MOLECULAR-GENETIC ANALYSIS IN MILD HYPERHOMOCYSTEINEMIA - A COMMON MUTATION IN THE METHYLENETETRAHYDROFOLATE REDUCTASE GENE IS A GENETIC RISK FACTOR FOR CARDIOVASCULAR-DISEASE

Mild hyperhomocysteinemia is an established risk factor for cardiovasc ular disease. Genetic aberrations in the cystathionine beta-synthase ( CBS) and methylenetetrahydrofolate reductase (MTHFR) genes may account for reduced enzyme activities and elevated plasma homocysteine levels . In 15 unrelated Dutch patients with homozygous CBS deficiency, we ob served the 833T-->C (I278T) mutation in 50% of the alleles. Very recen tly, we identified a common mutation (677C-->T; A-->V) in the MTHFR ge ne, which, in homozygous state, is responsible for the thermolabile ph enotype and which is associated with decreased specific MTHFR activity and elevated homocysteine levels. We screened 60 cardiovascular patie nts and 111 controls for these two mutations, to determine whether the se mutations are risk factors for premature cardiovascular disease. He terozygosity for the 833T-->C mutation in the CBS gene was observed in one individual of the control group but was absent in patients with p remature cardiovascular disease. Homozygosity for the 677C-->T mutatio n in the MTHFR gene was found in 9 (15%) of 60 cardiovascular patients and in only 6 (similar to 5%) of 111 control individuals (odds ratio 3.1 [95% confidence interval 1.0-9.2]). Because of both the high preva lence of the 833T-->C mutation among homozygotes for CBS deficiency an d its absence in 60 cardiovascular patients, we may conclude that hete rozygosity for CBS deficiency does not appear to be involved in premat ure cardiovascular disease. However, a frequent homozygous mutation in the MTHFR gene is associated with a threefold increase in risk for pr emature cardiovascular disease.