THERMOLABILE METHYLENETETRAHYDROFOLATE REDUCTASE IN CORONARY-ARTERY DISEASE

Background Hyperhomocysteinemia, an independent and graded risk factor for coronary artery disease (CAD), may result from both environmental and hereditary factors. Methylenetetrahydrofolate reductase (MTHFR) c atalyzes the conversion of methylenetetrahydrofolate to methyltetrahyd rofolate, the methyl donor in the remethylation of homocysteine to met hionine. A 677C-->T mutation in the MTHFR gene has been associated wit h elevated homocysteine concentrations in homozygous (+/+) individuals . Methods and Results We assessed the frequency of this common mutatio n in 735 CAD patients from the Regression Growth Evaluation Statin Stu dy (REGRESS), a lipid-lowering coronary-regression trial, and in 1250 population-based control subjects. Furthermore, the association betwee n the mutation and serum homocysteine concentrations was studied. The frequency of the homozygous (+/+) mutation was 9.5% among patients ver sus 8.5% among control subjects, resulting in an odds ratio of 1.21 (9 5% confidence interval [CI], 0.87 to 1.68), relative to the (-/-) geno type. Homocysteine concentrations were significantly elevated in both (+/+) and (+/-) individuals compared with (-/-) individuals (median ho mocysteine levels, 15.4, 13.4, and 12.6 mu mol/L, for (+/+), (+/-), an d (-/-) individuals, respectively). For a summary estimation of the ri sk of the (+/+) genotype for CAD, we performed a meta-analysis on 8 di fferent case-control studies on thermolabile MTHFR in CAD. In the meta -analysis, the homozygous (+/+) genotype was present in 299 of 2476 pa tients (12.1%) and in 257 (10.4%) of 2481 control subjects, resulting in a significant odds ratio of 1.22 (95% CI, 1.01 to 1.47) relative to the (-/-) genotype. Conclusions Both the homozygous (+/+) and heteroz ygous (+/-) genotype result in elevated homocysteine concentrations. F rom our meta-analysis, we conclude that the homozygous (+/+) genotype is a modest but significant risk factor for CAD.