Additional food folate derived exclusively from natural sources improves folate status in young women with the MTHFR 677 CC or TT genotype

Abstract

The effectiveness of additional food folate in improving folate status in humans is uncertain particularly in people with the common genetic variant (677 C→T) in the methylenetetrahydrofolate reductase (MTHFR) gene. To examine the effect of a doubling of food folate consumption on folate status response variables, women (n=32; 18–46 years) with the MTHFR 677 CC or TT genotype consumed either 400 (n=15; 7 CC and 8 TT) or 800 (n=17; 8 CC and 9 TT) μg/day of dietary folate equivalents (DFE) derived exclusively from naturally occurring food folate for 12 weeks. A repeated measures two-factor ANOVA was used to examine the effect of the dietary treatment, the MTHFR C677T genotype and their interactions on serum folate, RBC folate and plasma total homocysteine (tHcy) during the last 3 weeks of the study. Consumption of 800 μg DFE/day resulted in serum folate concentrations that were 67% (P=.005) higher than consumption of 400 μg DFE/day (18.6±2.9 vs. 31.0±2.7 nmol/L, respectively) and RBC folate concentrations that were 33% (P=.001) higher (1172±75 vs. 1559±70 nmol/L, respectively). Serum folate (P=.065) and RBC folate (P=.022) concentrations were lower and plasma tHcy was higher (P=.039) in women with the MTHFR 677 TT genotype relative to the CC genotype. However, no genotype by dietary treatment interaction was detected. These data suggest that a doubling of food folate intake will lead to marked improvements in folate status in women with the MTHFR 677 CC or TT genotype.

Introduction

Suboptimal folate status is associated with vascular disease, certain cancers, impaired cognition, pregnancy complications and fetal malformations including neural tube defects or NTDs [1], [2]. In an effort to increase folate consumption among women of childbearing age and reduce the incidence of NTD-affected pregnancies, the United States and a limited number of other countries (i.e., Canada and Chile) mandated folic acid fortification of staple food items [3]. Folic acid is the oxidized monoglutamate form of folate and is about twice as bioavailable as naturally occurring food folates [4], [5], most of which exist in the reduced form as a mixture of mono- and polyglutamates [6]. In the United States, folic acid fortification has resulted in substantial improvements in the folate status of women of childbearing age [7], [8] and has virtually eliminated folate deficiency in American adults [9]. However, most of the world's population is not exposed to widespread folic acid fortification and, therefore, must rely on supplemental folic acid or increased consumption of foods with a high content of natural folate to optimize their folate intake/status.

A valid concern of relying exclusively on increased consumption of folate-rich foods to optimize folate status is the efficacy of naturally occurring food folate. Studies providing about onefold additional food folate report percent changes ranging from +15% to 85% for serum folate, nonsignificant to +18% for RBC folate and nonsignificant to −16% for plasma total homocysteine (tHcy) [10], [11], [12], [13], [14], [15], [16]. The short-term nature (i.e., ≤5 weeks) of these studies and/or the lack of controlled folate intake may have contributed to the poor response and/or to the large amount of variability observed overall.

The question as to whether additional food folate is effective in improving folate status may be especially critical in people with genetic variations that alter folate requirements. A common polymorphism in methylenetetrahydrofolate reductase (MTHFR), a key regulatory gene in folate metabolism, occurs at nucleotide 677 and involves a cytosine-to-thymine transition [17]. People with the MTHFR 677 TT genotype have lower blood folate and higher plasma tHcy concentrations than those with the CC genotype [18], particularly under conditions of folate insufficiency, and are at greater risk for NTD-affected pregnancies and other pathologies [19], [20]. While folic acid administration is efficacious in persons with the MTHFR 677 TT genotype [21], [22], only limited data are available on the usefulness of additional food folate in improving their folate nutriture.

The objective of this study was to examine the effect of a doubling of food folate consumption on serum folate, RBC folate and plasma tHcy in women with the MTHFR 677 CC (n=15) or TT (n=17) genotype under conditions of controlled folate intakes.