Venous Thromboembolic Disease and the Prothrombin, Methylene Tetrahydrofolate Reductase and Factor V Genes

Martine Alhenc-Gelas; Emmanuel Arnaud; Viviane Nicaud; Marie-Laurence Aubry; Jean-Noël Fiessinger; Martine Aiach; Joseph Emmerich

doi:10.1055/s-0037-1614514

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1999; 81(04): 506-510
DOI: 10.1055/s-0037-1614514

Rapid Communication

Schattauer GmbH

Venous Thromboembolic Disease and the Prothrombin, Methylene Tetrahydrofolate Reductase and Factor V Genes

Authors

Martine Alhenc-Gelas

¹From Unité INSERM 428, Unité INSERM 258, and Centre Claude Bernard de Recherche sur les Maladies Vasculaires, Hôpital Broussais – AP-HP, Paris, France
Emmanuel Arnaud

¹From Unité INSERM 428, Unité INSERM 258, and Centre Claude Bernard de Recherche sur les Maladies Vasculaires, Hôpital Broussais – AP-HP, Paris, France
Viviane Nicaud

¹From Unité INSERM 428, Unité INSERM 258, and Centre Claude Bernard de Recherche sur les Maladies Vasculaires, Hôpital Broussais – AP-HP, Paris, France
Marie-Laurence Aubry

¹From Unité INSERM 428, Unité INSERM 258, and Centre Claude Bernard de Recherche sur les Maladies Vasculaires, Hôpital Broussais – AP-HP, Paris, France
Jean-Noël Fiessinger

¹From Unité INSERM 428, Unité INSERM 258, and Centre Claude Bernard de Recherche sur les Maladies Vasculaires, Hôpital Broussais – AP-HP, Paris, France
Martine Aiach

¹From Unité INSERM 428, Unité INSERM 258, and Centre Claude Bernard de Recherche sur les Maladies Vasculaires, Hôpital Broussais – AP-HP, Paris, France
Joseph Emmerich

¹From Unité INSERM 428, Unité INSERM 258, and Centre Claude Bernard de Recherche sur les Maladies Vasculaires, Hôpital Broussais – AP-HP, Paris, France

Abstract

Summary

The prevalence of the A20210 allele of the prothrombin (PT) gene and the T677 allele of the methylene tetrahydrofolate reductase (MTHFR) gene was determined in 205 patients with venous thromboembolism (VTE) and in 398 healthy subjects of similar age and sex distribution. We also determined the frequency of these two candidate risk alleles in subjects carrying the factor V (FV) Q506 allele, to identify a possible interaction. Forty patients (19.5%) and 14 control subjects (3.5%) were heterozygous for the FV R506Q mutation. Twenty-one patients (10.2%) and 11 controls (2.8%) were heterozygous for the PT A20210 allele (odds ratio (OR) 4.02, 95% confidence interval (CI): 1.90-8.50, p <0.001). This confirmed that the PT A20210 allele was a risk factor for VTE in our population. Among the FV Q506 allele carriers, 9 patients (22.5%) and no control also had the PT gene G20210A mutation. The absence of the combined abnormality in the control group made it impossible to calculate the relevant ORs but the lower bound of the 95% CI was 3.94, suggesting that individuals bearing the two mutations have a higher risk than those with a single mutation. Twenty-six patients (12.7%) and 49 controls (12.3%) were homozygous for the MTHFR T677 allele (OR 1.04, 95% CI: 0.62-1.72, not significant). Four patients and 1 control were also heterozygous for the FV R506Q mutation (OR 9.33, 95% CI: 1.03-84.23). However, the ORs for carriers of the FV R506Q mutation were not significantly influenced by MTHFR gene C677T homozygosity.

Full Text

References

References
1 Dahlbäck B. Resistance to activated protein C caused by the factor V R506Q mutation is a common risk factor for venous thrombosis. Thromb Haemost 1997; 78: 483-8.
2 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation of the 3’ untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
3 Boers GHJ. Hyperhomocysteinemia as a risk factor for arterial and venous disease. A review of evidence and relevance. Thromb Haemost 1997; 78: 520-2.
4 Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluijtmans LAJ, van den Heuvel LP, Rozen R. A candidate gene risk factor for vascular disease: a common mutation in methylene tetrahydrofolate reductase. Nature Genet 1995; 10: 111-3.
5 Rozen R. Genetic predisposition to hyperhomocysteinemia: deficiency of methylene tetrahydrofolate reductase (MTHFR). Thromb Haemost 1997; 78: 523-6.
6 Working group on haemostasis of the Société Française de Biologie Clinique: Comparison of a standardized procedure with current laboratory practices for the detection of lupus anticoagulant in France Thromb Haemost 1993 70. 781-6.
7 Gandrille S, Alhenc-Gelas M, Aiach M. A rapid screening method for the factor V Arg 506 Gln mutation. Blood Coag Fibrinol 1995; 6: 245-9.
8 Ridker PM, Miletich JP, Stampfer MJ, Goldhaber SZ, Lindpaintner K, Hennekens CH. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. Circulation 1995; 92: 2800-2.
9 Simioni P, Prandoni P, Lensing AW, Scudeller A, Sardella C, Prins MH, Villalta S, Dazzi F, Girolami A. The risk of recurrent venous thromboembolism in patients with an Arg 506 Gln mutation in the gene for factor V (factor V Leiden). New Engl J Med 1997; 336: 399-403.
10 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. Brit J Haematol 1997; 98: 907-9.
11 Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CRM. The prothrombin gene G20210A variant: prevalence in a UK anticoagulant clinic population. Brit J Haematol 1997; 98: 353-5.
12 Hillarp A, Zöller B, Svensson PJ, Dahlbäck B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost 1997; 78: 990-2.
13 Leroyer C, Mercier B, Oger E, Chenu E, Abgrall JF, Ferec C, Mottier D. Prevalence of 20210 A allele of the prothrombin gene in venous thromboembolism patients. Thromb Haemost 1998; 80: 49-51.
14 Arruda VR, Annichino-Bizzacchi JM, Goncalves MS, Costa FF. Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease. Thromb Haemost 1997; 78: 1430-3.
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. Brit J Haematol 1997; 97: 804-6.
16 Cattaneo M, Tsai MY, Bucciarelli P, Taioli E, Zighetti ML, Bignell M, Mannucci PM. A common mutation in the methylene tetrahydrofolate reductase gene (C677T) increases the risk for deep-vein thrombosis in patients with mutant factor V (factor V:Q506). Arterioscler Thromb Vasc Biol 1997; 17: 1662-6.
17 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: 907-11.
18 Salden A, Keeney S, Hay CRM, Cumming AM. The C677T MTHFR variant and the risk of venous thrombosis. Brit J Haematol 1997; 99: 464-72.
19 Kluijtmans LAJ, den Heijer M, Reitsma PH, Heil SG, Blom HJ, Rosendaal FR. Thermolabile methylenetetrahydrofolatereductase and factor V Leiden in the risk of deep-vein thrombosis. Thromb Haemost 1998; 79: 254-8.
20 Arruda VR, von Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF. The mutation Ala677 to Val in the methylene tetrahydrofolate reducatase gene: a risk factor for arterial disease and venous thrombosis. Thromb Haemost 1997; 77: 818-21.
21 Koeleman BPC, Reitsma PH, Allaart RC, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood 1994; 84: 1031-5.
22 Zöller B, Berntsdotter A, Garcia de Frutos P, Dahlbäck B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995; 85: 3518-23.
23 Gandrille S, Greengard JS, Alhenc-Gelas M, Juhan-Vague I, Abgrall JF, Jude B, Griffin JH, Aiach M. Incidence of activated protein C resistance caused by the Arg 506 Gln mutation in factor V in 113 unrelated symptomatic protein C deficient patients. Blood 1995; 86: 219-24.
24 Hallam PJ, Millar DS, Krawczak M, Kakkar VV, Cooper DN. Population differences in the frequency of the factor V Leiden variant among people with clinically symptomatic protein C deficiency. J Med Genet 1995; 32: 543-5.
25 Makris M, Preston FE, Beauchamp NJ, Cooper PC, Daly ME, Hampton KK, Bayliss P, Peake IR, Miller GJ. Co-inheritance of the 20210A allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia. Thromb Haemost 1997; 78: 1426-9.
26 Alhenc-Gelas M, Emmerich J, Fiessinger JN, Aiach M, Le Cam-Duchez V, Frebourg T, Borg JY. The A20210 allele of the prothrombin gene is not frequently associated with the factor V Arg 506 to Gln mutation in thrombophilic families. Blood 1997; 90: 1711
27 Zöller B, Svensson PJ, Dahlbäck B, Hillarp A. The A20210 allele of the prothrombin gene is frequently associated with the factor V Arg 506 to Gln mutation but not with protein S deficicency in thrombophilic families. Blood 1998; 91: 2210-1.
28 Ehrenforth S, Ludwig G, Klinke S, Krause M, Scharrer I. The prothrombin 20210A allele is frequently coinherited in young carriers of the factor V Arg 506 to Gln mutation with venous thrombophilia. Blood 1998; 91: 2209-10.
29 Mandel H, Brenner B, Berant M, Rosenberg N, Lanir N, Jakobs C, Fowler B, Seligsohn U. Coexistence of hereditary homocystinuria and factor V Leiden. Effect on thrombosis. New Engl J Med 1996; 334: 763-8.