Methylenetetrahydrofolate Reductase 677C→T Variant Modulates Folate Status Response to Controlled Folate Intakes in Young Women

Guinotte, Cheryl L.; Burns, Michael; Axume, Juan; Hata, Hiroko; Urrutia, Tania F.; Alamilla, Aaron; McCabe, Dale C.; Singgih, Anny; Cogger, E. A.; Caudill, Marie A.

doi:10.1093/jn/133.5.1272

Cited by 80 publications

(100 citation statements)

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“…These correlations were substantially stronger among those with TT (8,9,(11)(12)(13)(14)(15) and those consuming relatively lower amounts of folate (8,12,13). In previous interventional studies using folate supplements or fortified foods, increased folate intake raised blood folate (16)(17)(18)(19)(20)(21) and reduced tHcy levels (17)(18)(19)(20)(21).…”

mentioning

confidence: 85%

A Cross-Sectional Study to Find Out the Relationship of Methylenetetrahydrofolate Reductase (MTHFR) C677T Genotype with Plasma Levels of Folate and Total Homocysteine by Daily Folate Intake in Japanese

Fukuda

Hamajima

Wakai

et al. 2014

J Nutr Sci Vitaminol

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l-5-Methyl-tetrahydrofolate (THF), derived from dietary folate, is involved in the conversion of homocysteine into methionine ( Fig. 1; 1-3). Folate deficiency increases total homocysteine (tHcy) levels (4). Hyperhomocysteinemia is one of the risk factors of cardiovascular disease (4,5) and neural tube defects (NTDs) (6). Maintaining adequate blood folate levels and controlling tHcy levels are important in preventing these diseases.In the folate metabolic pathway, 5,10-methylene-THF is converted into 5-methyl-THF by the enzyme 10-methylene-THF reductase (MTHFR). In the MTHFR C677T polymorphism (rs 1801133), the T allele reduces thermostability of the enzyme and lowers its activity, which were found to be decreased by 30% in heterozygotes and by 65% in homozygotes of minor alleles compared with the CC genotype in an in vitro study (7). However, folate intake could increase blood folate levels even among those with the TT genotype. In previous observational studies, decreased tHcy levels were related to increased blood folate levels (8-11), and increased folate intake was associated with increased blood folate levels (8, 12) and decreased tHcy levels (8,13,14) in each of the MTHFR genotype. These correlations were substantially stronger among those with TT (8,9,[11][12][13][14][15] and those consuming relatively lower amounts of folate (8,12,13). In previous interventional studies using folate supplements or fortified foods, increased folate intake raised blood folate (16-21) and reduced tHcy levels (17-21).However, one study in Japan found no association of serum folate with energy-adjusted folate intake among those with the TT genotype (22). This may be partly explained by the difference in the amount of folate intake and sources of folate. The mean folate intake among Japanese aged 20 y or more was 329 mg/d for men and 189 mg/d for women and the mean intake from supplements or fortified foods among the population was only 1 mg/d in 2008 (23 (Received November 12, 2013) Summary In those with the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype, enzyme activity is lowered. Therefore, these individuals might require an increased intake of folate to maintain or control blood levels of plasma folate or total homocysteine (tHcy). We examined associations of dietary folate intake with fasting plasma folate and total homocysteine (tHcy) according to genotype among 554 Japanese (207 men and 347 women aged 39-89 y) recruited in 2009. Intake of folate was estimated with a food frequency questionnaire. The MTHFR polymorphism was genotyped by a polymerase chain reaction with confronting two-pair primers. The log-transformed concentration of folate or tHcy was regressed on energy-adjusted folate intake in a linear regression analysis. Higher folate intake was associated with higher plasma folate among those with the CC (b50.165, p50.066) or CT (b50.248, p,0.001) genotypes, and with lower tHcy levels only among those with the CC (b520.141, p50.013) genotype. Plasma folate was significantly and inversely associat...

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confidence: 85%

A Cross-Sectional Study to Find Out the Relationship of Methylenetetrahydrofolate Reductase (MTHFR) C677T Genotype with Plasma Levels of Folate and Total Homocysteine by Daily Folate Intake in Japanese

Fukuda

Hamajima

Wakai

et al. 2014

J Nutr Sci Vitaminol

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“…For those with the appropriate MTHFR genotype, another fasting blood sample was obtained for clinical chemistry evaluation. Additional inclusion criteria have been described elsewhere [14]. The screening and experimental procedures were reviewed and approved by the Institutional Review Board of Cal Poly Pomona University and informed consent was obtained from each participant.…”

Section: Human Subjectsmentioning

confidence: 99%

“…As an extension of previous work [14], the objective of the present study was to assess the influence of folate intake and the MTHFR C677T genotype on choline status (i.e., betaine, choline, phosphatidylcholine and sphingomyelin) in young Mexican-American women consuming controlled folate and choline intakes for 14 weeks. Women of Mexican descent were chosen as the study population because of the high prevalence of the MTHFR 677TT genotype in this ethnic group.…”

Section: Introductionmentioning

confidence: 97%

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Folate intake and the MTHFR C677T genotype influence choline status in young Mexican American women

Abratte

Wang

et al. 2008

The Journal of Nutritional Biochemistry

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Numerous studies have reported a relationship between folate status, the methylenetetrahydrofolate reductase (MTHFR) 677C→T variant and disease risk. Although folate and choline metabolism are inter-related, only limited data are available on the relationship between choline and folate status in humans. This study sought to examine the influences of folate intake and the MTHFR 677C→T variant on choline status. Mexican-American women (n =43; 14 CC, 12 CT and 17 TT) consumed 135 μg/day as dietary folate equivalents (DFE) for 7 weeks followed by randomization to 400 or 800 μg DFE/day for 7 weeks. Throughout the study, total choline intake remained unchanged at ∼350 mg/day. Plasma concentrations of betaine, choline, glycerophosphocholine, phosphatidylcholine and sphingomyelin were measured via LC-MS/MS for Weeks 0, 7 and 14. Phosphatidylcholine and sphingomyelin declined ( P=.001, P=.009, respectively) in response to folate restriction and increased ( P=.08, P=.029, respectively) in response to folate treatment. The increase in phosphatidylcholine occurred in response to 800 ( P=.03) not 400 ( P=.85) μg DFE/day (week×folate interaction, P=. 017). The response of phosphatidylcholine to folate intake appeared to be influenced by MTHFR C677T genotype. The decline in phosphatidylcholine during folate restriction occurred primarily in women with the CC or CT genotype and not in the TT genotype (week×genotype interaction, P=. 089). Moreover, when examined independent of folate status, phosphatidylcholine was higher ( P <. 05) in the TT genotype relative to the CT genotype. These data suggest that folate intake and the MTHFR C677T genotype influence choline status in humans.

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“…Methylenetetrahydrofolate reductase (MTHFR) is a flavin adenine dinucleotide-dependent enzyme (Guinotte et al, 2003) that catalyzes the primary methyl donor for homocysteine remethylation: 5-methyltetrahydrofolate (5-MTHF). Individuals homozygous for the MTHFR C677T mutation have approximately 50% of the wild-type activity, and this is regarded as a cause of hyperhomocysteinemia (Lathrop et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Effects of short-term folic acid and/or riboflavin supplementation on serum folate and plasma total homocysteine concentrations in young Japanese male subjects

et al. 2005

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Objective: To investigate the effects of short-term folic acid and/or riboflavin supplementation on serum folate and plasma plasma total homocysteine (tHcy) concentrations in young Japanese male subjects. Design: In a double blind, randomized controlled trial. Intervention: Subjects were randomly assigned to one of four groups and received a placebo (control group), 800 mg/day folic acid (FA group), 8.4 mg/day riboflavin (R group), or both (FAR group) for 2 weeks. Setting: Tokyo, Japan. Subjects: In total, 32 healthy male volunteers aged 20-29 years. Results: At the end of the 2 week supplementation period, the tHcy concentration decreased significantly in the FA group. Serum folate concentrations had increased between 2.7 and 2.0-fold in the FA and FAR groups, respectively, but the mean within-group changes in serum folate and plasma tHcy concentrations did not differ between these two groups. At the end of the study, alanine amino transferase was decreased in the R and FAR groups, while alanine amino transferase was increased in the FA group. Conclusion: Supplementation with folic acid, 800 mg/day, for 2 weeks, increased the serum and red blood cell folate concentrations and decreased the plasma tHcy concentrations in healthy young male subjects. Riboflavin supplementation may have blunted the effect of folic acid, which resulted in a diminished reduction of tHcy in our subjects.

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Methylenetetrahydrofolate Reductase 677C→T Variant Modulates Folate Status Response to Controlled Folate Intakes in Young Women

Cited by 80 publications

References 46 publications

A Cross-Sectional Study to Find Out the Relationship of Methylenetetrahydrofolate Reductase (MTHFR) C677T Genotype with Plasma Levels of Folate and Total Homocysteine by Daily Folate Intake in Japanese

A Cross-Sectional Study to Find Out the Relationship of Methylenetetrahydrofolate Reductase (MTHFR) C677T Genotype with Plasma Levels of Folate and Total Homocysteine by Daily Folate Intake in Japanese

Folate intake and the MTHFR C677T genotype influence choline status in young Mexican American women

Effects of short-term folic acid and/or riboflavin supplementation on serum folate and plasma total homocysteine concentrations in young Japanese male subjects

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