Received on November 29, 2006
Accepted on January 9, 2007

Molecular Diagnostics and Genetics

Homocysteine, 5,10-Methylenetetrahydrofolate Reductase 677C>T Polymorphism, Nutrient Intake, and Incident Cardiovascular Disease in 24,968 Initially Healthy Women

¹ Donald W. Reynolds Center for Cardiovascular Research, Leducq Center for Molecular and Genetic Epidemiology, and Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine, Brigham and Women's Hospital, Boston, MA
² Donald W. Reynolds Center for Cardiovascular Research, Leducq Center for Molecular and Genetic Epidemiology, and Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine, and Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA
³ Department of Human Genetics, Roche Molecular Systems, Inc., Alameda, CA
⁴ Roche Center for Medical Genomics, Basel, Switzerland
⁵ Department of Department of Laboratory Medicine, Children's Hospital, Harvard Medical School, Boston, MA
⁶ Donald W. Reynolds Center for Cardiovascular Research, Leducq Center for Molecular and Genetic Epidemiology, and Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine, and Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, and Department of Epidemiology, Harvard School of Public Health, Boston, MA

^* To whom correspondence should be addressed. E-mail: rzee{at}rics.bwh.harvard.edu.

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% confidence intervals) 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 µmol/L higher homocysteine for TT vs CC, P <0.001) and inversely with intake of folate, vitamin B₂, B₆, and B₁₂, 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.