title: 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?
abstract: OBJECTIVE
  To investigate the association between the MTHFR 677C-->T polymorphism and coronary heart disease, assessing small study bias and heterogeneity between studies.
  
  
  METHODS
  Medline and Embase citation searches between January 2001 and August 2004; no language restrictions.
  
  
  METHODS
  Case-control and prospective studies of association between MTHFR 677C-->T variant and myocardial infarction, coronary artery occlusion, or both; 80 studies were included.
  
  
  METHODS
  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.
authors.affiliation: Department of Social Medicine, University of Bristol, Bristol BS8 2PR. s.j.lewis@bristol.ac.uk
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lewis
authors.forename: Shah
authors.initials: S
authors.lastname: Ebrahim
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
mesh_terms: D016022:Case-Control Studies; D023921:Coronary Stenosis / Q000235:genetics* / Q000517:prevention & control; D005492:Folic Acid / Q000502:physiology*; D005838:Genotype; D014943:Global Health; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D009203:Myocardial Infarction / Q000235:genetics* / Q000517:prevention & control; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012111:Residence Characteristics
chemical_list: D006710:Homocysteine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)