisch E, Schellong S, Siegert G. Polymorphisms in the TAFI gene and the risk of venous thrombosis. Clin Lab. 2003;49:645–7.

    PubMed  CAS  Google Scholar 

  95. Kostka H, Schwarz T, Schellong S, Mix C, Kuhlisch E, Temelkova-Kurktschiev T, Henkel E, Köhler C, Gehrisch S, Siegert G. Coagulation factor V G allele and HR2 haplotype: factor V activity, activated protein C resistance and risk of venous thrombosis. Blood Coagul Fibrinolysis. 2003;14:49–56.

    Article  PubMed  CAS  Google Scholar 

  96. Legnani C, Cosmi B, Valdrè L, Boggian O, Bernardi F, Coccheri S, Palareti G. Venous thromboembolism, oral contraceptives and high prothrombin levels. J Thromb Haemost. 2003;1:112–7.

    Article  PubMed  CAS  Google Scholar 

  97. Leroyer C, Mercier B, Escoffre M, Férec C, Mottier D. Factor V Leiden prevalence in venous thromboembolism patients. Chest. 1997;111:1603–6.

    Article  PubMed  CAS  Google Scholar 

  98. Lindmarker P, Schulman S, Sten-Linder M, Wiman B, Egberg N, Johnsson H. The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation. Thromb Haemost. 1999;81:684–9.

    PubMed  CAS  Google Scholar 

  99. Luddington R, Jackson A, Pannerselvam S, Brown K, Baglin T. The factor V R2 allele: risk of venous thromboembolism, factor V levels and resistance to activated protein C. Thromb Haemost. 2000;83:204–8.

    PubMed  CAS  Google Scholar 

  100. Mansilha A, Araújo F, Sampaio S, Cunha Ribeiro LM, Braga A. The PORtromb Project: prothrombin G20210A mutation and venous thromboembolism in young people. Cardiovasc Surg. 2002;10:45–8.

    Article  PubMed  CAS  Google Scholar 

  101. Margaglione M, Bossone A, Brancaccio V, Ciampa A, Di Minno G. Factor XIII Val34Leu polymorphism and risk of deep vein thrombosis. Thromb Haemost. 2000;84:1118–9.

    PubMed  CAS  Google Scholar 

  102. Margaglione M, Brancaccio V, De Lucia D, Martinelli I, Ciampa A, Grandone E, Di Minno G. Inherited thrombophilic risk factors and venous thromboembolism: distinct role in peripheral deep venous thrombosis and pulmonary embolism. Chest. 2000;118:1405–11.

    Article  PubMed  CAS  Google Scholar 

  103. Margaglione M, D’Andrea G, d’Addedda M, Giuliani N, Cappucci G, Iannaccone L, Vecchione G, Grandone E, Brancaccio V, Di Minno G. The methylenetetrahydrofolate reductase TT677 genotype is associated with venous thrombosis independently of the coexistence of the FV Leiden and the prothrombin A20210 mutation. Thromb Haemost. 1998;79(5):907–11.

    PubMed  CAS  Google Scholar 

  104. Meyer M, Kutscher G, Vogel G. The prothrombin nt20210 A allele as a risk factor for venous thromboembolism: detection of heterozygous and homozygous carriers by alternative methods. Thromb Res. 2000;97:359–63.

    Article  PubMed  CAS  Google Scholar 

  105. Morelli VM, Lourenço DM, D’Almeida V, Franco RF, Miranda F, Zago MA, Noguti MA, Cruz E, Kerbauy J. Hyperhomocysteinemia increases the risk of venous thrombosis independent of the C677T mutation of the methylenetetrahydrofolate reductase gene in selected Brazilian patients. Blood Coagul Fibrinolysis. 2002;13:271–5.

    Article  PubMed  CAS  Google Scholar 

  106. Ocal IT, Sadeghi A, Press RD. Risk of venous thrombosis in carriers of a common mutation in the homocysteine regulatory enzyme methylenetetrahydrofolate reductase. Mol Diagn. 1997;2:61–8.

    Article  PubMed  CAS  Google Scholar 

  107. Oger E, Lacut K, Le Gal G, Couturaud F, Abalain JH, Mercier B, Mottier D. EDITH (Etude des Déterminants/Interaction de la THrombose veineuse) Collaborative Study Group. Interrelation of hyperhomocysteinemia and inherited risk factors for venous thromboembolism.Results from the E.D.I.TH. study: a hospital based case-control study. Thromb Res. 2007;120:207–14.

    Article  PubMed  CAS  Google Scholar 

  108. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. 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.

    PubMed  CAS  Google Scholar 

  109. Quéré I, Chassé JF, Dupuy E, Bellet E, Molho-Sabatier P, Tobelem G, Janbon C. Homocysteine, 5,10-methylenetetrahydrofolate reductase and deep venous thrombosis. Survey of 120 patients in internal medicine. Rev Med Interne. 1998;19:29–33.

    Article  PubMed  Google Scholar 

  110. Quéré I, Perneger TV, Zittoun J, Bellet H, Gris JC, Daurès JP, Schved JF, Mercier E, Laroche JP, Dauzat M, Bounameaux H, Janbon C, de Moerloose P. Red blood cell methylfolate and plasma homocysteine as risk factors for venous thromboembolism: a matched case-control study. Lancet. 2002;359:747–52.

    Article  PubMed  Google Scholar 

  111. Ray JG, Langman LJ, Vermeulen MJ, Evrovski J, Yeo EL, Cole DE. Genetics University of Toronto Thrombophilia Study in Women (GUTTSI): genetic and other risk factors for venous thromboembolism in women. Curr Control Trials Cardiovasc Med. 2001;2:141–9.

    Article  PubMed  CAS  Google Scholar 

  112. Renner W, Köppel H, Hoffmann C, Schallmoser K, Stanger O, Toplak H, Wascher TC, Pilger E. Prothrombin G20210A, factor V Leiden, and factor XIII Val34Leu: common mutations of blood coagulation factors and deep vein thrombosis in Austria. Thromb Res. 2000;99:35–9.

    Article  PubMed  CAS  Google Scholar 

  113. Renner W, Winkler M, Hoffmann C, Köppel H, Seinost G, Brodmann M, Pilger E. The PlA1/A2 polymorphism of platelet glycoprotein IIIa is not associated with deep venous thrombosis. Int Angiol. 2001;20(2):148–51.

    PubMed  CAS  Google Scholar 

  114. Reuner KH, Ruf A, Litfin F, Patscheke H. The mutation G20210– > A in the prothrombin gene is a strong risk factor for pulmonary embolism. Clin Chem. 1998;44:1365–6.

    PubMed  CAS  Google Scholar 

  115. Ruiz-Argüelles GJ, Garcés-Eisele J, Reyes-Núñez V, Ramírez-Cisneros FJ, et al. Primary thrombophilia in Mexico. II. Factor V G1691A (Leiden), prothrombin G20210A, and methylenetetrahydrofolate reductase C677T polymorphism in thrombophilic Mexican mestizos. Am J Hematol. 2001;66:28–31.

    Article  PubMed  Google Scholar 

  116. Salazar-Sánchez L, Leon MP, Cartin M, Schuster G, Wulff K, Schröder W, Jiménez-Arce G, Chacon R, Herrmann FH. The FXIIIVal34Leu, common and risk factors of venous thrombosis in early middle-age Costa Rican patients. Cell Biochem Funct. 2007;25:739–45.

    Article  PubMed  CAS  Google Scholar 

  117. Salden A, Keeney S, Hay CR, Cumming AM. The C677T MTHFR variant and the risk of venous thrombosis. Br J Haematol. 1997;99:472.

    PubMed  CAS  Google Scholar 

  118. Salomon O, Rosenberg N, Zivelin A, Steinberg DM, Kornbrot N, Dardik R, Inbal A, Seligsohn U. Methionine synthase A2756G and methylenetetrahydrofolate reductase A1298C polymorphisms are not risk factors for idiopathic venous thromboembolism. Hematol J. 2001;2:38–41.

    Article  PubMed  CAS  Google Scholar 

  119. Salomon O, Steinberg DM, Zivelin A, Gitel S, Dardik R, Rosenberg N, Berliner S, Inbal A, Many A, Lubetsky A, Varon D, Martinowitz U, Seligsohn U. Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment. Arterioscler Thromb Vasc Biol. 1999;19:511–8.

    Article  PubMed  CAS  Google Scholar 

  120. Schobess R, Junker R, Auberger K, Münchow N, Burdach S, Nowak-Göttl U. Factor V G1691A and prothrombin G20210A in childhood spontaneous venous thrombosis- evidence of an age-dependent thrombotic onset in carriers of factor V G1691A and prothrombin G20210A mutation. Eur J Pediatr. 1999;158(Suppl 3):S105–8.

    Article  PubMed  CAS  Google Scholar 

  121. Seinost G, Renner W, Brodmann M, Winkler M, Köppel H, Pilger E. C677T mutation in the methylene tetrahydrofolate reductase gene as a risk factor for venous thrombotic disease in Austrian patients. Thromb Res. 2000;100:405–7.

    Article  PubMed  CAS  Google Scholar 

  122. Souto JC, Coll I, Llobet D, del Río E, Oliver A, Mateo J, Borrell M, Fontcuberta J. The prothrombin 20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population. Thromb Haemost. 1998;80:366–9.

    PubMed  CAS  Google Scholar 

  123. Tosetto A, Missiaglia E, Frezzato M, Rodeghiero F. The VITA project: C677T mutation in the methylene-tetrahydrofolate reductase gene and risk of venous thromboembolism. Br J Haematol. 1997;97:804–6.

    Article  PubMed  CAS  Google Scholar 

  124. Varela ML, Adamczuk YP, Forastiero RR, Martinuzzo ME, Cerrato GS, Pombo G, Carreras LO. Major and potential prothrombotic genotypes in a cohort of patients with venous thromboembolism. Thromb Res. 2001;104:317–24.

    Article  PubMed  CAS  Google Scholar 

  125. Vargas M, Soto I, Pinto CR, Urgelles MF, Batalla A, Rodriguez-Reguero J, Cortina A, Alvarez V, Coto E. The prothrombin 20210A allele and the factor V Leiden are associated with venous thrombosis but not with early coronary artery disease. Blood Coagul Fibrinolysis. 1999;10(1):39–41.

    Article  PubMed  CAS  Google Scholar 

  126. von Depka M, Czwalinna A, Wermes C, Eisert R, Scharrer I, Ganser A, Ehrenforth S. The deletion polymorphism in the angiotensin-converting enzyme gene is a moderate risk factor for venous thromboembolism.

  127. von Depka M, Nowak-Göttl U, Eisert R, Dieterich C, Barthels M, Scharrer I, Ganser A, Ehrenforth S. Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism. Blood. 2000;96:3364–8.

    Google Scholar 

  128. Wells PS, Rodger MA, Forgie MA, Langlois NJ, Armstrong L, Carson NL, Jaffey J. The ACE D/D genotype is protective against the development of idiopathic deep vein thrombosis and pulmonary embolism. Thromb Haemost. 2003;90:829–34.

    PubMed  CAS  Google Scholar 

  129. Zalavras ChG, Giotopoulou S, Dokou E, Mitsis M, Ioannou HV, Tzolou A, Kolaitis N, Vartholomatos G. Lack of association between the C677T mutation in the 5,10-methylenetetrahydrofolate reductase gene and venous thromboembolism in Northwestern Greece. Int Angiol. 2002;21:268–71.

    PubMed  Google Scholar 

  130. De Stefano V, Rossi E, Paciaroni K, Leone G. Screening for inherited thrombophilia: indications and therapeutic implications. Haematologica. 2002;87:1095–108.

    PubMed  Google Scholar 

  131. De Stefano V, Chiusolo P, Paciaroni K, Leone G. Epidemiology of factor V Leiden: clinical implications. Sem Thromb Haemost. 1998;24:367–79.

    Article  Google Scholar 

  132. Rosendaal FR, Doggen CJM, Zivelin A, Arruda VR, Aiach M, Siscovick DS, Hillarp A, Watzke HH, Bernardi F, Cumming AM, Preston FE, Reitsma PH. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost. 1998;79:706–8.

    PubMed  CAS  Google Scholar 

  133. De Stefano V, Casorelli I, Rossi E, Zappacosta B, Leone G. Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism. Sem Thromb Haemost. 2000;26:305–11.

    Article  Google Scholar 

  134. Bezemer ID, Doggen CJ, Vos HL, Rosendaal FR. No association between the common MTHFR 677C > T polymorphism and venous thrombosis: results from the MEGA study. Arch Intern Med. 2007;167:497–501.

    Article  PubMed  CAS  Google Scholar 

  135. Zöller B, Li X, Sundquist J, et al. Parental history and venous thromboembolism: a nationwide study of age-specific and sex-specific familial risks in Sweden. J Thromb Haemost. 2011;9:64–70.

    Article  PubMed  Google Scholar 

  136. Sørensen HT, Riis AH, Diaz LJ, et al. Familial risk of venous thromboembolism: a nationwide cohort study. J Thromb Haemost. 2011;9:320–4.

    Article  PubMed  Google Scholar 

  137. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ. Risk factors for deep vein thrombosis and pulmonary embolism. A population-based case-control study. Arch Intern Med. 2000;160:809–15.

    Article  PubMed  CAS  Google Scholar 

  138. Heit JA, O’Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism. A population-based case-control study. Arch Intern Med. 2002;162:1245–8.

    Article  PubMed  Google Scholar 

  139. Cushman M, Tsai AW, White RH, Heckbert SR, Rosamond WD, Enright P, Folsom AR. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med. 2004;117:19–25.

    Article  PubMed  Google Scholar 

  140. Bates SM. Pregnancy-associated venous thromboembolism: prevention and treatment. Semin Hematol. 2011;48:271–84.

    Article  PubMed  Google Scholar 

  141. van Hylckama Vlieg A, Middeldorp S. Hormone therapies and venous thromboembolism: where are we now? J Thromb Haemostasis. 2011;9:257–66.

    Article  CAS  Google Scholar 

  142. Wu O, Robertson L, Langhorne P, Twaddle S, Lowe GD, Clark P, Greaves M, Walker ID, Brenkel I, Regan L, Greer IA. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thromb Haemost. 2005;94:17–25.

    PubMed  CAS  Google Scholar 

  143. Mohllajee AP, Curtis KM, Martins SL, Peterson HB. Does use of hormonal contraceptives among women with thrombogenic mutations increase their risk of venous thromboembolism? A systematic review. Contraception. 2006;73:166–78.

    Article  PubMed  CAS  Google Scholar 

  144. Martinelli I, Battaglioli T, De Stefano V, Tormene D, Valdrè L, Grandone E, Tosetto A, Mannucci PM, GIT (Gruppo Italiano Trombofilia). The risk of first venous thromboembolism during pregnancy and puerperium in double heterozygotes for factor V Leiden and prothrombin G20210A. J Thromb Haemost. 2008;6:494–8.

    Article  PubMed  CAS  Google Scholar 

  145. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (20210G > A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members. Genet Med. 2011;13:67–76.

    Google Scholar 

  146. Marjot T, Yadav S, Hasan N, Bentley P, Sharma P. Genes associated with adult cerebral venous thrombosis. Stroke. 2011;42(4):913–8.

    Google Scholar 

  147. Gouveia LO, Canhão P. MTHFR and the risk for cerebral venous thrombosis-a meta-analysis. Thromb Res. 2010;125(4):e153–8.

    Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge funding from the Italian Ministry for Education and University (PRIN 2007) for the project: Health Technology Assessment per gli screening genetici: lo studio dell’appropriatezza dei test genetici di suscettibilità alla malattia tromboembolica venosa come modello di studio (health thechnology assessment for genetic screening tests: appropriateness of susceptibility genetic tests to venous thromboembolism as a model of study). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). The authors thank the staff and participants of the ARIC study for their important contributions. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whiscience.org/publications/WHI_investigators_shortlist.pdf. The Cardiovascular Health Study was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grant HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org.

Conflict of interests

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Institute of Public Health - Section of Hygiene, Department of Public Health, Università Cattolica del Sacro Cuore, L.go F.Vito 1, 00168, Rome, Italy

    Benedetto Simone, Emanuele Leoncini, Nicola Nicolotti, Emma De Feo, Walter Ricciardi & Stefania Boccia

  2. Institute of Hematology, Università Cattolica del Sacro Cuore, Rome, Italy

    Valerio De Stefano & Elena Rossi

  3. Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark

    Jeppe Zacho

  4. A. Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Internal Medicine and Medical Specialties, Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico, Milan, Italy

    Ida Martinelli

  5. Hôpital Européen Georges Pompidou, Service de Médecine Vasculaire, Centre Claude Bernard et Laboratoire d’Hémostase, Paris, France

    Joseph Emmerich

  6. Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA

    Aaron R. Folsom

  7. Department of Medical Biochemistry, Arabian Gulf University, Manama, Bahrain

    Wassim Y. Almawi

  8. INSERM, UMRS 1018, Villejuif, France

    Pierre Y. Scarabin

  9. Department of Internal Medicine, VU Medical Center, PO-box 7057, 1007 MB, Amsterdam, The Netherlands

    Martin den Heijer

  10. Department of Medicine, University of Vermont, Burlington, VT, 05446, USA

    Mary Cushman

  11. Medical Genetics, Clinical Chemistry and Clinical Pathology Laboratory, Niguarda Ca’ Granda Hospital, Piazza Ospedale Maggiore 3, 20100, Milan, Italy

    Silvana Penco

  12. Thrombosis and Hemostasis Unit, Department of Clinical Pathology, La Fe University Hospital, Valencia, Spain

    Amparo Vaya

  13. Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

    Pantep Angchaisuksiri

  14. Department of Pulmonary Diseases, Istanbul Medical Faculty, Istanbul University, Capa-Istanbul, Turkey

    Gulfer Okumus

  15. Centre for the Study of Haemostasis and Thrombosis Institute of Human Anatomy, The University of Ferrara, Ferrara, Italy

    Donato Gemmati & Simona Cima

  16. Department of Pediatric Molecular Genetics, Ankara University, Ankara, Turkey

    Nejat Akar

  17. Department of Pulmonary Medicine, Gazi University School of Medicine, Ankara, Turkey

    Kivilcim I. Oguzulgen

  18. Département de Biochimie, Toxicologie et Pharmacologie, Centre Hospitalier Universitaire, BP 217, 38043, Grenoble, France

    Véronique Ducros

  19. Department of Neurology, Klinikum Memmingen, Bismarckstrasse 23, 87700, Memmingen, Germany

    Christoph Lichy

  20. Servicio de Medicina Interna, Hospital Universitario, 12 de Octubre, Madrid, Spain

    Consuelo Fernandez-Miranda

  21. Department of Medicine, Jagiellonian University School of Medicine, Cracow, Poland

    Andrzej Szczeklik

  22. Department of of Internal Medicine, Virgen de la Luz Hospital, Cuenca, Spain

    José A. Nieto

  23. Grupo de Investigación en Trombosis, Hospital Universitario San Vicente de Paúl, Universidad de Antioquia, Medellín, Colombia

    Jose Domingo Torres

  24. Department of Biochemistry, Toxicology and Pharmacology, Grenoble Universitary Hospital, BP 217, 38043 Grenoble, France

    Véronique Le Cam-Duchez

  25. Department of Biochemistry, University of Medicine, Pleven, Bulgaria

    Petar Ivanov

  26. Stroke Clinic, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico, Mexico

    Carlos Cantu-Brito

  27. Russian Institute of Haematology and Transfusion, 2-nd Sovietskaya 16, St. Petersburg, Russia

    Veronika M. Shmeleva

  28. Department of Vascular Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia

    Mojka Stegnar

  29. Perinatology Unit, Morristown Memorial Hospital, Morristown, NJ, USA

    Dotun Ogunyemi

  30. King Hussein Medical Center, Princess Iman Research Center for Laboratory Sciences, Amman, Jordan

    Suhair S. Eid

  31. IRCCS S. Raffaele Pisana, Rome, Italy

    Stefania Boccia

Authors
  1. Benedetto Simone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valerio De Stefano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emanuele Leoncini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeppe Zacho
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ida Martinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joseph Emmerich
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elena Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Aaron R. Folsom
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wassim Y. Almawi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Pierre Y. Scarabin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Martin den Heijer
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mary Cushman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Silvana Penco
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Amparo Vaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Pantep Angchaisuksiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Gulfer Okumus
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Donato Gemmati
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Simona Cima
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Nejat Akar
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Kivilcim I. Oguzulgen
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Véronique Ducros
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Christoph Lichy
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Consuelo Fernandez-Miranda
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Andrzej Szczeklik
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. José A. Nieto
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Jose Domingo Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Véronique Le Cam-Duchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Petar Ivanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Carlos Cantu-Brito
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Veronika M. Shmeleva
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Mojka Stegnar
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Dotun Ogunyemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Suhair S. Eid
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Nicola Nicolotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. Emma De Feo
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. Walter Ricciardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. Stefania Boccia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefania Boccia.

Appendices

Appendix 1

See Table 8.

Table 8 Overall and stratum-specific adjusted odds ratios (OR) by polymorphic variants for homozygous carriers of Factor V Leiden and Prothrombin 20210A
Full size table

Appendix 2

See Fig. 8.

Fig. 8
figure 8

Forrest plot of the studies not included: association between Factor V Leiden and risk of venous thromboembolism (odds ratios are represented on log scale)

Full size image

Appendix 3

See Fig. 9.

Fig. 9
figure 9

Forrest plot of the studies not included: association between Prothrombin 20210A and risk of venous thromboembolism (odds ratios are represented on log scale)

Full size image

Appendix 4

See Fig. 10.

Fig. 10
figure 10

Forrest plot of the studies not included: association between Methylenetetrahydrofolate reductase C677T and venous thromboembolism (odds ratios are represented on log scale)

Full size image

Rights and permissions

Reprints and permissions

About this article

Cite this article

Simone, B., De Stefano, V., Leoncini, E. et al. Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. Eur J Epidemiol 28, 621–647 (2013). https://doi.org/10.1007/s10654-013-9825-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10654-013-9825-8

Keywords

Search

Navigation