title: Homocysteine and stroke: evidence on a causal link from mendelian randomisation.
abstract: BACKGROUND
  Individuals homozygous for the T allele of the MTHFR C677T polymorphism have higher plasma homocysteine concentrations (the phenotype) than those with the CC genotype, which, if pathogenetic, should put them at increased risk of stroke. Since this polymorphism is distributed randomly during gamete formation, its association with stroke should not be biased or confounded. We investigated consistency between the expected odds ratio for stroke among TT homozygotes, extrapolated from genotype-phenotype and phenotype-disease studies, and the observed odds ratio from a meta-analysis of genotype-disease association studies.
  
  
  METHODS
  We searched MEDLINE and EMBASE up to June, 2003, for all relevant studies on the association between homocysteine concentration and the MTHFR polymorphism, and until December, 2003, for those on the association between the polymorphism and the risk of stroke. Pooled odds ratios and 95% CI were calculated by random-effects and fixed-effects models. Consistency between expected and observed odds ratios was assessed by interaction test.
  
  
  RESULTS
  111 studies met the selection criteria. Among 15635 people without cardiovascular disease, the weighted mean difference in homocysteine concentration between TT and CC homozygotes was 1.93 micromol/L (95% CI 1.38 to 2.47). The expected odds ratio for stroke corresponding to this difference based on previous observational studies was 1.20 (1.10 to 1.31). In our genetic meta-analysis (n=13928) the odds ratio for stroke was 1.26 (1.14 to 1.40) for TT versus CC homozygotes, similar to the expected odds ratio (p=0.29). Consistency between the odds ratios was preserved in analyses by age-group, ethnic background, and geographical location.
  
  
  CONCLUSIONS
  The observed increase in risk of stroke among individuals homozygous for the MTHFR T allele is close to that predicted from the differences in homocysteine concentration conferred by this variant. This concordance is consistent with a causal relation between homocysteine concentration and stroke.
authors.affiliation: Centre for Clinical Pharmacology, Department of Medicine, British Heart Foundation Laboratories, Royal Free and University College Medical School, University College London, Rayne Building, 5 University Street, London WC1E 6 JJ, UK.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Casas
authors.forename: Leonelo E
authors.initials: LE
authors.lastname: Bautista
authors.forename: Liam
authors.initials: L
authors.lastname: Smeeth
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
mesh_terms: D015984:Causality; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006710:Homocysteine / Q000097:blood*; D006720:Homozygote; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic; D012307:Risk Factors; D020521:Stroke / Q000097:blood* / Q000235:genetics*
chemical_list: D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)