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DOI: 10.1160/TH09-01-0013
The genetics of venous thromboembolism
A meta-analysis involving ∼120,000 cases and 180,000 controlsPublikationsverlauf
Received:
07. Januar 2009
Accepted after major revision:
14. April 2009
Publikationsdatum:
22. November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200902/lookinside/thumbnails/10-1160-th09-01-0013-1.jpg)
Summary
We conducted a systematic and comprehensive meta-analysis on all candidate genes to assess their genetic contribution to the aetiology of venous thromboembolism (VTE) (pulmonary embolism and deep venous thrombosis) in all ethnic groups. Electronic databases were searched until and including January 2008 for any candidate gene investigated in VTE. Odds ratios (OR) and 95% confidence intervals (CI) were determined for each gene disease association using fixed and random effect models. Our meta-analyses included ∼126,525 cases and 184,068 controls derived from 173 case-control studies, which included 21 genes (28 polymorphisms). Statistically significant associations with VTE were identified for factor V G1691A (OR 9.45; 95% CI 6.72–13.30, p<0.0001), factor V A4070G (OR 1.24; 95% CI
Keywords
Genes - candidate genes - polymorphism - venous thrombosis - meta-analysis - deep vein thrombosis - pulmonary embolismFootnote: PS holds a Dept. of Health (UK) Senior Fellowship.
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References
- 1 Snow V. et al. 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: 204-210.
- 2 Heit JA. Venous thromboembolism epidemiology: implications for prevention and management. Semin Thromb Hemost 2002; 28 (Suppl. 02) 3-13.
- 3 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107 (23) (Suppl. 01) I4-I8.
- 4 Heit JA. The epidemiology of venous thromboembolism in the community: implications for prevention and management. J Thromb Thrombolysis 2006; 21: 23-29.
- 5 Zoller B. et al. Thrombophilia as a multigenic disease. Haematologica 1999; 84: 59-70.
- 6 Ariyaratnam R. et al. Genetics of ischaemic stroke among persons of non-European descent: a metaanalysis of eight genes involving approximately 32,500 individuals. PLoS Med 2007; 04: e131.
- 7 Casas JP. et al. Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol 2004; 61: 1652-1661.
- 8 Casas JP. et al. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet 2005; 365: 224-232.
- 9 Akar N. et al. Search for genetic factors favoring thrombosis in Turkish population. Thromb Res 1998; 92: 79-82.
- 10 Akar N, Akar E. Methylenetetrahydrofolate-dehydrogenase 1958 G-A (R653 Q) polymorphism in Turkish patients with venous thromboembolism. Acta Haematol 1999; 102: 199-200.
- 11 Akar N. et al. Effect of plasminogen activator inhibitor-1 4G/5G polymorphism in Turkish deep vein thrombotic patients with and without FV1691 G-A. Thromb Res 2000; 97: 227-230.
- 12 Akar N. et al. Factor V (His 1299 Arg) in Turkish patients with venous thromboembolism. Am J Hematol 2000; 63: 102-103.
- 13 Almawi WY. et al. 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. J Thromb Thrombolysis 2005; 19: 189-196.
- 14 Altinisik J. et al. Factor V Leiden, Prothrombin G20210A, and Protein C Mutation Frequency in Turkish Venous Thrombosis Patients. Clin Appl Thromb Hemost 2008; 14: 415-420.
- 15 Arruda VR. et al. Factor V Leiden (FVQ 506) is common in a Brazilian population. Am J Hematol 1995; 49: 242-243.
- 16 Avdonin PV. et al. 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: 70-76.
- 17 Ay C. et al. High concentrations of soluble P-selectin are associated with risk of venous thromboembolism and the P-selectin Thr715 variant. Clin Chem 2007; 53: 1235-1243.
- 18 Aznar J. et al. Risk of venous thrombosis in carriers of the prothrombin G20210A variant and factor V Leiden and their interaction with oral contraceptives. Haematologica 2000; 85: 1271-1276.
- 19 Balogh I. et al. Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia. Blood 2000; 96: 2479-2486.
- 20 Benson JM. et al. Factor V Leiden and factor V R2 allele: high-throughput analysis and association with venous thromboembolism. Thromb Haemost 2001; 86: 1188-1192.
- 21 Bouaziz-Borgi L. et al. Distinct association of factor V-Leiden and prothrombin G20210A mutations with deep venous thrombosis in Tunisia and Lebanon. Am J Hematol 2006; 81: 641-643.
- 22 Bouaziz-Borgi L. et al. A case control study of deep venous thrombosis in relation to factor V G1691A (Leiden) and A4070G (HR2 Haplotype) polymorphisms. Exp Mol Pathol 2007; 83: 480-483.
- 23 Boyanovsky B. et al. 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: 639-642.
- 24 Brown K. et al. Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3’-untranslated region of the prothrombin gene. Br J Haematol 1997; 98: 907-909.
- 25 Brown K. et al. 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: 480-482.
- 26 Brown K. et al. Risk of venous thromboembolism associated with the common hereditary haemochromatosis Hfe gene (C282Y) mutation. Br J Haematol 1999; 105: 95-97.
- 27 Cappucci G. et al. Comparative prevalence of antiphospholipid antibodies and thrombophilic genotypes in consecutive patients with venous thrombosis. Blood Coagul Fibrinolysis 2001; 12: 659-665.
- 28 Cattaneo M. 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.
- 29 Coen D. et al. Prevalence and association of the factor V Leiden and prothrombin G20210A in healthy subjects and patients with venous thromboembolism. Croat Med J 2001; 42: 488-492.
- 30 Colaizzo D. et al. Gain-of-function gene mutations and venous thromboembolism: distinct roles in different clinical settings. J Med Genet 2007; 44: 412-416.
- 31 Corral J. et al. A nonsense polymorphism in the protein Z-dependent protease inhibitor increases the risk for venous thrombosis. Blood 2006; 108: 177-183.
- 32 de Moerloose P. et al. Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thromboembolism. Br J Haematol 2000; 110: 125-129.
- 33 De S V. 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: 564-568.
- 34 De Stefano V. et al. Different circumstances of the first venous thromboembolism among younger or older heterozygous carriers of the G20210A polymorphism in the prothrombin gene. Haematologica 2003; 88: 61-66.
- 35 Dilley A. et al. Relation of three genetic traits to venous thrombosis in an African-American population. Am J Epidemiol 1998; 147: 30-35.
- 36 Dolek B. et al. 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: 435-438.
- 37 Dowling NF. et al. The epidemiology of venous thromboembolism in Caucasians and African-Americans: the GATE Study. J Thromb Haemost 2003; 01: 80-87.
- 38 Emmerich J. et al. 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: 809-816.
- 39 Erkekol FO. et al. High plasma levels of factor VIII: an important risk factor for isolated pulmonary embolism. Respirology 2006; 11: 70-74.
- 40 Faioni EM. et al. Association of factor V deficiency with factor V HR2. Haematologica 2004; 89: 195-200.
- 41 Folsom AR. Update on factor V Leiden association with venous thromboembolism in the LITE Study. Blood 2007; 109: 1336-1337.
- 42 Frances F. et al. 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.
- 43 Franco RF. et al. A second mutation in the methylenetetrahydrofolate reductase gene and the risk of venous thrombotic disease. Br J Haematol 1999; 105: 556-559.
- 44 Franco RF. et al. 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: 510-517.
- 45 Garcia-Gala JM. et al. Factor V Leiden (R506Q) and risk of venous thromboembolism: a case-control study based on the Spanish population. Clin Genet 1997; 52: 206-210.
- 46 Gaustadnes M. et al. Thrombophilic predisposition in stroke and venous thromboembolism in Danish patients. Blood Coagul Fibrinolysis 1999; 10: 251-259.
- 47 Gonzalez-Conejero R. et al. The TFPI 536C-->T mutation is not associated with increased risk for venous or arterial thrombosis. Thromb Haemost 2000; 83: 787-788.
- 48 Grossmann R. et al. CBS 844ins68, MTHFR TT677 and EPCR 4031ins23 genotypes in patients with deep-vein thrombosis. Thromb Res 2002; 107: 13-15.
- 49 Guedon C. et al. 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.
- 50 Alhenc-Gelas M. et al. Venous thromboembolic disease and the prothrombin, methylene tetrahydrofolate reductase and factor V genes. Thromb Haemost 1999; 81: 506-510.
- 51 Alhenc-Gelas M. et al. The factor V gene A4070G mutation and the risk of venous thrombosis. Thromb Haemost 1999; 81: 193-197.
- 52 Hoppe B. et al. Marburg I polymorphism of factor VII-activating protease is associated with idiopathic venous thromboembolism. Blood 2005; 105: 1549-1551.
- 53 Ioannou HV. et al. The prevalence of factor V Leiden as a risk factor for venous thromboembolism in the population of North-Western Greece. Int Angiol 2000; 19: 314-318.
- 54 Irani-Hakime N. et al. Factor V R506Q mutation Leiden: an independent risk factor for venous thrombosis but not coronary artery disease. J Thromb Thrombolysis 2001; 11: 111-116.
- 55 Ivanov P. et al. Impact of thrombophilic genetic factors on pulmonary embolism: early onset and recurrent incidences. Lung 2008; 186: 27-36.
- 56 Jackson A. et al. Effect of the angiotensin-converting enzyme gene deletion polymorphism on the risk of venous thromboembolism. Br J Haematol 2000; 111: 562-564.
- 57 Junker R. et al. Prothrombin G20210A gene mutation and further prothrombotic risk factors in childhood thrombophilia. Arterioscler Thromb Vasc Biol 1999; 19: 2568-2572.
- 58 Keijzer MB. et al. Interaction between hyperhomocysteinemia, mutated methylenetetrahydrofolatereductase (MTHFR) and inherited thrombophilic factors in recurrent venous thrombosis. Thromb Haemost 2002; 88: 723-728.
- 59 Koch HG. et al. The 677T genotype of the common MTHFR thermolabile variant and fasting homocysteine in childhood venous thrombosis. Eur J Pediatr 1999; 158 (Suppl. 03) S113-116.
- 60 Koppel H. et al. The angiotensin-convertingenzyme insertion/deletion polymorphism is not related to venous thrombosis. Thromb Haemost 2004; 91: 76-79.
- 61 Kostka H. et al. Polymorphisms in the TAFI gene and the risk of venous thrombosis. Clin Lab 2003; 49: 645-647.
- 62 Kostka H. et al. 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.
- 63 la Valle CJ. et al. The relationship of the factor V Leiden mutation or the deletion-deletion polymorphism of the angiotensin converting enzyme to postoperative thromboembolic events following total joint arthroplasty. BMC Musculoskelet Disord 2001; 02: 1.
- 64 Leroyer C. et al. Factor V Leiden prevalence in venous thromboembolism patients. Chest 1997; 111: 1603-1606.
- 65 Lindmarker P. et al. 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: 684-689.
- 66 Luddington R. et al. The factor V R2 allele: risk of venous thromboembolism, factor V levels and resistance to activated protein C. Thromb Haemost 2000; 83: 204-208.
- 67 Margaglione 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: 907-911.
- 68 Margaglione M. et al. Inherited thrombophilic risk factors and venous thromboembolism: distinct role in peripheral deep venous thrombosis and pulmonary embolism. Chest 2000; 118: 1405-1411.
- 69 Margaglione M. et al. Factor XIII Val34Leu polymorphism and risk of deep vein thrombosis. Thromb Haemost 2000; 84: 1118-1119.
- 70 Martinelli I. et al. Low prevalence of factor V:Q506 in 41 patients with isolated pulmonary embolism. Thromb Haemost 1997; 77: 440-443.
- 71 Martinelli I. et al. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis. Arterioscler Thromb Vasc Biol 1999; 19: 700-703.
- 72 Martinelli I. et al. Low levels of protein Z and the risk of venous thromboembolism. J Thromb Haemost 2005; 03: 2817-2819.
- 73 Nizankowska-Mogilnicka E. et al. Genetic polymorphisms associated with acute pulmonary embolism and deep venous thrombosis. Eur Respir J 2003; 21: 25-30.
- 74 Oger E. et al. Interrelation of hyperhomocysteinemia and inherited risk factors for venous thromboembolism. Results from the E.D.I.TH. study: a hospitalbased case-control study. Thromb Res 2007; 120: 207-214.
- 75 Paciaroni K. et al. Prevalence of the C536T mutation in the tissue factor pathway inhibitor (TFPI) gene among patients with venous thromboembolic disease. Thromb Haemost 2001; 85: 938-939.
- 76 Philipp CS. et al. Deletion polymorphism in the angiotensin-converting enzyme gene as a thrombophilic risk factor after hip arthroplasty. Thromb Haemost 1998; 80: 869-873.
- 77 Quere I. et al. Red blood cell methylfolate and plasma homocysteine as risk factors for venous thromboembolism: a matched case-control study. Lancet 2002; 359: 747-752.
- 78 Ray JG. et al. 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; 02: 141-149.
- 79 Renner W. et al. 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: 35-39.
- 80 Renner W. et al. The PlA1/A2 polymorphism of platelet glycoprotein IIIa is not associated with deep venous thrombosis. Int Angiol 2001; 20: 148-151.
- 81 Ruiz-Arguelles GJ. 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.
- 82 Salazar-Sanchez L. et al. The FXIIIVal34Leu, common and risk factors of venous thrombosis in early middle-age Costa Rican patients. Cell Biochem Funct 2007; 25: 739-745.
- 83 Salomon O. et al. Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment. Arterioscler Thromb Vasc Biol 1999; 19: 511-518.
- 84 Schobess R. et al. 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. 03) S105-108.
- 85 Torres JD, et al. Inherited thrombophilia is associated with deep vein thrombosis in a Colombian population. Am J Hematol 2006; 81: 933-937.
- 86 Toydemir PB. et al. Effects of factor V gene G1691A, methylenetetrahydrofolate reductase gene C677T, and prothombin gene G20210A mutations on deep venous thrombogenesis in Behcet’s disease. J Rheumatol 2000; 27: 2849-2854.
- 87 Varela ML. et al. Major and potential prothrombotic genotypes in a cohort of patients with venous thromboembolism. Thromb Res 2001; 104: 317-324.
- 88 Vargas M. et al. 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: 39-41.
- 89 von Depka M. et al. Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism. Blood 2000; 96: 3364-3368.
- 90 von Depka M. et al. The deletion polymorphism in the angiotensin-converting enzyme gene is a moderate risk factor for venous thromboembolism. Thromb Haemost 2003; 89: 847-852.
- 91 Wells PS. et al. The ACE D/D genotype is protective against the development of idiopathic deep vein thrombosis and pulmonary embolism. Thromb Haemost 2003; 90: 829-834.
- 92 Garcia-Gala JM. et al. Factor V Leiden (R506Q) and risk of venous thromboembolism: a case-control study based on the Spanish population. Clin Genet 1997; 52: 206-210.
- 93 Corral J. et al. Antithrombin Cambridge II (A384S): an underestimated genetic risk factor for venous thrombosis. Blood 2007; 109: 4258-4263.
- 94 Alhenc-Gelas M. et al. The factor V gene A4070G mutation and the risk of venous thrombosis. Thromb Haemost 1999; 81: 193-197.
- 95 de Paula SA. et al. Increased Factor V Leiden frequency is associated with venous thrombotic events among young Brazilian patients. J Thromb Thrombolysis 2007; 24: 261-266.
- 96 de Visser MC. et al. The HR2 haplotype of factor V: effects on factor V levels, normalized activated protein C sensitivity ratios and the risk of venous thrombosis. Thromb Haemost 2000; 83: 577-582.
- 97 Folsom AR. et al. A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. Blood 2002; 99: 2720-2725.
- 98 Jadaon MM, Dashti AA. HR2 haplotype in Arab population and patients with venous thrombosis in Kuwait. J Thromb Haemost 2005; 03: 1467-1471.
- 99 Margaglione M. et al. FV HR2 haplotype as additional inherited risk factor for deep vein thrombosis in individuals with a high-risk profile. Thromb Haemost 2002; 87: 32-36.
- 100 Salazar-Sanchez L. et al. The FXIIIVal34Leu, common and risk factors of venous thrombosis in early middle-age Costa Rican patients. Cell Biochem Funct 2007; 25: 739-745.
- 101 Ayyildiz O. et al. Prothrombin G20210A gene mutation with LightCycler polymerase chain reaction in venous thrombosis and healthy population in the southeast of Turkey. Heart Vessels 2004; 19: 164-166.
- 102 Barcellona D. et al. Allele 4G of gene PAI-1 associated with prothrombin mutation G20210A increases the risk for venous thrombosis. Thromb Haemost 2003; 90: 1061-1064.
- 103 Chan DK. et al. A comparison of polymorphism in the 3’-untranslated region of the prothrombin gene between Chinese and Caucasians in Australia. Br J Haematol 2000; 111: 1253-1255.
- 104 Ferraresi P. et al. The heterozygous 20210 G/A prothrombin genotype is associated with early venous thrombosis in inherited thrombophilias and is not increased in frequency in artery disease. Arterioscler Thromb Vasc Biol 1997; 17: 2418-2422.
- 105 Hainaut P. et al. Hyperhomocysteinemia and venous thromboembolism: a risk factor more prevalent in the elderly and in idiopathic cases. Thromb Res 2002; 106: 121-125.
- 106 Kapur RK. et al. A prothrombin gene mutation is significantly associated with venous thrombosis. Arterioscler Thromb Vasc Biol 1997; 17: 2875-2879.
- 107 Legnani C. et al. Venous thromboembolism, oral contraceptives and high prothrombin levels. J Thromb Haemost 2003; 01: 112-117.
- 108 Leroyer C. et al. Prevalence of 20210 A allele of the prothrombin gene in venous thromboembolism patients. Thromb Haemost 1998; 80: 49-51.
- 109 Margaglione M. et al. Factor XIII Val34Leu polymorphism and risk of deep vein thrombosis. Thromb Haemost 2000; 84: 1118-1119.
- 110 Mansilha A. et al. The PORtromb Project: prothrombin G20210A mutation and venous thromboembolism in young people. Cardiovasc Surg 2002; 10: 45-48.
- 111 Margaglione M. et al. Increased risk for venous thrombosis in carriers of the prothrombin G-->A20210 gene variant. Ann Intern Med 1998; 129: 89-93.
- 112 Meyer M. et al. 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: 359-363.
- 113 Gonzalez Ordonez AJ. et al. Genetic polymorphism of methylenetetrahydrofolate reductase and venous thromboembolism: a case-control study. Haematologica 1999; 84: 190-191.
- 114 Poort SR. et al. 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: 3698-3703.
- 115 Reuner KH. et al. The mutation G20210-->A in the prothrombin gene is a strong risk factor for pulmonary embolism. Clin Chem 1998; 44: 1365-1366.
- 116 Souto JC. et al. The prothrombin 20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population. Thromb Haemost 1998; 80: 366-369.
- 117 Wells PS. et al. The factor XIII Val34Leu polymorphism: is it protective against idiopathic venous thromboembolism?. Blood Coagul Fibrinolysis 2006; 17: 533-538.
- 118 Zalavras C. et al. Lack of association between the C677T mutation in the 5,10-methylenetetrahydrofolate reductase gene and venous thromboembolism in Northwestern Greece. Int Angiol 2002; 21: 268-271.
- 119 Jun ZJ. et al. Prevalence of factor V Leiden and prothrombin G20210A mutations in Chinese patients with deep venous thrombosis and pulmonary embolism. Clin Lab Haematol 2006; 28: 111-116.
- 120 Ho CH. Prevalence of prothrombin 20210A allele and methylenetetrahydrofolate reductase C677T genetic mutations in the Chinese population. Ann Hematol 2000; 79: 239-242.
- 121 Lu Y. et al. Factor V gene G1691A mutation, prothrombin gene G20210A mutation, and MTHFR gene C677T mutation are not risk factors for pulmonary thromboembolism in Chinese population. Thromb Res 2002; 106: 7-12.
- 122 Akar N. et al. 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.
- 123 Arruda VR. et al. 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.
- 124 Balta G, Gurgey A. Methylenetetrahydrofolate reductase (MTHFR) C677T mutation in Turkish patients with thrombosis. Turk J Pediatr 1999; 41: 197-199.
- 125 Bezemer ID. et al. No association between the common MTHFR 677C->T polymorphism and venous thrombosis: results from the MEGA study. Arch Intern Med 2007; 167: 497-501.
- 126 Brown K. et al. 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.
- 127 Cattaneo M. 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:Q506). Arterioscler Thromb Vasc Biol 1997; 17: 1662-1666.
- 128 Couturaud F. et al. Methylenetetrahydrofolate reductase C677T genotype and venous thromboembolic disease. Respiration 2000; 67: 657-661.
- 129 de Franchis R. et al. 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.
- 130 De Stefano V. et al. Prevalence of the 677C to T mutation in the methylenetetrahydrofolate reductase gene in Italian patients with venous thrombotic disease. Thromb Haemost 1998; 79: 686-687.
- 131 Domagala TB. et al. Mutations C677T and A1298C of the 5,10-methylenetetrahydrofolate reductase gene and fasting plasma homocysteine levels are not associated with the increased risk of venous thromboembolic disease. Blood Coagul Fibrinolysis 2002; 13: 423-431.
- 132 Gemmati D. et al. 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.
- 133 Gemmati D. et al. Low folate levels and thermolabile methylenetetrahydrofolate reductase as primary determinant of mild hyperhomocystinemia in normal and thromboembolic subjects. Arterioscler Thromb Vasc Biol 1999; 19: 1761-1767.
- 134 Hanson NQ. et al. 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 2000; 47: 661-666.
- 135 Hessner MJ. et al. Prevalence of prothrombin G20210A, factor V G1691A (Leiden), and methylenetetrahydrofolate reductase (MTHFR) C677T in seven different populations determined by multiplex allelespecific PCR. Thromb Haemost 1999; 81: 733-738.
- 136 Isotalo PA, Donnelly JG. Prevalence of methylenetetrahydrofolate reductase mutations in patients with venous thrombosis. Mol Diagn 2000; 05: 59-66.
- 137 Kluijtmans LA. et al. Thermolabile methylenetetrahydrofolate reductase and factor V Leiden in the risk of deep-vein thrombosis. Thromb Haemost 1998; 79: 254-258.
- 138 Morelli VM. et al. 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: 271-275.
- 139 Ocal IT. et al. Risk of venous thrombosis in carriers of a common mutation in the homocysteine regulatory enzyme methylenetetrahydrofolate reductase. Mol Diagn 1997; 02: 61-68.
- 140 Quere I. et al. Homocysteine, 5,10-methylenetetrahydrofolate reductase and deep venous thrombosis. Survey of 120 patients in internal medicine. Rev Med Interne 1998; 19: 29-33.
- 141 Ray JG. et al. Common C677T polymorphism of the methylenetetrahydrofolate reductase gene and the risk of venous thromboembolism: meta-analysis of 31 studies. Pathophysiol Haemost Thromb 2002; 32: 51-58.
- 142 Salden A. et al. The C677T MTHFR variant and the risk of venous thrombosis. Br J Haematol 1997; 99: 472.
- 143 Salomon O. et al. Methionine synthase A2756G and methylenetetrahydrofolate reductase A1298C polymorphisms are not risk factors for idiopathic venous thromboembolism. Hematol J 2001; 02: 38-41.
- 144 Seinost G. et al. C677T mutation in the methylene tetrahydrofolate reductase gene as a risk factor for venous thrombotic disease in Austrian patients. Thromb Res 2000; 100: 405-407.
- 145 Tosetto A. et al. The VITA project: C677T mutation in the methylene-tetrahydrofolate reductase gene and risk of venous thromboembolism. Br J Haematol 1997; 97: 804-806.
- 146 Tsai AW. 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.
- 147 Angchaisuksiri P. et al. Prevalence of the C677T methylenetetra-hydrofolate reductase mutation in Thai patients with deep vein thrombosis. Acta Haematol 2000; 103: 191-196.
- 148 Guo C. et al. The C677T mutation in the methylenetetrahydrofolate reductase gene and its association with deep vein thrombophilia in Shandong Hans. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2002; 19: 295-297.
- 149 Hsu TS. et al. Importance of hyperhomocysteinemia as a risk factor for venous thromboembolism in a Taiwanese population. A case-control study. Thromb Res 2001; 102: 387-395.
- 150 Hsu LA. et al. 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.
- 151 Lin JS. et al. 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.
- 152 Qiu L. et al. Hyperhomocysteinemia and deepvein thrombosis. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2003; 25: 706-709.
- 153 Wang MT. et al. Relationship of plasma homocysteine and folic acid levels and 5,10-methylenetetrahydrofolate reductase gene mutation with venous thromboembolism. Zhonghua Nei Ke Za Zhi 2004; 43: 591-594.
- 154 Yu HD. et al. Study on the association of polymorphisms in homocysteine metabolism related enzymes with deep venous thrombosis. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2006; 23: 635-639.
- 155 Zheng YZ. et al. Prevalence of methylenetetrahydrofolate reductase C677T and its association with arterial and venous thrombosis in the Chinese population. Br J Haematol 2000; 109: 870-874.
- 156 Hanson NQ. et al. 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.
- 157 Zetterberg H. et al. No association between the MTHFR A1298C and transcobalamin C776G genetic polymorphisms and hyperhomocysteinemia in thrombotic disease. Thromb Res 2002; 108: 127-131.
- 158 Espinosa G. et al. Vascular involvement in Behcet’s disease: relation with thrombophilic factors, coagulation activation, and thrombomodulin. Am J Med 2002; 112: 37-43.
- 159 Folsom AR. et al. Prospective study of fibrinolytic markers and venous thromboembolism. J Clin Epidemiol 2003; 56: 598-603.
- 160 Grubic N. et al. A novel G/A and the 4G/5G polymorphism within the promoter of the plasminogen activator inhibitor-1 gene in patients with deep vein thrombosis. Thromb Res 1996; 84: 431-443.
- 161 Mansilha A. The association between the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor-1 gene and deep venous thrombosis in young people. Phlebology 2005; 20: 48.
- 162 Ridker PM. et al. Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of US men. Circulation 1997; 95: 59-62.
- 163 Sartori MT. et al. 4G/5G polymorphism of PAI-1 gene promoter and fibrinolytic capacity in patients with deep vein thrombosis. Thromb Haemost 1998; 80: 956-960.
- 164 Sartori MT. et al. The PAI-1 gene 4G/5G polymorphism and deep vein thrombosis in patients with inherited thrombophilia. Clin Appl Thromb Hemost 2003; 09: 299-307.
- 165 Segui R. et al. PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects. Br J Haematol 2000; 111: 122-128.
- 166 Stegnar M. et al. The 4G/5G sequence polymorphism in the promoter of plasminogen activator inhibitor-1 (PAI-1) gene: relationship to plasma PAI-1 level in venous thromboembolism. Thromb Haemost 1998; 79: 975-979.
- 167 Tassies D. et al. The 4G/5G polymorphism of the type 1 plasminogen activator inhibitor gene and thrombosis in patients with antiphospholipid syndrome. Arthritis Rheum 2000; 43: 2349-2358.
- 168 Visanji JM. et al. Influence of the -675 4G/5G dimorphism of the plasminogen activator inhibitor 1 promoter on thrombotic risk in patients with factor V Leiden. Br J Haematol 2000; 110: 135-138.
- 169 Ay C. et al. The angiotensin-converting enzyme insertion/deletion polymorphism and serum levels of angiotensin-converting enzyme in venous thromboembolism. Data from a case control study. Thromb Haemost 2007; 98: 777-782.
- 170 Buddingh EP. et al. The angiotensin-converting enzyme gene insertion/deletion polymorphism: insufficient evidence for a role in deep venous thrombosis. J Thromb Haemost 2005; 03: 403-404.
- 171 Ekim N. et al. The role of angiotensin-converting enzyme gene polymorphism in pulmonary thromboembolism. Thromb Haemost 2004; 92: 432-433.
- 172 Fatini C. et al. ACE DD genotype: an independent predisposition factor to venous thromboembolism. Eur J Clin Invest 2003; 33: 642-647.
- 173 Gonzalez Ordonez AJ. et al. Risk of venous thromboembolism associated with the insertion/deletion polymorphism in the angiotensin-converting enzyme gene. Blood Coagul Fibrinolysis 2000; 11: 485-490.
- 174 Hooper WC. et al. Relationship of venous thromboembolism and myocardial infarction with the reninangiotensin system in African-Americans. Am J Hematol 2002; 70: 1-8.
- 175 Salazar-Sanchez L. et al. The FXIIIVal34Leu, common and risk factors of venous thrombosis in early middle-age Costa Rican patients. Cell Biochem Funct 2007; 25: 739-745.
- 176 Salazar-Sanchez L. et al. The FXIIIVal34Leu, common and risk factors of venous thrombosis in early middle-age Costa Rican patients. Cell Biochem Funct 2007; 25: 739-745.
- 177 Catto AJ. et al. Association of a common polymorphism in the factor XIII gene with venous thrombosis. Blood 1999; 93: 906-908.
- 178 Corral J. et al. The FXIII Val34Leu polymorphism in venous and arterial thromboembolism. Haematologica 2000; 85: 293-297.
- 179 Cushman M. et al. Associations of the beta-fibrinogen Hae III and factor XIII Val34Leu gene variants with venous thrombosis. Thromb Res 2007; 121: 339-345.
- 180 Franco RF. et al. Factor XIII Val34Leu is a genetic factor involved in the etiology of venous thrombosis. Thromb Haemost 1999; 81: 676-679.
- 181 Le Gal G. et al. Fibrinogen Aalpha-Thr312Ala and factor XIII-A Val34Leu polymorphisms in idiopathic venous thromboembolism. Thromb Res 2007; 121: 333-338.
- 182 Renner W. et al. 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: 35-39.
- 183 Salazar-Sanchez L. et al. The FXIIIVal34Leu, common and risk factors of venous thrombosis in early middle-age Costa Rican patients. Cell Biochem Funct 2007; 25: 739-745.
- 184 Zidane M. et al. Frequency of the TAFI -438 G/A and factor XIIIA Val34Leu polymorphisms in patients with objectively proven pulmonary embolism. Thromb Haemost 2003; 90: 439-445.
- 185 Margaglione M. et al. Factor XIII Val34Leu polymorphism and risk of deep vein thrombosis. Thromb Haemost 2000; 84: 1118-1119.
- 186 Bykowska K. The factor XIII Val34Leu polymorphism and the risk of venous thromboembolism. Acta Haematol Polonica 2002; 33: 475.
- 187 Franco RF. et al. Factor XIII Val34Leu is a genetic factor involved in the etiology of venous thrombosis. Thromb Haemost 1999; 81: 676-679.
- 188 Cushman M. et al. Associations of the beta-fibrinogen Hae III and factor XIII Val34Leu gene variants with venous thrombosis. Thromb Res 2007; 121: 339-345.
- 189 Camilleri RS, Cohen H. No association between pulmonary embolism or deep vein thrombosis and the -455G/A beta-fibrinogen gene polymorphism. Blood Coagul Fibrinolysis 2005; 16: 193-198.
- 190 Renner W. et al. G-455A polymorphism of the fibrinogen beta gene and deep vein thrombosis. Eur J Clin Invest 2002; 32: 755-758.
- 191 Koster T. et al. Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms--the Leiden Thrombophilia Study (LETS). Thromb Haemost 1994; 71: 719-722.
- 192 Bozic M. et al. Fibrinogen polymorphisms TaqI, HaeIII and BclI are not associated with a higher risk of deep vein thrombosis. Pathophysiol Haemost Thromb 2003; 33: 164-169.
- 193 Rosendaal FR. et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998; 79: 706-708.
- 194 Rees DC. et al. World distribution of factor V Leiden. Lancet 1995; 346: 1133-1134.
- 195 Samani NJ. et al. Genomewide association analysis of coronary artery disease. N Engl J Med 2007; 357: 443-453.
- 196 Wallace C. et al. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am J Hum Genet 2008; 82: 139-149.
- 197 Easton DF. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 2007; 447: 1087-1093.
- 198 Matarin M. et al. A genome-wide genotyping study in patients with ischaemic stroke: initial analysis and data release. Lancet Neurol 2007; 06: 414-420.
- 199 Lunetta KL. Genetic association studies. Circulation 2008; 118: 96-101.
- 200 Ioannidis JP. et al. ‘Racial’ differences in genetic effects for complex diseases. Nat Genet 2004; 36: 1312-1318.
- 201 Pan Z. et al. Local literature bias in genetic epidemiology: an empirical evaluation of the Chinese literature. PLoS Med 2005; 02: e334.
- 202 Ridker PM. et al. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332: 912-917.
- 203 Koster T. et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-1506.
- 204 Goldhaber SZ. Pulmonary embolism. Lancet 2004; 363: 1295-1305.
- 205 Unal S. et al. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) levels and IL-6, TNF-polymorphisms in children with thrombosis. J Pediatr Hematol Oncol 2008; 30: 26-31.