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Methylenetetrahydrofolate reductase 677CT genotype modulates homocysteine responses to a folate-rich diet or a low-dose folic acid supplement: a randomized controlled trial^1,2,3

¹ Cardiovascular Sciences Research Group, Wales Heart Research Institute (PALA-W, CHP, JMW, ZEC, MJL, and IFWM), and the Departments of Epidemiology and Public Health Medicine (MLB) and Medical Computing and Statistics (RGN), University of Wales College of Medicine, Cardiff, Wales, United Kingdom, and the University of Sheffield, Centre for Human Nutrition, The Northern General Hospital, Sheffield, United Kingdom (SJM and HJP).

Background: Low folate status and elevated plasma homocysteine are associated with increased risk of neural tube defects and cardiovascular disease. Homocysteine responses to folate may be influenced by genetic variants in folate metabolism.

Objective: We determined the effect of folate-enhancing dietary interventions on plasma folate and plasma total homocysteine (tHcy) with respect to the methylenetetrahydrofolate reductase 677CT genotype.

Design: A total of 126 healthy subjects (42 TT, 42 CT, and 42 CC genotypes) completed 3 dietary interventions (4 mo each) in random order: 1) exclusion diet (avoidance of folic acid–fortified foods and ingestion of a placebo daily), 2) folate-rich diet (increased intake of fortified and naturally folate-rich foods to achieve 400 µg folate/d), and 3) supplement (exclusion diet plus a folate supplement of 400 µg/d).

Results: Plasma folate was higher (P 0.001) and plasma tHcy lower (P 0.001) after the folate-rich and supplement interventions than after the exclusion diet. Plasma folate was significantly greater after supplementation than after the folate-rich diet, but there was no significant difference in tHcy concentration (P = 0.72). TT homozygotes had higher plasma tHcy (14.5 compared with 8.9 µmol/L, P 0.001) and lower plasma folate (14.8 compared with 19.0 nmol/L, P 0.01) than did subjects with the CC genotype after the exclusion diet. CT heterozygotes had intermediate concentrations. The trend toward higher tHcy in TT homozygotes persisted throughout the study but was less marked with increasing folate intake (TT compared with CC after supplementation, P = 0.097).

Conclusions: A folate-rich diet including folic acid–fortified foods or low-dose supplements effectively increases folate status. TT homozygotes require higher folate intakes than do individuals with the CT or CC genotype to achieve similar tHcy concentrations but are responsive to folate intervention.

Key Words: Folic acid • folate • homocysteine • MTHFR genotype • methylenetetrahydrofolate reductase • fortification • healthy population • dietary intake • neural tube defects

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