title: Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis.
abstract: BACKGROUND
  The results of retrospective and prospective case-control studies have clearly established that mild elevations of the plasma homocysteine level are associated with increased risk of coronary, cerebral, and peripheral vascular disease. Recently, a mutation (677C-->T) was identified in the methylenetetrahydrofolate reductase (MTHFR) gene that results in reduced folate-dependent enzyme activity and reduced remethylation of homocysteine to methionine. Mutant homozygotes (TT genotype) constitute approximately 12% of the white population and frequently have mildly elevated circulating homocysteine. Therefore, it seems likely that they would also be at increased risk of vascular disease. A number of studies have investigated this during the past 3 years, and the present article evaluates the results in a meta-analysis.
  
  
  RESULTS
  We identified 13 studies in which there were measurements of plasma homocysteine in relation to the 3 genotypes (TT, CT, and CC) and 23 case-control studies comprising 5869 genotyped cardiovascular disease patients (mostly coronary artery disease) and 6644 genotyped control subjects. Those bearing the TT genotype had plasma homocysteine concentrations 2.6 micromol/L (25%) higher than those with the CC genotype. However, there was no difference between patients and control subjects either in the frequency of mutant alleles (T) (34.3% versus 33.8%) or the TT genotype (11.9% versus 11.7%). In the analysis of the 23 studies, the relative risk (OR) of vascular disease associated with the TT genotype was 1.12 (95% CI, 0.92 to 1.37).
  
  
  CONCLUSIONS
  We conclude that although the C677T/MTHFR mutation is a major cause of mild hyperhomocysteinemia, the mutation does not increase cardiovascular risk. Our findings suggest that the mild hyperhomocysteinemia found frequently in vascular disease patients is not causally related to the pathogenesis of the vascular disease.
authors.affiliation: Department of Medicine, County Hospital, Kalmar, Sweden. lars.brattstrom@alinks.se
authors.forename: L
authors.initials: L
authors.lastname: Brattström
authors.forename: D E
authors.initials: DE
authors.lastname: Wilcken
authors.forename: J
authors.initials: J
authors.lastname: Ohrvik
authors.forename: L
authors.initials: L
authors.lastname: Brudin
mesh_terms: D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D009154:Mutation; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D012307:Risk Factors
chemical_list: D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)