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

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• 作者：Benedetto Simone ; Valerio De Stefano ; Emanuele Leoncini…
• 关键词：Venous thromboembolism ; Genetic susceptibility ; Factor V Leiden ; Prothrombin G202010A ; Methylenetetrahydrofolate reductase C677T
• 刊名：European Journal of Epidemiology
• 出版年：2013
• 出版时间：August 2013
• 年：2013
• 卷：28
• 期：8
• 页码：621-647
• 全文大小：1321KB
• 参考文献：1. White RH. The epidemiology of venous thromboembolism MD. Circulation. 2003;107:I-4-. CrossRef
  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):204-0. CrossRef
  3. White RH, Keenan CR. Effects of race and ethnicity on the incidence of venous thromboembolism. Thromb Res. 2009;123(Suppl. 4):S11-. CrossRef
  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;102:360-0.
  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-. CrossRef
  7. Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2001;151(9):862-. CrossRef
  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;145:807-5. CrossRef
  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;86:809-6.
  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-. CrossRef
  12. Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Intern Med. 1999;159(12):1289-8. CrossRef
  13. Graham IM, Daly LE, Refsum HM, Robinson K, Brattstr?m 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):1775-1. CrossRef
  14. Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss. Fertil Steril 2008; 89:1603.
  15. Schwahn B, Rozen R. Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences. Am J Pharmacogenomics. 2001;1(3):189-01. CrossRef
  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-. CrossRef
  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):189-6. CrossRef
  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-. CrossRef
  19. Aznar J, Vayá A, Estellés A, Mira Y, Seguí R, Villa P, Ferrando F, Falcó C, Corella D, Espa?a 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-.
  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):58-3. CrossRef
  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-. CrossRef
  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):1573-0. CrossRef
  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-.
  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-. CrossRef
  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):517-2. CrossRef
  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-. CrossRef
  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-. CrossRef
  28. Folsom AR. Update on factor V Leiden association with venous thromboembolism in the LITE Study. Blood. 2007;109(3):1336-. CrossRef
  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):3046-1. CrossRef
  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-. CrossRef
  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-.
  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):27-6. CrossRef
  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-.
  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):495-00. CrossRef
  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):316-0. CrossRef
  36. Martinelli I, Battaglioli T, Pedotti P, Cattaneo M, Mannucci PM. Hyperhomocysteinemia in cerebral vein thrombosis. Blood. 2003;102(4):1363-. CrossRef
  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):25-0. CrossRef
  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):17-4. CrossRef
  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-. 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):168-3. Epub 2007 Sep 25.
  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):693-06. CrossRef
  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-. CrossRef
  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):3495-00. CrossRef
  44. Torres JD, Cardona H, Alvarez L, Cardona-Maya W, Casta?eda 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-. CrossRef
  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-.
  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):506-0.
  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-.
  48. Arruda VR, von Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF. The mutation Ala677–?gt;?Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis. Thromb Haemost. 1997;77:818-1.
  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-.
  50. Balta G, Gurgey A. Methylenetetrahydrofolate reductase (MTHFR) C677T mutation in Turkish patients with thrombosis. Turk J Pediatr. 1999;41:197-.
  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-.
  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;86:1188-2.
  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-. CrossRef
  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;12:639-2. CrossRef
  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-. CrossRef
  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-. CrossRef
  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-. CrossRef
  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;12:659-5. CrossRef
  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-. CrossRef
  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-. CrossRef
  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-. CrossRef
  62. Coen D, Zadro R, Honovi? L, Banfi? L, Stavljeni? 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;42:488-2.
  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-. CrossRef
  64. Corral J, González-Conejero R, Soria JM, González-Porras JR, Pérez-Ceballos E, Lecumberri R, Roldán V, Souto JC, Mi?ano 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;108:177-3. CrossRef
  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;67:657-1. CrossRef
  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;84:576-2.
  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-. CrossRef
  68. de Paula Sabino A, Guimar?es DA, Ribeiro DD, Paiva SG, Sant’Ana Dusse LM, das Gra?as 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-. CrossRef
  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-. CrossRef
  70. D?lek B, Eraslan S, Ero?lu S, Kesim BE, Ulutin T, Yal?iner A, Laleli YR, G?zükirmizi 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-. CrossRef
  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-. CrossRef
  72. Faioni EM, Castaman G, Asti D, Lussana F, Rodeghiero F. Association of factor V deficiency with factor V HR2. Haematologica. 2004;89:195-00.
  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;17:2418-2. CrossRef
  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;134:13-0. CrossRef
  75. Franco RF, Fagundes MG, Meijers JC, Reitsma PH, Louren?o 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-.
  76. Franco RF, Morelli V, Louren?o 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-. CrossRef
  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;52:206-0. CrossRef
  78. Gaustadnes M, Rüdiger N, M?ller J, Rasmussen K, Bjerregaard Larsen T, Ingerslev J. Thrombophilic predisposition in stroke and venous thromboembolism in Danish patients. Blood Coagul Fibrinolysis. 1999;10:251-. CrossRef
  79. González Ordó?ez 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-.
  80. González-Conejero R, Lozano ML, Corral J, Martínez C, Vicente V. The TFPI 536C–?gt;?T mutation is not associated with increased risk for venous or arterial thrombosis. Thromb Haemost. 2000;83:787-.
  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-. CrossRef
  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-. CrossRef
  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-.
  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-.
  85. Hoppe B, Tolou F, Radtke H, Kiesewetter H, D?rner T, Salama A. Marburg I polymorphism of factor VII-activating protease is associated with idiopathic venous thromboembolism. Blood. 2005;105:1549-1. CrossRef
  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-.
  87. Isotalo PA, Donnelly JG. Prevalence of methylenetetrahydrofolate reductase mutations in patients with venous thrombosis. Mol Diagn. 2000;5:59-6.
  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-. CrossRef
  89. Junker R, Koch HG, Auberger K, Münchow N, Ehrenforth S, Nowak-G?ttl U. Prothrombin G20210A gene mutation and further prothrombotic risk factors in childhood thrombophilia. Arterioscler Thromb Vasc Biol. 1999;19:2568-2. CrossRef
  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-. CrossRef
  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-.
  92. Koch HG, Nabel P, Junker R, Auberger K, Schobess R, Homberger A, Linnebank M, Nowak-G?ttl 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-. CrossRef
  93. K?ppel 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-.
  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-.
  95. Kostka H, Schwarz T, Schellong S, Mix C, Kuhlisch E, Temelkova-Kurktschiev T, Henkel E, K?hler 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;14:49-6. CrossRef
  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-. CrossRef
  97. Leroyer C, Mercier B, Escoffre M, Férec C, Mottier D. Factor V Leiden prevalence in venous thromboembolism patients. Chest. 1997;111:1603-. CrossRef
  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-.
  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-.
  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-. CrossRef
  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-.
  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;118:1405-1. CrossRef
  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):907-1.
  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;97:359-3. CrossRef
  105. Morelli VM, Louren?o 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-. CrossRef
  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-. CrossRef
  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;120:207-4. CrossRef
  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;88:3698-03.
  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;19:29-3. CrossRef
  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;359:747-2. CrossRef
  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-. CrossRef
  112. Renner W, K?ppel 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-. CrossRef
  113. Renner W, Winkler M, Hoffmann C, K?ppel 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):148-1.
  114. Reuner KH, Ruf A, Litfin F, Patscheke H. The mutation G20210–?gt;?A in the prothrombin gene is a strong risk factor for pulmonary embolism. Clin Chem. 1998;44:1365-.
  115. Ruiz-Argüelles GJ, Garcés-Eisele J, Reyes-Nú?ez 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;66:28-1. CrossRef
  116. Salazar-Sánchez L, Leon MP, Cartin M, Schuster G, Wulff K, Schr?der 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;25:739-5. CrossRef
  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.
  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;2:38-1. CrossRef
  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-. CrossRef
  120. Schobess R, Junker R, Auberger K, Münchow N, Burdach S, Nowak-G?ttl 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-. CrossRef
  121. Seinost G, Renner W, Brodmann M, Winkler M, K?ppel 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-. CrossRef
  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-.
  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-. CrossRef
  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;104:317-4. CrossRef
  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):39-1. CrossRef
  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-G?ttl 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-.
  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;90:829-4.
  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;21:268-1.
  130. De Stefano V, Rossi E, Paciaroni K, Leone G. Screening for inherited thrombophilia: indications and therapeutic implications. Haematologica. 2002;87:1095-08.
  131. De Stefano V, Chiusolo P, Paciaroni K, Leone G. Epidemiology of factor V Leiden: clinical implications. Sem Thromb Haemost. 1998;24:367-9. CrossRef
  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-.
  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;26:305-1. CrossRef
  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;167:497-01. CrossRef
  135. Z?ller 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;9:64-0. CrossRef
  136. S?rensen HT, Riis AH, Diaz LJ, et al. Familial risk of venous thromboembolism: a nationwide cohort study. J Thromb Haemost. 2011;9:320-. CrossRef
  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;160:809-5. CrossRef
  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-. CrossRef
  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;117:19-5. CrossRef
  140. Bates SM. Pregnancy-associated venous thromboembolism: prevention and treatment. Semin Hematol. 2011;48:271-4. CrossRef
  141. van Hylckama Vlieg A, Middeldorp S. Hormone therapies and venous thromboembolism: where are we now? J Thromb Haemostasis. 2011;9:257-6. CrossRef
  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;94:17-5.
  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;73:166-8. CrossRef
  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-. CrossRef
  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;13:67-6.
  146. Marjot T, Yadav S, Hasan N, Bentley P, Sharma P. Genes associated with adult cerebral venous thrombosis. Stroke. 2011;42(4):913-.
  147. Gouveia LO, Canh?o P. MTHFR and the risk for cerebral venous thrombosis-a meta-analysis. Thromb Res. 2010;125(4):e153-.
  
• 作者单位：Benedetto Simone (1)
  Valerio De Stefano (2)
  Emanuele Leoncini (1)
  Jeppe Zacho (3)
  Ida Martinelli (4)
  Joseph Emmerich (5)
  Elena Rossi (2)
  Aaron R. Folsom (6)
  Wassim Y. Almawi (7)
  Pierre Y. Scarabin (8)
  Martin den Heijer (9)
  Mary Cushman (10)
  Silvana Penco (11)
  Amparo Vaya (12)
  Pantep Angchaisuksiri (13)
  Gulfer Okumus (14)
  Donato Gemmati (15)
  Simona Cima (15)
  Nejat Akar (16)
  Kivilcim I. Oguzulgen (17)
  Véronique Ducros (18)
  Christoph Lichy (19)
  Consuelo Fernandez-Miranda (20)
  Andrzej Szczeklik (21)
  José A. Nieto (22)
  Jose Domingo Torres (23)
  Véronique Le Cam-Duchez (24)
  Petar Ivanov (25)
  Carlos Cantu-Brito (26)
  Veronika M. Shmeleva (27)
  Mojka Stegnar (28)
  Dotun Ogunyemi (29)
  Suhair S. Eid (30)
  Nicola Nicolotti (1)
  Emma De Feo (1)
  Walter Ricciardi (1)
  Stefania Boccia (1) (31)
  
  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
  2. Institute of Hematology, Università Cattolica del Sacro Cuore, Rome, Italy
  3. Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark
  4. A. Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Internal Medicine and Medical Specialties, Fondazione IRCCS Ca-Granda - Ospedale Maggiore Policlinico, Milan, Italy
  5. H?pital Européen Georges Pompidou, Service de Médecine Vasculaire, Centre Claude Bernard et Laboratoire d’Hémostase, Paris, France
  6. Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA
  7. Department of Medical Biochemistry, Arabian Gulf University, Manama, Bahrain
  8. INSERM, UMRS 1018, Villejuif, France
  9. Department of Internal Medicine, VU Medical Center, PO-box 7057, 1007 MB, Amsterdam, The Netherlands
  10. Department of Medicine, University of Vermont, Burlington, VT, 05446, USA
  11. Medical Genetics, Clinical Chemistry and Clinical Pathology Laboratory, Niguarda Ca-Granda Hospital, Piazza Ospedale Maggiore 3, 20100, Milan, Italy
  12. Thrombosis and Hemostasis Unit, Department of Clinical Pathology, La Fe University Hospital, Valencia, Spain
  13. Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
  14. Department of Pulmonary Diseases, Istanbul Medical Faculty, Istanbul University, Capa-Istanbul, Turkey
  15. Centre for the Study of Haemostasis and Thrombosis Institute of Human Anatomy, The University of Ferrara, Ferrara, Italy
  16. Department of Pediatric Molecular Genetics, Ankara University, Ankara, Turkey
  17. Department of Pulmonary Medicine, Gazi University School of Medicine, Ankara, Turkey
  18. Département de Biochimie, Toxicologie et Pharmacologie, Centre Hospitalier Universitaire, BP 217, 38043, Grenoble, France
  19. Department of Neurology, Klinikum Memmingen, Bismarckstrasse 23, 87700, Memmingen, Germany
  20. Servicio de Medicina Interna, Hospital Universitario, 12 de Octubre, Madrid, Spain
  21. Department of Medicine, Jagiellonian University School of Medicine, Cracow, Poland
  22. Department of of Internal Medicine, Virgen de la Luz Hospital, Cuenca, Spain
  23. Grupo de Investigación en Trombosis, Hospital Universitario San Vicente de Paúl, Universidad de Antioquia, Medellín, Colombia
  24. Department of Biochemistry, Toxicology and Pharmacology, Grenoble Universitary Hospital, BP 217, 38043 Grenoble, France
  25. Department of Biochemistry, University of Medicine, Pleven, Bulgaria
  26. Stroke Clinic, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico, Mexico
  27. Russian Institute of Haematology and Transfusion, 2-nd Sovietskaya 16, St. Petersburg, Russia
  28. Department of Vascular Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia
  29. Perinatology Unit, Morristown Memorial Hospital, Morristown, NJ, USA
  30. King Hussein Medical Center, Princess Iman Research Center for Laboratory Sciences, Amman, Jordan
  31. IRCCS S. Raffaele Pisana, Rome, Italy
  
• ISSN：1573-7284

文摘

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-.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR?=?4.22; 95?% CI: 3.35-.32; and OR?=?2.79;95?% CI: 2.25-.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?% 2.19-0.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals?≤?5?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.