in disease incidence between the highest and lowest quintiles of intake for each of the vitamins. For folate the data are compatible with the Framingham study (Selhub et al., 1993), in which the lowest deciles of folate intake were associated with higher circulating homocysteine. In the Rimm et al. (1998) study, although multivariate analysis indicated a trend in risk reduction across the quintiles of intake, the major reduction appeared to occur between the first and second quintiles of intake (median intakes 158 and 217 mg of folate). In the subgroup analysis there appeared to be no risk reduction beyond the second quintile of folate intake (217 mg) in nondrinkers, but in alcohol consumers risk reduction increased over the quintiles of intake. Although these data are consistent with the hypothesis that self-selection for increased folate reduces vascular disease risk, other variables associated with lifestyle differences of individuals who consume higher vitamin intakes may also have influenced CHD risk. Some of these variables were not or could not have been considered in the analysis. Several ongoing randomized trials are addressing whether supplements per se will decrease risk of CHD.
Individuals homozygous for the 5,10-MTHFR T677 allele tend to have high homocysteine concentrations as a result of reduced enzymatic activity (Frosst et al., 1995). A few investigations found the risk of vascular disease to be increased in persons homozygous for the T677 allele (deFranchis et al., 1996; Gallagher et al., 1996; Kluijtmans et al., 1996) but the association has not been found in most studies (Ma et al., 1996; Schmitz et al., 1996; Schwartz et al., 1997; Verhoef et al., 1997a; Wilcken et al., 1996). In a meta-analysis the combined odds ratio of CHD associated with homozygosity for T677 allele was 0.98 (95 percent CI, 0.83 to 1.17) (Verhoef et al., 1997b).
The inverse relationship between folate intake and homocysteine concentration is well established. However, there are conflicting data on the association among indicators of folate status or metabolism, homocysteine concentration, and risk of vascular disease. Whether increasing intake of folate could reduce the risk of vascular disease remains to be demonstrated. Folate may reduce the risk of cardiovascular disease through other mechanisms. For example, the data from the study by Verhaar and colleagues (1998) support a direct effect of folate catabolites in restoring or preserving the endothelium function and integrity by affecting cellular oxidative metabolism. More evidence concerning a causal relationship between folate status and vascular disease will be provided by data from prospective controlled intervention trials that are currently under