BACKGROUND:

Hyperhomocysteinemia has been associated with a higher risk of cardiovascular disease (CVD) in epidemiological studies, but recent trials have failed to show a benefit of lowering homocysteine. To address this apparent paradox, we explored whether interaction between genetic and dietary factors related to homocysteine metabolism contributes to CVD risk.

METHODS:

We evaluated the associations of homocysteine, methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype, and dietary intake of folate/B-vitamins with subsequent CVD events in 24 968 apparently healthy white American women followed for 10 years. Plasma homocysteine was measured using an enzymatic assay. MTHFR genotype was determined with a multiplex PCR using biotinylated primers.

RESULTS:

In unadjusted analyses, homocysteine showed moderately strong linear associations with CVD, with hazard ratios (95% CI) comparing top with bottom quintiles for total CVD of 1.92 (1.55-2.37), myocardial infarction 2.32 (1.52-3.54), and ischemic stroke 2.25 (1.45-3.50), all P(trend) <0.001. These ratios were markedly attenuated after adjusting for traditional risk factors and socioeconomic status to 1.08 (0.86-1.36), P(trend) = 0.12; 1.20 (0.76-1.87), P(trend) = 0.14; and 1.21 (0.75-1.94), P(trend) = 0.50, respectively. Homocysteine was associated with MTHFR genotype (1.4 micromol/L higher homocysteine for TT vs CC, P <0.001) and inversely with intake of folate, vitamin B(2), B(6), and B(12), all P(trend) <0.001. However, there was no association of MTHFR genotype or dietary folate/B-vitamins with CVD. In addition, there were no gene-diet or gene-homocysteine interactions in relation to CVD.

CONCLUSIONS:

In this large-scale prospective study, the association of homocysteine with CVD was markedly attenuated after adjusting for risk factors and was not modified by MTHFR 677C>T or intake of folate or B-vitamins.