GENETIC-POLYMORPHISM OF 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) AS A RISK FACTOR FOR CORONARY-ARTERY DISEASE

Background Epidemiological studies have identified hyperhomocyst(e)ine mia as an independent risk factor for coronary artery disease (CAD). R ecently, the alanine/valine (AN) polymorphism of the 5,10-methylenetet rahydrofolate reductase (MTHFR) gene, one of the key enzymes catalyzin g remethylation of homocysteine, has been reported. The VV genotype co rrelates with increased plasma homocyst(e)ine levels as a result of th e reduced activity and increased thermolability of this enzyme. In thi s study, we examined the distribution of the MTHFR genotypes in Japane se men and the association between the VV genotype and CAD. Methods an d Results The diagnoses of CAD of all the studied patients were confir med by coronary angiography. The MTHFR genotype was analyzed by PCR fo llowed by HinfI digestion. In 778 healthy male subjects, the frequency of the V allele was 0.33, comparable to that in a French Canadian pop ulation. In 362 patients with CAD, the VV genotype was significantly m ore frequent than in control subjects (16% versus 10%, P=.0067). The a ssociation of the VV genotype with CAD was further increased in patien ts with greater than or equal to 99% stenotic lesions (18%, P=.0010), whereas no significant association with the VV genotype was observed i n patients without a greater than or equal to 99% stenosis. When the g enotype frequency was compared among patients with different numbers o f stenotic coronary arteries, the frequency of the VV genotype was sig nificantly higher in patients with triple-vessel disease (26%) than in patients with single- or double-vessel disease (15% and 14%, respecti vely). Conclusions The VV genotype of MTHFR was also common in the Jap anese population and was significantly associated with CAD. The freque ncy of this genotype in particular was correlated with the severity of disease. The VV genotype associated with a predisposition to increase d plasma homocyst(e)ine levels may represent a genetic risk factor for CAD.