(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1157-1162.)


The Effects of Folic Acid Supplementation on Plasma Total Homocysteine Are Modulated by Multivitamin Use and Methylenetetrahydrofolate Reductase Genotypes
M.R. Malinow; F.J. Nieto; W.D. Kruger; P.B. Duell; D.L. Hess; R.A. Gluckman; P.C. Block; C.R. Holzgang; P.H. Anderson; D. Seltzer; B. Upson; ; Q.R. Lin

Abstract
Elevated concentration of plasma total homocysteine (tHcy) is a common risk factor for arterial occlusive diseases. Folic acid (FA) supplementation usually lowers [homocysteine] tHcy levels , but initial tHcy and vitamin levels, multivitamin use, and polymorphisms in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR) may contribute to variability in reduction. We tested the effects of a 3-week daily intake of 1 or 2 mg of FA supplements on tHcy levels in patients with and without coronary heart disease (CHD) who were analyzed for the C677T MTHFR mutation. Prior multivitamin intake and baseline vitamin and tHcy levels were also compared with responsiveness to folate supplementation. Both dosages of FA lowered tHcy levels similarly, regardless of sex, age, CHD status, body mass index, smoking, or plasma creatinine concentration. In non–multivitamin users, FA supplements reduced tHcy by 7% in C/C homozygotes and by 13% or 21% in subjects with one or two copies of the T677 allele, respectively; the corresponding reductions were smaller in users of multivitamins. Moreover, T/T homozygotes had elevated tHcy and increased susceptibility to high levels of tHcy at marginally low plasma folate levels, as well as enhanced response to the tHcy-lowering effects of FA. Although other factors are probably involved in the responsiveness of tHcy levels to FA supplementation, about one third of heterogeneity in responsiveness was attributable to baseline tHcy and folate levels and to multivitamin use.


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American Journal of Clinical Nutrition, Vol. 76, No. 2, 301-302, August 2002

Methylenetetrahydrofolate reductase: a link between folate and riboflavin?
Rima Rozen

In this issue, McNulty et al (1) present data suggesting that the plasma homocysteine concentration in individuals with a mutation in methylenetetrahydrofolate reductase (MTHFR; EC 1.7.99.5) is influenced by riboflavin status. Hyperhomocysteinemia has received considerable attention as a possible risk factor for cardiovascular disease. It has also been observed in several other common conditions, including birth defects, pregnancy complications, and Alzheimer disease. Homocysteine concentrations can certainly be reduced with folate, vitamin B-6, and vitamin B-12 supplementation, but the benefit of riboflavin in hyperhomocysteinemia is a relatively new concept.

JAMA 1998 Feb 4;279(5):359-64

Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women.

Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JE, Hennekens C, Stampfer MJ.

Department of Epidemiology, Harvard School of Public Health, Boston, Mass 02115, USA. eric.rimm~channing.harvard.edu

CONTEXT: Hyperhomocysteinemia is caused by genetic and lifestyle influences, including low intakes of folate and vitamin B6. However, prospective data relating intake of these vitamins to risk of coronary heart disease (CHD) are not available. OBJECTIVE: To examine intakes of folate and vitamin B6 in relation to the incidence of nonfatal myocardial infarction (MI) and fatal CHD. DESIGN: Prospective cohort study. SETTING AND PATIENTS: In 1980, a total of 80082 women from the Nurses' Health Study with no previous history of cardiovascular disease, cancer, hypercholesterolemia, or diabetes completed a detailed food frequency questionnaire from which we derived usual intake of folate and vitamin B6. MAIN OUTCOME MEASURE: Nonfatal MI and fatal CHD confirmed by World Health Organization criteria. RESULTS: During 14 years of follow-up, we documented 658 incident cases of nonfatal MI and 281 cases of fatal CHD. After controlling for cardiovascular risk factors, including smoking and hypertension and intake of alcohol, fiber, vitamin E, and saturated, polyunsaturated, and trans fat, the relative risks (RRs) of CHD between extreme quintiles were 0.69 (95% confidence interval [CI], 0.55-0.87) for folate (median intake, 696 microg/d vs 158 microg/d) and 0.67 (95% CI, 0.53-0.85) for vitamin B6 (median intake, 4.6 mg/d vs 1.1 mg/d). Controlling for the same variables, the RR was 0.55 (95% CI, 0.41-0.74) among women in the highest quintile of both folate and vitamin B6 intake compared with the opposite extreme. Risk of CHD was reduced among women who regularly used multiple vitamins (RR=0.76; 95% CI, 0.65-0.90), the major source of folate and vitamin B6, and after excluding multiple vitamin users, among those with higher dietary intakes of folate and vitamin B6. In a subgroup analysis, compared with nondrinkers, the inverse association between a high-folate diet and CHD was strongest among women who consumed up to 1 alcoholic beverage per day (RR =0.69; 95% CI, 0.49-0.97) or more than 1 drink per day (RR=0.27; 95% CI, 0.13-0.58). CONCLUSION: These results suggest that intake of folate and vitamin B6 above the current recommended dietary allowance may be important in the primary prevention of CHD among women.