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Table of Contents
Vol. 32, No. 2, 2002
Issue release date: March–April 2002 (July 2002)
Section title: Original Paper
Pathophysiol Haemost Thromb 2002;32:51–58
(DOI:10.1159/000065076)

Common C677T Polymorphism of the Methylenetetrahydrofolate Reductase Gene and the Risk of Venous Thromboembolism: Meta-Analysis of 31 Studies

Ray J.G.a,b · Shmorgun D.b · Chan W.S.a
aDepartment of Medicine, Women’s College Campus, Sunnybrook and Women’s College Health Sciences Centre, Toronto, Ont., bMcMaster University, Hamilton, Ont., Canada
email Corresponding Author

Abstract

Background: Although the common 677 C → T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene is implicated in the development of hyperhomocysteinemia, its correlation with venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis of previously published studies to clarify the role of the MTHFR 677 TT homozygous genotype in association with VTE. Methods and Results: Relevant articles were retrieved from a systematic search of Medline and Embase from 1990 to September 2001. Two independent reviewers abstracted data on the characteristics of the cases with VTE and controls without VTE. We pooled the rates of the MTHFR 677 TT genotype in both groups, as well as the odds ratio (OR) of VTE in the presence of the TT versus CC or CT genotypes. In 31 published studies, comprising 4,901 cases and 7,886 controls, the pooled prevalence of the MTHFR 677 TT genotype was slightly higher among cases (14.3%) than controls (11.7%), conferring a borderline degree of heightened risk [pooled OR (ORp) 1.2, 95% confidence interval (CI) 1.1–1.4]. After excluding cases with a classic thrombophilia factor, the pooled prevalence rates of the MTHFR 677 TT genotype among 11 studies were 17.7 and 12.3%, respectively (ORp 1.5, 95% CI 1.2–1.9). Conclusions: The classic MTHFR C677T gene polymorphism is weakly associated with an increased risk of VTE. It is unlikely that the purported relationship between hyperhomocysteinemia and VTE is mediated by this gene defect to a substantial degree, although other undiscovered gene polymorphisms may explain this association. Until more compelling data are made available, we do not recommend that testing for the MTHFR C677T polymorphism be routinely included as part of any clinical thrombophilia assessment.

© 2002 S. Karger AG, Basel


  

Key Words

  • Venous thromboembolism
  • Deep vein thrombosis
  • Pulmonary embolism
  • Homocysteine
  • Methylenetetrahydrofolate reductase
  • Thrombophilia
  • Genetics
  • Meta-analysis

References

  1. Ray JG: Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med 1998;158:2101–2106.
  2. Kang SS, Wong PW, Zhou JM, Sora J, Lessick M, Ruggie N, Grcevich G: Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease. Metabolism 1988;37:611–613.

    External Resources

  3. Rozen R: Genetic modulation of homocysteinemia. Semin Thromb Hemost 2000;26:255–261.
  4. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG: A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995;274:1049–1057.
  5. Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom 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 Luis AC, Parrot-Rouland FM, Tan KS, Higgins I, Garcon D, Andria G: Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997;277:1775–1781.
  6. Brattstrom L, Wilcken DE, Ohrvik J, Brudin L: Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: The result of a meta-analysis. Circulation 1998;98:2520–2526.
  7. 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;77:818–821.
  8. De Stefano V, Casorelli I, Rossi E, Zappacosta B, Leone G: Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism. Semin Thromb Hemost 2000;26:305–311.
  9. DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–188.
  10. Breslow NE, Day NE: Statistical methods in cancer research. Volume I – The analysis of case-control studies. IARC Sci Publ 1980;32:5–338.

    External Resources

  11. Lau J: Meta-Analyst0.998 Statistical Software. Boston, 1995.
  12. 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;17:1662–1666.
  13. 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;2:61–68.

    External Resources

  14. Salden A, Keeney S, Hay CRM, Cumming AM: The C677T MTHFR variant and the risk of venous thrombosis. Br J Haematol 1997;99:472.
  15. 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;97:804–806.
  16. Brown K, Luddington R, Baglin T: Effect of the MTHFRC677T variant on risk of venous thromboembolism: Interaction with factor V Leiden and prothrombin (F2G20210A) mutations. Br J Haematol 1998;103:42–44.
  17. 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;147:30–35.
  18. Grandone E, Margaglione M, Colaizzo D, D’Andrea G, Cappucci G, Brancaccio V, Di Minno G: Genetic susceptibility to pregnancy-related venous thromboembolism: Roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations. AM J Obstet Gynecol 1998;179:1324–1328.
  19. 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;79:254–258.
  20. 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;79:907–911.
  21. Rintelen C, Mannhalter C, Lechner K, Eichinger S, Kyrle PA, Papagiannopoulos M, Schneider B, Pabinger I: No evidence for an increased risk of venous thrombosis in patients with factor V Leiden by the homozygous 677 C to T mutation in the methylenetetrahydrofolate-reductase gene. Blood Coagul Fibrinolysis 1999;10:101–105.
  22. 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;81:506–511.
  23. 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.
  24. Ho CH: Prevalence of prothrombin 20210A allele and methylenetetrahydrofolate reductase C677T genetic mutations in the Chinese population. Ann Hematol 2000;79:239–242.
  25. Franco RF, Morelli V, Lourenco 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;105:556–559.
  26. 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 hyperhomocysteinemia in normal and thromboembolic subjects. Arterioscler Thromb Vasc Biol 1999;19:1761–1767.
  27. 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;84:824–828.
  28. 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;19:511–518.
  29. Lin JS, Shen MC, Tsai W: The prevalence of C677T mutation in the methylenetetrahydrofolate reductase gene and its association with venous thrombophilia in Taiwanese Chinese. Thromb Res 2000;97:89–94.
  30. 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;97:163–167.
  31. Angchaisuksiri P, Pingsuthiwong S, Sura T, Aryuchai K, Busabaratana M, Atichartakarn V: Prevalence of the C677T methylenetetrahydrofolate reductase mutation in Thai patients with deep vein thrombosis. Acta Haematol 2000;103:191–196.
  32. 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;67:657–661.
  33. 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;84:576–582.

    External Resources

  34. Fujimura H, Kawasaki T, Sakata T, Ariyoshi H, Kato H, Monden M, Miyata T: Common C677T polymorphism in the methylenetetrahydrofolate reductase gene increases the risk for deep vein thrombosis in patients with predisposition of thrombophilia. Thromb Res 2000;98:1–8.
  35. Gerhardt A, Scharf RE, Beckmann MW, Struve S, Bender HG, Pillny M, Sandmann W, Zotz RB: Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000;342:374–380.
  36. Toydemir PB, Elhan AH, Tukun A, Toydemir R, Gurler A, Tuzuner A, Bokesoy I: Effects of factor V gene G1691A, methylenetetrahydrofolate reductase gene C677T, and prothrombin gene G20210A mutations on deep venous thrombogenesis in Behcet’s disease. J Rheumatol 2000;27:2849–2854.
  37. Zheng YZ, Tong J, Do XP, Pu XQ, Zhou BT: Prevalence of methylenetetrahydrofolate reductase C677T and its association with arterial and venous thrombosis in the Chinese population. Br J Haematol 2000;109:870–874.

    External Resources

  38. Guedon C, Le Cam-Duchez V, Lalaude O, Menard JF, Lerebours E, Borg JY: Prothrombotic inherited abnormalities other than factor V Leiden mutation do not play a role in venous thrombosis in inflammatory bowel disease. Am J Gastroenterol 2001;96:1448–1454.

    External Resources

  39. 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;47:661–666.

    External Resources

  40. Hsu LA, Ko YL, Wang SM, Chang CJ, Hsu TS, Chiang CW, Lee YS: The C677T mutation of the methylenetetrahydrofolate reductase gene is not associated with the risk of coronary artery disease or venous thrombosis among Chinese in Taiwan. Hum Hered 2001;51:41–45.
  41. 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;2:141–149.
  42. Sutton AJ, Song F, Gilbody SM, Abrams KR: Modelling publication bias in meta-analysis: A review. Stat Methods Med Res 2000;9:421–445.

    External Resources

  43. 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;81:733–738.
  44. Mager A: Methylenetetrahydrofolate reductase gene and coronary artery disease. Circulation 2000;101:E172–E173.

    External Resources

  45. Zoller B, Garcia de Frutos P, Hillarp A, Dahlback B: Thrombophilia as a multigenic disease. Haematologica 1999;84:59–70.
  46. Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, Ueland M, Kvale G: Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA 1995;274:1526–1533.
  47. Ehrenforth S, Junker R, Koch HG, Kreuz W, Munchow N, Scharrer I, Nowak-Gottl U: Multicentre evaluation of combined prothrombotic defects associated with thrombophilia in childhood. Childhood Thrombophilia Study Group. Eur J Pediatr 1999;158(suppl 3):S97–S104.

  

Author Contacts

Dr. J.G. Ray
E-Mail rayjg@mcmaster.ca

  

Article Information

Received: Received: December 1, 2001
Accepted in revised form: January 21, 2002
Number of Print Pages : 8
Number of Figures : 1, Number of Tables : 3, Number of References : 47

  

Publication Details

Pathophysiology of Haemostasis and Thrombosis
Official Journal of the ‘Mediterranean League against Thromboembolic Diseases’

Vol. 32, No. 2, Year 2002 (Cover Date: March-April 2002 (Released July 2002))

Journal Editor: H.C. Hemker, Maastricht
ISSN: 1424–8832 (print), 1424–8840 (Online)

For additional information: http://www.karger.com/journals/pht


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References

  1. Ray JG: Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med 1998;158:2101–2106.
  2. Kang SS, Wong PW, Zhou JM, Sora J, Lessick M, Ruggie N, Grcevich G: Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease. Metabolism 1988;37:611–613.

    External Resources

  3. Rozen R: Genetic modulation of homocysteinemia. Semin Thromb Hemost 2000;26:255–261.
  4. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG: A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995;274:1049–1057.
  5. Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom 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 Luis AC, Parrot-Rouland FM, Tan KS, Higgins I, Garcon D, Andria G: Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997;277:1775–1781.
  6. Brattstrom L, Wilcken DE, Ohrvik J, Brudin L: Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: The result of a meta-analysis. Circulation 1998;98:2520–2526.
  7. 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;77:818–821.
  8. De Stefano V, Casorelli I, Rossi E, Zappacosta B, Leone G: Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism. Semin Thromb Hemost 2000;26:305–311.
  9. DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–188.
  10. Breslow NE, Day NE: Statistical methods in cancer research. Volume I – The analysis of case-control studies. IARC Sci Publ 1980;32:5–338.

    External Resources

  11. Lau J: Meta-Analyst0.998 Statistical Software. Boston, 1995.
  12. 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;17:1662–1666.
  13. 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;2:61–68.

    External Resources

  14. Salden A, Keeney S, Hay CRM, Cumming AM: The C677T MTHFR variant and the risk of venous thrombosis. Br J Haematol 1997;99:472.
  15. 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;97:804–806.
  16. Brown K, Luddington R, Baglin T: Effect of the MTHFRC677T variant on risk of venous thromboembolism: Interaction with factor V Leiden and prothrombin (F2G20210A) mutations. Br J Haematol 1998;103:42–44.
  17. 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;147:30–35.
  18. Grandone E, Margaglione M, Colaizzo D, D’Andrea G, Cappucci G, Brancaccio V, Di Minno G: Genetic susceptibility to pregnancy-related venous thromboembolism: Roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations. AM J Obstet Gynecol 1998;179:1324–1328.
  19. 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;79:254–258.
  20. 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;79:907–911.
  21. Rintelen C, Mannhalter C, Lechner K, Eichinger S, Kyrle PA, Papagiannopoulos M, Schneider B, Pabinger I: No evidence for an increased risk of venous thrombosis in patients with factor V Leiden by the homozygous 677 C to T mutation in the methylenetetrahydrofolate-reductase gene. Blood Coagul Fibrinolysis 1999;10:101–105.
  22. 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;81:506–511.
  23. 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.
  24. Ho CH: Prevalence of prothrombin 20210A allele and methylenetetrahydrofolate reductase C677T genetic mutations in the Chinese population. Ann Hematol 2000;79:239–242.
  25. Franco RF, Morelli V, Lourenco 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;105:556–559.
  26. 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 hyperhomocysteinemia in normal and thromboembolic subjects. Arterioscler Thromb Vasc Biol 1999;19:1761–1767.
  27. 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;84:824–828.
  28. 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;19:511–518.
  29. Lin JS, Shen MC, Tsai W: The prevalence of C677T mutation in the methylenetetrahydrofolate reductase gene and its association with venous thrombophilia in Taiwanese Chinese. Thromb Res 2000;97:89–94.
  30. 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;97:163–167.
  31. Angchaisuksiri P, Pingsuthiwong S, Sura T, Aryuchai K, Busabaratana M, Atichartakarn V: Prevalence of the C677T methylenetetrahydrofolate reductase mutation in Thai patients with deep vein thrombosis. Acta Haematol 2000;103:191–196.
  32. 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;67:657–661.
  33. 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;84:576–582.

    External Resources

  34. Fujimura H, Kawasaki T, Sakata T, Ariyoshi H, Kato H, Monden M, Miyata T: Common C677T polymorphism in the methylenetetrahydrofolate reductase gene increases the risk for deep vein thrombosis in patients with predisposition of thrombophilia. Thromb Res 2000;98:1–8.
  35. Gerhardt A, Scharf RE, Beckmann MW, Struve S, Bender HG, Pillny M, Sandmann W, Zotz RB: Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000;342:374–380.
  36. Toydemir PB, Elhan AH, Tukun A, Toydemir R, Gurler A, Tuzuner A, Bokesoy I: Effects of factor V gene G1691A, methylenetetrahydrofolate reductase gene C677T, and prothrombin gene G20210A mutations on deep venous thrombogenesis in Behcet’s disease. J Rheumatol 2000;27:2849–2854.
  37. Zheng YZ, Tong J, Do XP, Pu XQ, Zhou BT: Prevalence of methylenetetrahydrofolate reductase C677T and its association with arterial and venous thrombosis in the Chinese population. Br J Haematol 2000;109:870–874.

    External Resources

  38. Guedon C, Le Cam-Duchez V, Lalaude O, Menard JF, Lerebours E, Borg JY: Prothrombotic inherited abnormalities other than factor V Leiden mutation do not play a role in venous thrombosis in inflammatory bowel disease. Am J Gastroenterol 2001;96:1448–1454.

    External Resources

  39. 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;47:661–666.

    External Resources

  40. Hsu LA, Ko YL, Wang SM, Chang CJ, Hsu TS, Chiang CW, Lee YS: The C677T mutation of the methylenetetrahydrofolate reductase gene is not associated with the risk of coronary artery disease or venous thrombosis among Chinese in Taiwan. Hum Hered 2001;51:41–45.
  41. 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;2:141–149.
  42. Sutton AJ, Song F, Gilbody SM, Abrams KR: Modelling publication bias in meta-analysis: A review. Stat Methods Med Res 2000;9:421–445.

    External Resources

  43. 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;81:733–738.
  44. Mager A: Methylenetetrahydrofolate reductase gene and coronary artery disease. Circulation 2000;101:E172–E173.

    External Resources

  45. Zoller B, Garcia de Frutos P, Hillarp A, Dahlback B: Thrombophilia as a multigenic disease. Haematologica 1999;84:59–70.
  46. Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, Ueland M, Kvale G: Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA 1995;274:1526–1533.
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