High plasma homocyst(e)ine (Hcy) concentrations may be a determinant of coronary artery disease (CAD). Folate and vitamin B-12 are required for the primary metabolic pathway to reduce Hcy concentrations. The interrelationships of Hcy and these two vitamin cofactors were investigated in a case-control study of 101 white males aged 30-50 y with angiographically demonstrated CAD, and 108 white male, similarly aged, control subjects living in the same community as the patients. The odds ratio (OR) of CAD per quartile increase of plasma Hcy concentration based on control values was 1.6 (95% CI: 1.3, 2.1). After age, HDL and LDL cholesterol, body mass index, smoking, hypertension, and diabetes were controlled for, Hcy remained an independent risk factor (OR: 1.4; 95% CI: 1.0, 2.0). The OR change per quartile increase of folate concentration was 0.8 (95% CI: 0.6, 1.0). This difference was reduced (OR: 0.9; 95% CI: 0.7, 1.2) after Hcy adjustment. No difference in the geometric mean of vitamin B-12 concentration was found between patients and control subjects, both 5.8 nmol/L. However, after Hcy and the other CAD risk factors were controlled for, the OR per quartile increase in vitamin B-12 concentration was 1.5 (95% CI: 1.0, 1.8). Reduction in plasma Hcy by interventions to increase plasma folate concentration may decrease CAD risk.

The classic vitamin deficiency syndromes are the result of acute and severe enzymatic disfunction resulting from extremely low vitamin levels. In recent years, more interest has been focused on less severe deficiencies that may lead to chronic disease. One such relationship is that of folate and homocysteine (HCY). Folate is a cofactor for methionine synthetase, an enzyme that recycles HCY into methionine.' If folate levels are insufficient, HCY levels rise. Elevated HCY levels have been associated with the risks of coronary, cerebral, and peripheral vascularThe relationship between folate and HCY can be used as a sensitive measure to determine what levels of folate are necessary to avoid increased plasma HCY levels. Thus, the objective of this study was to determine the level of plasma folate adequate to prevent an elevation of plasma homocysteine.Plasma folate was measured by microbiological assay, using L . casei as the assay ~rganism.~.' Plasma HCY was measured by electrochemical detection after separation by high-performance liquid chromatography (HPLC).6.7 The population studied included 108 community-based white males (controls) and 101 patients (cases) with angiographically demonstrated coronary artery disease, with comparable demographic characteristics. The cases had angiographic evidence of at least 50% occlusion of one or more major coronary arteries. All subjects were 50 years of age or younger.Cases were found to have lower plasma folate levels than controls (p < 0.0005).The geometric mean of folate was 10.2 nmol/L for cases and 12.5 nmol/L for controls. Plasma HCY levels were significantly higher among cases than among controls (p < 0.0005). The geometric mean of HCY concentration in p n o l / L was 13.5 for cases and 11.9 for controls. Folate levels were inversely associated with HCY levels (p = 0.0001) for both case and control groups. N o difference in the shape or slope of this association was found between cases and controls; thus the groups were combined, and the mean HCY level was plotted by folate level (FIG. I ) .A threshold for low folate can be observed from the FIGURE. Plasma folate levels at the lower range of those considered to be normal in the United States (>6.8 n m~l / L )~.~ were inadequate to prevent elevations in plasma HCY levels. The World Health Organization considered plasma folate levels above 13.6 nmol/ L (6.0 ng/ml) as acceptable.1° The NHANES I1 considered plasma folate levels of less than 6.8 nmol(3.0 ng/mL) asIn the NHANES study, the median plasma