MTHFR 677C→T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation

Crider, Krista S.; Zhu, Jianghui; Lü, Hao; Yang, Quanhe; Yang, Thomas P.; Gindler, Jacqueline; Maneval, David R.; Quinlivan, Eoin P.; Zhu, Li; Bailey, Lynn B.; Berry, R. J.

doi:10.3945/ajcn.110.004671

Cited by 128 publications

(128 citation statements)

References 33 publications

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“…A large, population‐based double‐blind folic intervention trial was conducted in northern China by Crider et al (2011). They examined the response of plasma and RBC folate concentrations and plasma tHcy concentrations to consumption of 100, 400, or 4000 μg folic acid/day or to a single dose of 4000 μg folic acid/week during 3‐ and 6‐month periods after discontinuation of supplementation and assessed responses according to the MTHFR C677T genotype.…”

Section: Response Of Folate Status To Folate Intake and Supplementationmentioning

confidence: 99%

Genetic polymorphisms and folate status

Hiraoka

Kagawa

2017

Congenital Anomalies

136

102

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Moderate hyperhomocysteinemia‐induced low folate status is an independent risk factor for cardiovascular disease, dementia, and depression. Folate is an essential cofactor in the one‐carbon metabolism pathway and is necessary in amino acid metabolism, purine and thymidylate synthesis, and DNA methylation. In the folate cycle and homocysteine metabolism, folate, vitamin B12, vitamin B6, and vitamin B2 are important cofactors. Many enzymes are involved in folate transport and uptake, the folate pathway, and homocysteine (Hcy) metabolism, and various polymorphisms have been documented in these enzymes. Serum folate and total Hcy (tHcy) levels are influenced by folate intake and genetic polymorphisms in 5,10‐methylenetertahydrofolate reductase (MTHFR) such as C677T. The prevalence of the MTHFR 677TT genotype varies across ethnic groups and regions, with a frequency of approximately 15% in Japanese populations. Individuals with the TT genotype have significantly higher tHcy levels and lower folate levels in serum than those with the CT and TT genotypes. However, administration of folic acid has been shown to eliminate these differences. Moreover, data have suggested that interventions based on genotype may be effective for motivating individuals to change their lifestyle and improve their nutrition status. Accordingly, in this review, we discuss the effects of MTHFR C677T polymorphisms on serum tHcy and folate levels with folic acid intervention and evaluate approaches for overcoming folic acid deficiency and related symptoms.

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Section: Response Of Folate Status To Folate Intake and Supplementationmentioning

confidence: 99%

Genetic polymorphisms and folate status

Hiraoka

Kagawa

2017

Congenital Anomalies

136

102

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“…Homozygosity for the 677C→T nucleotide substitution is associated with a reduction in MTHFR activity, and with reduced folate concentrations in serum and erythrocytes (Crider et al , 2011), but its prevalence in African populations is much lower than among Caucasians (Adjalla et al , 2003; Pegoraro et al , 2004). …”

Section: Determinants Of Folate Requirements In Africamentioning

confidence: 99%

Safety and benefits of interventions to increase folate status in malaria‐endemic areas

et al. 2017

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SummaryFor decades, folic acid has routinely been given to prevent or treat anaemia in children, pregnant women and people with sickle cell disease. However, there is no conclusive evidence that folate deficiency anaemia constitutes a public health problem in any of these groups. Industrial flour fortification is recommended and implemented in many countries to combat neural tube defects. Dietary folates or folic acid can antagonise the action of antifolate drugs that play a critical role in the prevention and treatment of malaria. Randomised trials have shown that folic acid supplementation increases the rate of treatment failures with sulfadoxine‐pyrimethamine. The efficacy of antifolate drugs against Plasmodium is maximized in the absence of exogenous folic acid, suggesting that there is no safe minimum dose of ingested folic acid. We here review the safety and benefits of interventions to increase folate status in malaria‐endemic countries. We conclude that formal cost‐benefit analyses are required.

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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).…”

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confidence: 91%

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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MTHFR 677C→T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation

Cited by 128 publications

References 33 publications

Genetic polymorphisms and folate status

Genetic polymorphisms and folate status

Safety and benefits of interventions to increase folate status in malaria‐endemic areas

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

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