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Meta-analysis of MTHFR 677C→ T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?

BMJ 2005; 331 doi: (Published 03 November 2005) Cite this as: BMJ 2005;331:1053
  1. Sarah J Lewis (s.j.lewis{at}, lecturer in genetic epidemiology1,
  2. Shah Ebrahim, professor of epidemiology of ageing1,
  3. George Davey Smith, professor of clinical epidemiology1
  1. 1 Department of Social Medicine, University of Bristol, Bristol BS8 2PR
  1. Correspondence to: S J Lewis
  • Accepted 19 August 2005


Objectives To investigate the association between the MTHFR 677C→ T polymorphism and coronary heart disease, assessing small study bias and heterogeneity between studies.

Data sources Medline and Embase citation searches between January 2001 and August 2004; no language restrictions.

Study selection Case-control and prospective studies of association between MTHFR 677C→ T variant and myocardial infarction, coronary artery occlusion, or both; 80 studies were included.

Data extraction Data on genotype frequency and mean homocysteine concentrations by genotype were extracted. Odds ratios were calculated for TT genotype versus CC genotype. Heterogeneity was explored, with stratification by geographical region of the study samples, and meta-regression by difference in mean serum homocysteine concentrations (CC minus TT genotypes) was carried out.

Results 26 000 cases and 31 183 controls were included. An overall random effects odds ratio of 1.14 (95% confidence intervals 1.05 to 1.24) was found for TT versus CC genotype. There was strong evidence of heterogeneity (P < 0.001, I2 = 38.4%), which largely disappeared after stratification by geographical region. Odds ratios in Europe, Australia, and North America attenuated towards the null, unlike those in the Middle East and Asia.

Conclusions No strong evidence exists to support an association of the MTHFR 677 C→T polymorphism and coronary heart disease in Europe, North America, or Australia. Geographical variability may be due to higher folate intake in North America and Europe or to publication bias. The conclusion drawn from previous meta-analyses that folic acid, through lowering homocysteine, has a role in prevention of cardiovascular disease is in some doubt.


  • Embedded ImageReferences to included studies are on

  • Contributors All authors contributed to the literature search, selection of studies, data extraction, statistical analysis, interpretation of results, and writing the paper. SJL coordinated the writing of the paper and is the guarantor.

  • Funding All researchers hold permanent positions at the University of Bristol.

  • Competing interests None declared.

  • Ethical approval Not needed.

  • Accepted 19 August 2005
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