The long-term objective of this study is to provide reliable information concerning the cardiovascular benefit likely to accrue from different strategies for increasing folic acid intake of the population. The strategies include: changing dietary intake of folate by increasing daily servings of fruits and vegetables, likely to result in a daily increase equivalent to 50 ug folic acid; adding a regular dietary supplement containing folic acid, likely to result in a daily increase of 400 ug folic acid; and fortification of enriched flour and cereal grain products at the level of 140 ug/100 g product, likely to result in a daily average increase in folic acid of between 50 ug and 160 ug.
The specific aim of this double-blind study is to characterize the relationship between change in folic acid and change in plasma homocysteine for modest changes in folic add intake. The specific hypotheses test differences in homocysteine levels associated with folic acid interventions at different doses: 1.400 ug cf. 50 ug; 2. 400 ug cf. 160 ug; 3. 160 ug cf. 0 ug. Volunteers will be screened for genotype of methylenetetrahydrofolate reductase variant, and casual level of homocysteine. Within genotype, gender and broad homocysteine level, 150 volunteers will be enrolled initially. Because of the hypothesized increased efficiency of homocysteine metabolism in blacks, an additional 50 African American volunteers will be enrolled to allow separate estimates of the dose-response curve. In all, 160 volunteers are expected to successfully complete the run-in and they will be assigned, using a Latin Square design, to receive five folic acid treatments in random order, each lasting six weeks: placebo, 5O ug, 160 ug, 400 ug, and 650 ug folic acid. There will be washout periods of six weeks between each treatment phase. Fasting venipuncture blood samples will be obtained at baseline and at the end of each treatment phase, and analyzed for homocysteine, red cell folate, plasma folate and plasma B12. Effects on homocysteine will be compared between each treatment, and dose-response curves will be estimated for each gender and broad homocysteine group (and separately for African Americans, for each gender and broad homocysteine level). Estimates of potential cardiovascular benefit will be calculated by integrating the results of this proposed study with a meta-analysis of studies of the relationship between homocysteine and risk of cardiovascular disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Public Health & Prev Medicine
Schools of Public Health
United States
Zip Code
Anderson, Cheryl A M; Beresford, Shirley A A; McLerran, Dale et al. (2013) Response of serum and red blood cell folate concentrations to folic acid supplementation depends on methylenetetrahydrofolate reductase C677T genotype: results from a crossover trial. Mol Nutr Food Res 57:637-44
Anderson, Cheryl A M; Jorgensen, Arne Lund; Deeb, Samir et al. (2005) Equal proportion of adult male and female homozygous for the 677C --> T mutation in the methylenetetrahydrofolate reductase polymorphism. Am J Med Genet A 134A:97-9
Neuhouser, M L; Beresford, S A (2001) Folic acid: are current fortification levels adequate? Nutrition 17:868-72