Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease - The result of a meta-analysis

Background-The results of retrospective and prospective case-control studie s have clearly established that mild elevations of the plasma homocysteine level are associated with increased risk of coronary, cerebral, and periphe ral vascular disease. Recently, a mutation (677C-->T) was identified in the methylenetetrahydrofolate reductase (MTHFR) gene that results in reduced f olate-dependent enzyme activity and reduced remethylation of homocysteine t o methionine. Mutant homozygotes (TT genotype) constitute approximate to 12 % of the white population and frequently have mildly elevated circulating h omocysteine, Therefore, it seems likely that they would also be at increase d risk of vascular disease. A number of studies have investigated this duri ng the past 3 years, and the present article evaluates the results in a met a-analysis, Methods and Results-We identified 13 studies in which there were measuremen ts of plasma homocysteine in relation to the 3 genotypes (TT: CT, and CC) a nd 23 case-control studies comprising 5869 genotyped cardiovascular disease patients (mostly coronary artery disease) and 6644 genotyped control subje cts. Those bearing the TT genotype had plasma homocysteine concentrations 2 .6 mu mol/L (25%) higher than those with the CC genotype, However, there wa s no difference between patients and control subjects either in the frequen cy of mutant alleles (T) (34.3% versus 33.8%) or the TT genotype (11.9% ver sus 11.7%). In the analysis of the 23 studies, the relative risk (OR) of va scular 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 c ause of mild hyperhomocysteinemia, the mutation does not increase cardiovas cular risk. Our findings suggest that the mild hyperhomocysteinemia found f requently in vascular disease patients is not causally related to the patho genesis of the vascular disease.