No interaction between factor V Leiden and hyperhomocysteinemia or MTHFR 677TT genotype in venous thrombosis

Summary

Homocysteine may have a thrombogenic effect through inhibition of inactivation of factor Va by activated protein C. Because factor V Leiden also leads to resistance of factor V to activated protein C, it would be possible that both factors show interaction for the risk of venous thrombosis. This has been reported in some studies, but not in others. We performed a meta-analysis to investigate a possible interaction between factor V Leiden and hyperhomocysteinemia, including 825 subjects with venous thrombosis and 2,109 controls, for the risk of venous thrombosis. In addition, we assessed a possible interaction between factor V Leiden and MTHFR 677TT genotype (the most common genetic determinant of homocysteine levels), including 2,547 subjects with venous thrombosis and 4,327 controls. We also investigated the interaction effect of factor V Leiden and hyperhomocysteinemia in a large case-only study using data of the VITRO study, including 2,077 subjects with first-time venous thrombosis. The meta-analysis yielded no evidence for additive or multiplicative interaction between factor V Leiden and hyperhomocysteinemia [relative excess risk due to interaction (RERI) –1.77 (95%CI –8.61 to 5.08) and multiplicative interaction term 0.86 (95%CI 0.35 to 2.14)].The case-only study also showed no interaction effect [0.58 (95%CI 0.29 to 1.16)]. Also the metaanalysis on factor V Leiden and MTHFR 677TT yielded no evidence of interaction; RERI 0.13 (95%CI –3.60 to 3.86) and multiplicative interaction term 1.23 (95%CI 0.72 to 2.11). Both the meta-analyses of published studies and a large case-only study did not show evidence for interaction between factor V Leiden and hyperhomocysteinemia for risk of venous thrombosis.

Keywords

MTHFR - Methylenetetrahydrofolatereductase - homocysteine - factor V Leiden - meta-analysis - case-only - case-control - VITRO

• References

• 1 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-73.
• 2 Rothman KJ, Greenland S.. Modern Epidemiology. Lippincott-Raven 1998
• 3 Koeleman BPC, Reitsma PH, Allaart CF. et al Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood 1994; 84: 1031-5.
• 4 Zöller B, Berntsdotter A, de Frutos PG. et al Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995; 85: 3518-23.
• 5 Zöller B, Dahlbäck B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet 1994; 343: 1536-8.
• 6 Bertina RM, Koeleman BPC, Koster T. et al Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
• 7 den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: a metaanalysis of published epidemiological studies. J Thromb Haemost 2005; 3: 292-9.
• 8 Frosst P, Blom HJ, Milos R. et al A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111-3.
• 9 Jacques PF, Bostom AG, Williams RR. et al Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996; 93: 7-9.
• 10 Smith GD, Ebrahim S. ’Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease?. Int J Epidemiol 2003; 32: 1-22.
• 11 Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Br Med J 2002; 325: 1202-8.
• 12 Ray JG, Shmorgun D, Chan WS. Common C677T polymorphism of the methylenetetrahydrofolate reductase gene and the risk of venous thromboembolism: Meta-analysis of 31 studies. Pathophysiol Haemost Thromb 2002; 32: 51-8.
• 13 Undas A, Williams EB, Butenas S. et al Homocysteine inhibits inactivation of factor Va by activated protein C. J Biol Chem 2001; 276: 4389-97.
• 14 Keijzer MBAJ, den Heijer M, Blom HJ. et al Interaction between hyperhomocysteinemia, mutated methylenetetrahydrofolatereductase (MTHFR) and inherited thrombophilic factors in recurrent venous thrombosis. Thromb Haemost 2002; 88: 723-8.
• 15 den Heijer M, Koster T, Blom HJ. et al Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759-62.
• 16 Ridker PM, Hennekens CH, Selhub J. et al Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation 1997; 95: 1777-82.
• 17 De Stefano V, Zappacosta B, Persichilli S. et al Prevalence of mild hyperhomocysteinaemia and association with thrombophilic genotypes (factor V Leiden and prothrombin G20210A) in Italian patients with venous thromboembolic disease. Br J Haematol 1999; 106: 564-8.
• 18 Tsai AW, Cushman M, Tsai MY. et al Serum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE). Am J Hematol 2003; 72: 192-200.
• 19 Salomon O, Steinberg DM, Zivelin A. et al Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism. Prevalence and risk assessment. Arterioscler Thromb Vasc Biol 1999; 19: 511-8.
• 20 Cattaneo M, Chantarangkul V, Taioli E. et al 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.
• 21 Grossmann R, Schwender S, Geisen U. et al CBS 844ins68, MTHFR TT677 and EPCR 4031ins23 genotypes in patients with deep-vein thrombosis. Thromb Res 2002; 107: 13-5.
• 22 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: 42-4.
• 23 Kluijtmans LAJ, den Heijer M, Reitsma PH. et al Thermolabile methylenetetrahydrofolate reductase and factor V Leiden in the risk of deep-vein thrombosis. Thromb Haemost 1998; 79: 254-8.
• 24 Margaglione M, D’Andrea G, d’Addedda M. et al 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: 907-1.
• 25 Alhenc-Gelas M, Arnaud E, Nicaud V. et al Venous thromboembolic disease and the prothrombin, methylene tetrahydrofolate reductase and factor V genes. Thromb Haemost 1999; 81: 506-10.
• 26 Akar N, Akar E, Misirlioglu M. et al Search for genetic factors favoring thrombosis in Turkish population. Thromb Res 1998; 92: 79-82.
• 27 Akar N, Akar E, Akçay R. et al Effect of metylenetetrahydrofolate 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.
• 28 Cappucci G, Margaglione M, Ames PRJ. Comparative prevalence of antiphospholipid antibodies and thrombophilic genotypes in consecutive patients with venous thrombosis. Blood Coagul fibrinolysis 2001; 12: 659-65.
• 29 Cattaneo M, Tsai MY, Bucciarelli P. et al A common mutation in the methylenetetrahydrofolate reductase gene (C677T) increases the risk for deep-vein thrombosis in patients with mutant factor V (factor V:Q 506). Arterioscler Thromb Vasc Biol 1997; 17: 1662-6.
• 30 Iglesias Varela ML, Adamczuk YP, Forastiero RR. et al Major and potential prothrombotic genotypes in a cohort of patients with venous thromboembolism. Thromb Res 2001; 104: 317-24.
• 31 den Heijer M, Willems H, Blom H. et al Homocysteine lowering by B vitamins and the secondary prevention of deep-vein thrombosis and pulmonary embolism. A randomised, placebo-controlled, double blind trial. Blood September 7. 2006 DOI: 10.1182/blood-2006–04–014654
• 32 Willems HPJ, Bos GMJ, Gerrits WBJ. et al Acidic citrate stabilizes blood samples for assay of total homocysteine. Clin Chem 1998; 44: 3425
• 33 Te Poele-Pothoff MT, van den Berg M, Franken DG. et al Three different methods for the determination of total homocysteine in plasma. Ann Clin Biochem 1995; 32: 218-20.
• 34 Hosmer DW. Lemeshow S. Confidence Interval estimation of interaction. Epidemiology 1992; 5: 452-6.
• 35 Zarychanski R, Houston DS. Plasma homocysteine concentration is not associated with activated protein C resistance in patients investigated for hypercoagulability. Thromb Haemost 2004; 91: 1115-22.
• 36 Ahlbom A, Alfredsson L. Interaction: A word with two meanings creates confusion. Eur J Epidemiol 2005; 20: 563-4.
• 37 Mandel H, Brenner B, Berant M. et al Coexistence of hereditary homocystinuria and factor V Leideneffect on thrombosis. New Engl J Med 1996; 334: 763-8.
• 38 Kalkanoğlu HS, Coşkun T, Aydoğdu SD. et al Factor V Leiden mutation in Turkish patients with homozygous cystathionine ? -synthase deficiency. J Inherit Metab Dis 2001; 24: 367-9.
• 39 Quere I, Lamarti H, Chadefaux-Vekemans B. Thrombophilia, homocystinuria, and mutation of the factor V gene. New Engl J Med 1996; 335: 289-90.
• 40 Kluijtmans LAJ, Boers GHJ, Verbruggen B. et al Homozygous cystathionine ß-synthase deficiency, combined with factor V Leiden or thermolabile methylenetetrahydrofolate reductase in the risk of venous thrombosis. Blood 1998; 91: 2015-8.
• 41 Yap S, O’Donnell KA, O’Neill C. et al Factor V Leiden (Arg506Gln), a confounding genetic risk factor but not mandatory for the occurrence of venous thromboembolism in homozygotes and obligate heterozygotes for cystathionine beta-synthase deficiency. Thromb Haemost 1999; 81: 502-5.