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CLINICAL STUDY: RISK FACTORS

Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype

Catherine H. Pullin, BSc^a, Pauline A. L. Ashfield-Watt, BA^a, Michael L. Burr, MD, FFPHM^a, Zoë E. Clark, MPhil^a, Malcolm J. Lewis, MB, DSc, FESC^a, Stuart J. Moat, PhD, Robert G. Newcombe, PhD, C. Stats, MFPHM, Hilary J. Powers, PhD, Jenny M. Whiting, RGN^a and Ian F. W. McDowell, MD, MRCP, FRCPath^*,a

^a Cardiovascular Sciences Research Group, Wales Heart Research Institute, Cardiff, United Kingdom
Centre for Human Nutrition, Division of Clinical Sciences, Northern General Hospital, Sheffield, United Kingdom
Department of Medical Computing and Statistics, University of Wales College of Medicine, Heath Park, Cardiff, United Kingdom

Manuscript received December 6, 2000; revised manuscript received August 15, 2001, accepted August 29, 2001.

^* Reprint requests and correspondence: Dr. Ian F. W. McDowell, Department of Medical Biochemistry, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, Wales United Kingdom
mcdowell{at}cardiff.ac.uk

OBJECTIVES

We sought to study the effect of low-dose folic acid supplementation or optimization of dietary folate intake on plasma homocysteine and endothelial function in healthy adults.

BACKGROUND

Elevated homocysteine is associated with cardiovascular disease, but it is not known whether this relationship is causal. Individuals homozygous (TT) for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (12% of the population) have increased homocysteine levels, particularly in association with suboptimal folate intake.

METHODS

Healthy subjects (n = 126; 42 of each MTHFR genotype) were included in this cross-over study of three interventions of four months each: 1) placebo plus natural diet; 2) daily 400-µg folic acid supplement plus natural diet; and 3) increased dietary folate intake to 400 µg/day.

RESULTS

At baseline, homocysteine was inversely related to plasma folate and was higher in TT homozygotes. For the whole group, plasma folate increased by 46% after dietary folate and by 79% after supplementation, with reductions of homocysteine of 14% and 16%, respectively. Within the genotype, TT homozygotes exhibited the most marked changes in these variables. Brachial artery endothelial function, as determined by a change in end-diastolic diameter in response to increased flow, was not changed by increased folate intake (98 ± 73 µm at baseline, 110 ± 69 µm after a high-folate diet, 114 ± 59 µm after supplementation and 118 ± 68 µm after placebo). Plasma von Willebrand factor antigen was unaltered.

CONCLUSIONS

Optimization of dietary folate or low-dose folic acid supplementation reduces plasma homocysteine but does not enhance endothelial function, irrespective of the MTHFR (C667T) genotype.

Abbreviations and Acronyms   ANOVA = analysis of variance   FMD = flow-mediated dilation   MTHFR = methylenetetrahydrofolate reductase   NO = nitric oxide   vWF(Ag) = von Willebrand factor (antigen)

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