Track A Basic Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138319/1/jia218438.pd

Plasma homocysteine as a risk factor for vascular disease: The European Concerted Action Project

Context. - Elevated plasma homocysteine is a known risk factor for atherosclerotic vascular disease, but the strength of the relationship and the interaction of plasma homocysteine with other risk factors are unclear. Objective. - To establish the magnitude of the vascular disease risk associated with an increased plasma homocysteine level and to examine interaction effects between elevated plasma homocysteine level and conventional risk factors. Design. - Case-control study. Setting. - Nineteen centers in 9 European countries. Patients. - A total of 750 cases of atherosclerotic vascular disease (cardiac, cerebral, and peripheral) and 800 controls of both sexes younger than 60 years. Measurements. - Plasma total homocysteine was measured while subjects were fasting and after a standardized methionine-loading test, which involves the administration 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, serum cholesterol, smoking, and blood pressure were also measured. Results. - The relative risk for vascular disease in the top fifth compared with the bottom four fifths of the control fasting total homocysteine distribution was 2.2 (95% confidence interval, 1.6-2.9). Methionine loading identified an additional 27% of at- risk cases. A dose-response effect was noted between total homocysteine level and risk. The risk was similar to and independent of that of other risk factors, but interaction 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 hypertensive 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 supplements, the small number of subjects taking such vitamins appeared to have a substantially lower risk of vascular disease, a proportion of which 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 hypertension. It is time to undertake randomized controlled trials of the effect of vitamins that reduce plasma homocysteine levels on vascular disease risk.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Thermolabile methylenetetrahydrofolate reductase, homocysteine, and cardiovascular disease risk: The European concerted action project

Background: Homozygotes for the thermolabile mutation (TT genotype) of the methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20) enzyme have elevated plasma concentrations of the cardiovascular disease risk factor homocysteine, particularly if folate depleted. Objective: We examined the relations between thermolabile MTHFR, plasma homocysteine, plasma folate, and vascular disease risk. Design: This was a case-control comparison in 711 vascular disease cases and 747 controls from 9 European countries. Results: The TT genotype was associated with higher homocysteine and lower plasma folate than the CC and CT genotypes in both cases and controls and a nonsignificant increase in vascular disease risk (1.26; 95% CI: 0.88, 1.81; P = 0.20). The frequency of the TT genotype in cases was not significantly different from that in controls (12.8% compared with 10.8%). After adjustment for traditional risk factors, the TT genotype was associated with an odds ratio of 1.48 (1.0, 2.20) for risk of vascular disease. This risk was attenuated after further adjustment for homocysteine. In subgroups with homocysteine concentrations ≥9 μmol/L, risk tended to be higher in CC than in TT subjects. However, CC subjects were characterized by a higher prevalence of the conventional risk factors associated with both elevated plasma homocysteine and serum creatinine. After adjustment, the risk of vascular disease associated with each genotype was not significantly different. Conclusions: There was a strong graded association between homocysteine and vascular risk in all genotypes. MTHFR genotype is a key determinant of plasma total homocysteine concentrations. The initially nonsignificant risk estimate associated with the TT genotype was strengthened after adjustment for conventional cardiovascular disease risk factors but was attenuated after adjustment for plasma folate and total homocysteine. The modest risk increase conferred by the TT genotype is mediated mainly by increased total homocysteine and low plasma folate concentrations.SCOPUS: ar.jinfo:eu-repo/semantics/publishe