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Clin Chem. 2007 May;53(5):845-51. Epub 2007 Mar 1.

Homocysteine, 5,10-methylenetetrahydrofolate reductase 677C>T polymorphism, nutrient intake, and incident cardiovascular disease in 24,968 initially healthy women.

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Donald W. Reynolds Center for Cardiovascular Research, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.



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.


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.


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.


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.


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