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Maintaining optimal one-carbon metabolism (OCM) is essential for health and pregnancy. In this cross-sectional study, folate status was assessed based on 5-methyltetrahydrofolate (5-MTHF) levels, and the association between 5-MTHF and OCM-related metabolites was investigated in 227 female Japanese university students aged 18-25 years. The participants were divided into high and low 5-MTHF groups based on their folate status. Serum samples of the participants were collected while they were fasting, and 18 OCM-related metabolites were measured using stable-isotope dilution liquid chromatography-electrospray tandem mass spectrometry. The association between serum 5-MTHF and OCM-related metabolite concentrations was assessed using Spearman's rank correlation coefficient. Serum 5-MTHF concentrations were negatively correlated with total homocysteine (tHcy) concentrations and positively correlated with S -adenosylmethionine (SAM) and total cysteine (tCys) concentrations. Serum 5-MTHF concentrations demonstrated a stronger negative correlation with tHcy/tCys than with tHcy alone. The negative correlation between betaine and tHcy concentrations was stronger in the low 5-MTHF group than in the high 5-MTHF group. The 5-MTHF status could be linked to Hcy flux into the transsulfuration pathway via SAM. Therefore, the tHcy/tCys ratio may be a more sensitive indicator of the 5-MTHF status than tHcy alone. Furthermore, a low 5-MTHF status can enhance Hcy metabolism via betaine.

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., (© 2017 The Authors. Congenital Anomalies published by John Wiley & Sons Australia, Ltd on behalf of Japanese Teratology Society.)

The introduction of mandatory fortification of grains with folate in 1998 in the United States resulted in 767 fewer spina bifida cases annually and a cost saving of $603 million per year. However, far more significant medical cost savings result from preventing common diseases, including myocardial infarction, stroke, dementia and osteoporosis. A cost-effectiveness analysis showed a gain of 266 649 quality-adjusted life-years and $3.6 billion saved annually, mainly due to the reduction of cardiac infarction. The recommended folate intake in Japan is 240 μg/day whereas it is 400 μg/day internationally. Our Sakado Folate Project targeted individuals with genetic polymorphism of methylenetetrahydrofolate reductase or with hyperhomocysteinemia. Using, for example, folate-fortified rice, resulted in an increase in serum folate and a decrease in serum homocysteine in the participants, and reduced medical costs were achieved by decreasing myocardial infarction, stroke, dementia and fracture. Due to the small population of Sakado City (approximately 101 000) and small number of births (693) in 2015, a decrease in spina bifida could not be confirmed but there was a significant decrease in the number of very low birthweight infants. The genome notification of subjects was effective in motivating intake of folate, but the increase in serum folate (from 17.4 to 22.5 nmol/L, 129%) was less than that observed following compulsory folic acid fortification of cereals in the USA (from 12.1 to 30.2 nmol/L, 149.6%). Mandatory folic acid fortification is cheap in decreasing medical costs and is thus recommended in Japan., (© 2017 The Authors. Congenital Anomalies published by John Wiley & Sons Australia, Ltd on behalf of Japanese Teratology Society.)

A case-control study was conducted in central Japan to investigate the relationship between dietary intake of folate and lung function, breathlessness and chronic obstructive pulmonary disease (COPD). A total of 278 referred patients (244 men and 34 women) aged 50-75 years with COPD diagnosed within the past four years and 340 community-based controls (272 men and 68 women) were assessed for dyspnoea and undertook spirometric measurements of lung function. A structured questionnaire was administered face-to-face to obtain information on demographics, lifestyle and habitual food consumption. Folate intake was derived from the Japanese food composition tables. The COPD patients had significantly lower habitual intake of folate (mean 231, SD 90 microg/day) than control subjects (mean 261, SD 110 microg/day), p<0.001. Lung function measures were found to be positively associated with dietary folate level. Reductions in prevalence of COPD and especially breathlessness were observed, the respective adjusted odds ratio (OR) being 0.74 (95% confidence interval (CI) 0.35 to 1.58) and 0.43 (95% CI 0.21 to 0.91) for the highest versus lowest quartile of folate intake. The corresponding tests for linear trend were also significant (p<0.05). In conclusion, an inverse association was evident between dietary folate intake and the prevalence of breathlessness for Japanese adults, together with a significant dose-response relationship for the COPD risk. Moreover, increased folate intake might be beneficial to lung function.

In order to prevent Alzheimer disease (AD), relationship between single nucleotide polymorphisms (SNPs) of methylene tetrahydrofolate reductase (MTHFR) and folate-homocysteine metabolism was studied. Subjects were 10 males and 42 females (87.9 +/- 7.7 years old) in the special nursing homes for the elderly. Their average care level was 4.2 +/- 0.9, and average cognitive ability estimated by MMSE was 6.9 +/-7.3. Dietary intake was measured by weighing method. Concentrations of serum folate and total serum homocysteine (tHcy), and genetic polymorphisms were determined. The daily nutrient intake was as follows: total energy 2.7 kcal/kg; protein, 1.0 g/kg; folic acid, 7.3 microg/kg; vitamin B12, 0.11 microg/kg. Compared with control elderly persons, serum folate was very low (4.5 ng/ml, control = 10.1 ng/ml) and serum homocysteine was very high (21.4 micromol/L, control = 10.2 microg/L), despite having an adequate folate intake (342 microg/day, mainly polyglutamyl folate). The frequency of TT homozygote of MTHFR was higher (21.1%) in Alzheimer patients than that in control (15%). TT homozygotes showed the lowest serum folate (3.5 ng/ml, 35% of control), the highest serum homocysteine 25 micromol/L, 250% of control and the lowest MMSE score (5) among all the genotypes. The bioavailability of polyglutamyl folate may be impaired in the subjects, even when their total folate intake was sufficient. The early prevention of Alzheimer's disease by monoglutamyl folate intake (400 mcg per day) is recommended especially in TT homozygote of MTHFR.

Elevated serum total homocysteine (tHcy) levels are associated with increased risk for cardiovascular disease and dementia. The prevalence rates of homozygous mutants among Japanese women (n = 300) were 17.3%, 1.3%, 18.6%, and 5.3% for methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, reduced folate carrier (RFC-1) A80G, and methionine synthase (MS) A2756G, respectively. The tHcy value was significantly lower (p < 0.001) in young women with CC or CT of MTHFR than with TT (10.9+/-4.7 micromol/L) (n =250). Diversities of serum folate and tHcy in women with 23 combinations of different alleles at low folate intake converged to the highest (34.0+/-8.6 nmol/L) and lowest (7.6+/-1.5 micromol/L) levels, respectively, after folic acid (400 microg/day) supplementation. In the regression equation ( y= ax + b) of serum folate ( y nmol/L) plotted against mean folate intake ( x microg/day), the values of "a" were 0.032, 0.037, and 0.045 for individuals with CC, CT, and TT alleles, respectively, of MTHFR.