PLASMA HOMOCYSTEINE AS A RISK FACTOR FOR VASCULAR-DISEASE - THE EUROPEAN CONCERTED ACTION PROJECT

Context.-Elevated plasma homocysteine is a known risk factor for ather osclerotic vascular disease, but the strength of the relationship and the interaction of plasma homocysteine with other risk factors are unc lear. Objective.-To establish the magnitude of the vascular disease ri sk associated with an increased plasma homocysteine level and to exami ne interaction effects between elevated plasma homocysteine level and conventional risk factors. Design.-Case-control study. Setting.-Ninete en centers in 9 European countries. Patients.-A total of 750 cases of atherosclerotic vascular disease (cardiac, cerebral, and peripheral) a nd 800 controls of both sexes younger than 60 years.Measurements.-Plas ma total homocysteine was measured while subjects were fasting and aft er a standardized methionine-loading test, which involves the administ ration of 100 mg of methionine per kilogram and stresses the metabolic pathway responsible for the irreversible degradation of homocysteine. Plasma cobalamin, pyridoxal 5'-phosphate, red blood cell folate, seru m cholesterol, smoking, and blood pressure were also measured. Results .-The relative risk for vascular disease in the top fifth compared wit h the bottom four fifths of the control fasting total homocysteine dis tribution was 2.2 (95% confidence interval, 1.6-2.9). Methionine loadi ng identified an additional 27% of at-risk cases. A dose-response effe ct was noted between total homocysteine level and risk. The risk was s imilar to and independent of that of other risk factors, but interacti on effects were noted between homocysteine and these risk factors; for both sexes combined, an increased fasting homocysteine level showed a more than multiplicative effect on risk in smokers and in hypertensiv e subjects. Red blood cell folate, cobalamin, and pyridoxal phosphate, all of which modulate homocysteine metabolism, were inversely related to total homocysteine levels. Compared with nonusers of vitamin suppl ements, the small number of subjects taking such vitamins appeared to have a substantially lower risk of vascular disease, a proportion of w hich was attributable to lower plasma homocysteine levels. Conclusions .-An increased plasma total homocysteine level confers an independent risk of vascular disease similar to that of smoking or hyperlipidemia. It powerfully increases the risk associated with smoking and hyperten sion. It is time to undertake randomized controlled trials of the effe ct of vitamins that reduce plasma homocysteine levels on vascular dise ase risk.