Elsevier

American Heart Journal

Volume 146, Issue 6, December 2003, Pages 948-957
American Heart Journal

Curriculum in cardiology
Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies

https://doi.org/10.1016/S0002-8703(03)00519-2Get rights and content

Abstract

Background

The association between the inherited gene mutations of factor V, prothrombin, and homocysteine metabolism and venous thromboembolic events is accepted widely; however, their influence on the arterial circulatory system remains controversial.

Methods

We performed a MEDLINE search to identify published case-control and cohort studies correlating the factor V Leiden, prothrombin (PT) G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T (TT genotype) mutations with myocardial infarction, ischemic stroke, or peripheral vascular disease. Studies were included only when they adhered to specific diagnostic criteria for ischemic events and met the published methodological criteria. Odds ratios (ORs) with accompanying 95% CIs were calculated for each mutation and clinical end points with a random-effects model (DerSimonian and Laird method).

Results

The association between inherited gene mutations and arterial ischemic events was modest: factor V Leiden mutation (OR, 1.21; 95% CI, 0.99–1.49), PT G20210A mutation (OR, 1.32; 95% CI, 1.03–1.69), and MTHFR TT mutation (OR, 1.20; 95% CI, 1.02–1.41). Subgroup analyses of younger patients (<55 years old) and of women revealed slightly stronger associations overall.

Conclusions

Genetic abnormalities specific to factor V, prothrombin ,and homocysteine metabolism increase the risk for myocardial infarction and ischemic stroke, particularly among younger patients and women. Because the overall association is only modest, screening studies should be limited to carefully selected patient populations. The individual propensity for arterial and venous thrombosis is likely influenced by differing local mechanisms, systemic mechanisms, or both.

Section snippets

Literature search

Using a systematic search of MEDLINE electronic database between 1990 and 2002, we identified all studies correlating the factor V Leiden, prothrombin G20210A, or methylenetetrahydrofolate reductase (MTHFR) C677T gene mutations with MI, ischemic stroke, or PVD. Terms used for the search were Medical Subject Heading (MeSH) terms and the text words “myocardial infarction,” “ischemic stroke,” or “peripheral vascular disease,” combined with “factor V,” “prothrombin,” “methylenetetrahydrofolate

Excluded studies

We excluded 1 study10 because it used a duplicate set of patients in separate studies.66 Four studies were excluded because we could not ascertain the absence of prior ischemic events in control subjects (inadequate control delineation).11, 12, 13, 14 Two studies were excluded because of an inadequate control population.15, 16 We eliminated 13 additional studies from consideration17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 because adequate definitions or diagnostic criteria for cited

Discussion

In our meta-analysis of >17,000 patients with coronary, cerebrovascular, or peripheral vascular events, several observations were made. First, the 3 common gene anomalies associated with venous thromboembolism (factor V Leiden mutation, prothrombin G20210A mutation, and MTHFR C677T mutation) increase the risk of arterial thrombotic events to comparatively modest degree. Second, the association is more robust in patients <55 years old and in women (for factor V Leiden and PT G20210A mutations).

Acknowledgements

We thank Dr Joseph Lau for his expert technical assistance with statistical analyses and data preparation; those who provided information about their past publications (Drs V. Arruda, A.J. Catto, V. de Stefano, J. Eikelboom, J. Genest, J. Holm, C. Irvine, R. Junker, W. Lalouschek, P.M. Manucci, G. Marchetti, M. Margaglione, A. Pezzini, W. Prohaska, W. Renner, P. Ridker, N. Samani, T. Tatlisumak, X.L. Wang, S. Whitehead, and D. Wilcken); and Robert Goldberg, PhD, and Frederick Spencer, MD, for

References (97)

  • J. Anderson et al.

    A mutation in the methylenetetrahydrofolate reductase gene is not associated with increased risk for coronary artery disease or myocardial infarction

    J Am Coll Cardiol

    (1997)
  • T.K. Makris et al.

    Resistance to activated protein C and FV Leiden mutations in patients with a history of acute myocardial infarction or primary hypertension

    Am J Hypertens

    (2000)
  • D. Ardissino et al.

    Prothrombotic genetic risk factors in young survivors of myocardial infarction

    Blood

    (1999)
  • V. de Stefano et al.

    Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients

    Blood

    (1998)
  • W. Lalouschek et al.

    C677T MTHFR mutation and factor V Leiden mutation in patients with TIA/minor strokea case-control study

    Thromb Res

    (1999)
  • D. Girelli et al.

    Methylenetetrahydrofolate reductase C677T mutation, plasma homocysteine, and folate in subjects from northern Italy with or without angiographically documented severe coronary atherosclerotic diseaseevidence for an important genetic-environmental interaction

    Blood

    (1998)
  • R. Brugada et al.

    A common mutation in methylenetetrahydrofolate reductase gene is not a major risk of coronary artery disease or myocardial infarction

    Atherosclerosis

    (1997)
  • K. Juul et al.

    Factor V Leidenthe Copenhagen City Heart Study and 2 meta-analyses

    Blood

    (2002)
  • N. Fernandez-Arcas et al.

    The genotype interactions of methylenetetrahydrofolate reductase and renin-angiotensin system genes are associated with myocardial infarction

    Atherosclerosis

    (1999)
  • U. Nowak-Gottl et al.

    Lipoprotein(a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischaemic stroke in childhood

    Blood

    (1999)
  • J.P. Vandenbroucke et al.

    Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden mutation

    Lancet

    (1994)
  • E. Tremoli et al.

    Tissue factor in atherosclerosis

    Atherosclerosis

    (1999)
  • G. Cella et al.

    Tissue factor pathway inhibitor levels in patients with homocysteinuria

    Thromb Res

    (2000)
  • J.K. French et al.

    Potential thrombophilic mutations/polymorphism in patients with no flow-limiting stenosis after myocardial infarction

    Am Heart J

    (2003)
  • R.M. Bertina et al.

    Mutations in blood coagulation factor V associated with resistance to activated protein C

    Nature

    (1994)
  • B. Dahlback et al.

    Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C

    Proc Natl Acad Sci U S A

    (1993)
  • P.J. Svensson et al.

    Resistance to activated protein C as a basis for venous thrombosis

    N Engl J Med

    (1994)
  • J.G. Ray

    Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease

    Arch Intern Med

    (1998)
  • S.T. Bogardus et al.

    Clinical epidemiological quality in molecular genetic researchthe need for methodological standards

    JAMA

    (1999)
  • J. Little et al.

    Reporting appraising and integrating data on genotype prevalence and gene-disease associations

    Am J Epidemiol

    (2002)
  • M. Egger et al.

    Meta-analysis software

    Brit Med J

    (1998)
  • H. Morita et al.

    Polymorphism of the methionine synthase geneassociation with homocysteine metabolism and late-onset vascular diseases in the Japanese population

    Arterioscler Thromb Vasc Biol

    (1999)
  • F. Rassoul et al.

    Plasma homocysteine and lipoprotein profile in patients with peripheral arterial occlusive disease

    Angiology

    (2000)
  • J. Iniesta et al.

    Factor-V (Arg506→Gln) mutation in ischemic cerebrovascular disease

    Haemostasis

    (1997)
  • A. Catto et al.

    Factor V Leiden gene mutation and thrombin generation in relation to the development of acute stroke

    Arterioscler Thromb Vasc Biol

    (1995)
  • F. Araujo et al.

    Genetic risk factors in acute coronary disease

    Haemostasis

    (1999)
  • V. Arruda et al.

    Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease

    Thromb Haemost

    (1997)
  • V.R. Arruda et al.

    Prevalence of the prothrombin gene variant 20210G→A among patients with myocardial infarction

    Cardiovasc Res

    (1998)
  • Y. Wu et al.

    Methylenetetrahydrofolate reductase gene polymorphism and ischemic strokesex difference in Japanese

    Kobe J Med Sci

    (2001)
  • A. D'Angelo et al.

    The role of vitamin B12 in fasting hyperhomocysteinemia and its interaction with the homozygous C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene

    Thromb Haemost

    (2000)
  • R.D. Press et al.

    Ischemic stroke in the elderlyrole of the common factor V Leiden mutation causing resistance to activated protein C

    Stroke

    (1996)
  • X.L. Wang et al.

    Polymorphisms of factor V, factor VII, and fibrinogen genesrelevance to severity of coronary artery disease

    Arterioscler Thromb Vasc Biol

    (1997)
  • M. Redondo et al.

    Coagulation factors II, V, VII, and X, prothrombin gene 20210G→A transition, and factor V Leiden in coronary artery disease

    Arterioscler Thromb Vasc Biol

    (1999)
  • J. Holm et al.

    Prevalence of factor V gene mutation amongst myocardial infarction patients and healthy controls is higher in Sweden than in other countries

    J Intern Med

    (1996)
  • J. Corral et al.

    The venous thrombosis risk factor 20210A allele of prothrombin gene is not a major risk factor for arterial thrombotic disease

    Br J Haematol

    (1997)
  • W. Prohaska et al.

    Evidence against heterozygous coagulation factor V 1691 G→A mutation with resistance to activated protein C being a risk factor for coronary artery disease and myocardial infarction

    J Mol Med

    (1995)
  • P.M. Ridker et al.

    G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men

    Circulation

    (1999)
  • S.A. Croft et al.

    The prothrombin 20210A allele and its association with myocardial infarction

    Thromb Haemost

    (1999)
  • Cited by (0)

    View full text