Serum Folate Concentrations Research Articles

Functional vitamin B12 deficiency in phenylketonuria patients and healthy controls: An evaluation with combined indicator of vitamin B12 status as a biochemical index.

Vitamin B12 deficiency frequently appears in phenylketonuria patients having a diet poor in natural protein. The aims of this study were to evaluate vitamin B12 status in phenylketonuria patients by using combined indicator of vitamin B12 status (cB12) as well as methylmalonic acid and homocysteine, more specific and sensitive markers, in comparison with healthy controls. Fifty-three children and adolescents with phenylketonuria under dietary treatment and 30 healthy controls were assessed cross-sectionally. Serum vitamin B12 and folate concentrations were analysed by chemiluminescence immunoassay. Plasma methylmalonic acid and total homocysteine concentrations were measured by liquid chromatography-tandem mass spectrometry and liquid chromatography, respectively. cB12 was calculated by using a formula involving blood parameters. Methylmalonic acid and folate concentrations in phenylketonuria group were higher compared with controls. Methylmalonic acid concentrations were high in 56.5% of the patients and 26.7% of the controls with normal vitamin B12 concentrations. Based on cB12, a significant difference within the normal values was detected between the groups. However, although 24.5% of phenylketonuria patients and 13.3% of controls had decreased vitamin B12 status according to cB12, there was no significant difference. Children and adolescents with phenylketonuria having a strict diet can be at risk of functional vitamin B12 deficiency. This deficiency can be accurately determined by measuring methylmalonic acid concentrations. Calculation of cB12 as a biochemical index did not provide additional information compared with the measurement of methylmalonic acid alone, but may be helpful for classification of some patients with increased methylmalonic acid as having adequate vitamin B12 status.

Association between serum folate levels and schizophrenia based on sex.

Sex differences in serum folate concentrations are well known, but no studies have investigated the association between serum folate levels and schizophrenia based on sex. With this study in a Japanese population, we examined the difference in serum folate levels between patients with schizophrenia and non-psychiatric controls stratified by sex. The relations among serum folate levels, plasma total homocysteine (tHcy), and serum vitamin B6 (pyridoxal) levels were also examined using data from our previous studies. The serum folate concentrations of 482 patients diagnosed with schizophrenia and 1350 non-psychiatric control subjects were measured. We conducted an analysis of covariance to examine the differences in serum folate levels between the two groups based on sex. Spearman's rank correlation was used to evaluate the relations among folate, tHcy, and vitamin B6 levels. In the control group, serum folate concentrations were higher in women than in men. Lower levels of serum folate were observed in both male and female patients with schizophrenia. An inverse correlation between serum folate and plasma tHcy and a weak positive correlation between serum folate and vitamin B6 were observed in the combined cohort. Our findings suggest that: (i) a low serum folate level may be associated with schizophrenia regardless of sex; and (ii) folate administration may be beneficial for the treatment of schizophrenia. In schizophrenic patients with low serum folate levels, folate administration might result in improvements in high tHcy and an increase in low vitamin B6 levels.

Prognostic impact of B-vitamins involved in one-carbon metabolism in patients with diffuse large B-cell lymphoma.

One-carbon metabolism (OCM) plays a pivotal role in both the stability and integrity of DNA and is mainly regulated by B-vitamins. This study aims to investigate the clinical relevance of B-vitamins and single nucleotide polymorphisms (SNPs) on OCM-related genes in diffuse large B-cell lymphoma (DLBCL). A total of 322 newly diagnosed DLBCL patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone-based immunochemotherapy were recruited into this study. The serum levels of B-vitamins (folate, vitamin B2 [riboflavin], vitamin B6 [pyridoxal 5'-phosphate], and vitamin B12 [cobalamin]), as well as SNPs on methylenetetrahydrofolate reductase, methionine synthase (MTR), MTR reductase (MTRR) and cystathionine gamma-lyase (CTH) genes, were assessed at diagnosis. The prognostic values were estimated using the Kaplan-Meier method and Cox proportional hazards regression methods. Overall, the low serum concentration of folate and vitamin B2, as well as the presence of CTH1364 TT genotype, were significantly associated with poor treatment response in DLBCL. Multivariate analysis indicated that compared with patients in the medium and high serum folate tertiles, low serum folate tertile patients had both significantly inferior progression-free survival (P = .033, Tertile 2 vs Tertile 1, and P = .031, Tertile 3 vs Tertile 1) and overall survival time (P < .001, Tertile 2 vs Tertile 1, and P = .001, Tertile 3 vs Tertile 1). Compared with patients in the medium and high serum vitamin B2 tertiles, low serum vitamin B2 tertile patients had both significantly inferior progression-free survival (P = .006, Tertile 2 vs Tertile 1, and P = .001, Tertile 3 vs Tertile 1) and overall survival time (P = .030, Tertile 2 vs Tertile 1, and P = .255, Tertile 3 vs Tertile 1). In conclusion, alterations in B-vitamin metabolism significantly affected disease progression and had a prognostic impact on DLBCL.

Effect of subchronic combined oral exposure of titanium dioxide nanoparticles and glucose on levels of serum folate and vitamin B12 in young SD rats

To explore the effect of subchronic combined oral exposure of titanium dioxide nanoparticles and glucose on levels of serum folate and vitamin B12 in young SD rats. At first, the physical and chemical properties of titanium dioxide nanoparticles, such as particle size, shape, crystal form and agglomeration degree in solution system, were characterized in detail. Eighty 4-week-old young SD rats were randomly divided into 8 groups (10 rats in each group, half male and half female). The rats were exposed to titanium dioxide nanoparticles through intragastric administration at 0, 2, 10 and 50 mg/kg body weight with or without 1.8 g/kg glucose daily for 90 days. At last, the concentrations of serum folate and vitamin B12 were detected. Titanium dioxide nanoparticles were anatase crystals, closely spherical shape, with an average particle size of (24±5) nm. In male young rats, compared with the control group, the serum folate concentration was significantly increased when exposed to titanium dioxide nanoparticles (10 mg/kg) and glucose. The difference was statistically significant (P<0.05). However, in female and male young rats, compared with glucose (1.8 g/kg) exposure group, titanium dioxide nanoparticles (50 mg/kg) and glucose significantly reduced the serum folate concentration. The difference was statistically significant (P<0.05). Through statistical analysis of factorial design and calculation of interaction, obvious antagonistic effect was observed between titanium dioxide nanoparticles and glucose on the serum folate concentration in the young female SD rats. The combined oral exposure of titanium dioxide nanoparticles and glucose had little effect on the concentration of serum vitamin B12 in the young SD rats, with no significant interaction between the two substances. It was only found that titanium dioxide nanoparticles (2 mg/kg) and glucose significantly increased the serum vitamin B12 concentration, compared with glucose (1.8 g/kg) exposure group. The difference was statistically significant (P<0.05). Subchronic combined oral exposure of titanium dioxide nanoparticles and glucose had an obvious antagonistic effect on serum folate concentrations in young SD rats.

Low folate intake and serum levels are associated with higher body mass index and abdominal fat accumulation: a case control study

BackgroundThe link between folate metabolism and obesity has recently been underlined, suggesting that folate deficiency may lead to body weight gain and adiposity. We thus wished to determine whether the inefficiency in folate metabolism caused by genetic variation in the MTHFR and DHFR genes in folate metabolism, or inadequate folate intake, is associated with obesity.MethodsA case–control study including 421 healthy participants (aged 20–40) was performed in Poznań, Poland. The cases were 213 subjects with BMI > 25 kg/m2, while the controls were 208 subjects with BMI < 25 kg/m2. Genotyping of rs70991108 (DHFR) and rs1801133 (MTHFR) was performed using TaqMan probes. Serum folate concentrations were measured using an enzyme-linked immunosorbent assay and homocysteine was assessed with high performance liquid chromatography.ResultsSubjects with overweight and obesity had 12% lower folate intake (p < 0.05) and 8.5% lower folate serum concentrations (p < 0.01) than the controls. Serum folate concentrations and folate intake were inversely associated with body fat percentage (p < 0.05) and waist circumference (p < 0.05 and p < 0.001, respectively). Serum folate concentration, though not folate intake, was negatively associated with WHR and BMI (p < 0.05, for both associations).ConclusionsLower folate intake and serum levels are weakly, but independently, associated with greater body weight and central adiposity in people aged 20–40. MTHFR and DHFR polymorphism seems not to have significant impact on body weight.

Serum Folate Levels and Lung Cancer Risk: A Meta- Epidemiological Study of Population-based Case-Control Studies.

Objective:While it has been claimed that lung cancer occurs due to epigenetic mechanisms, four systematic reviews were reported to investigate the association between serum folate levels and lung cancer risk. Considering some methodological problems founded in the systematic review, a meta-epidemiological study was conducted. Methods:The selection criteria of this study were defined that a case-control study was conducted to determine the risk of lung cancer occurrence according to the concentration of serum folate and its results showed odds ratio and its 95% confidence interval. Additional paper was explored from cited lists of 4 papers selected by previous systematic reviews. Random effect model was applied if I-squared value was over 50%. Results:For 5 case-control studies selected, the summary odds ratios (and their 95% confidence intervals) were 0.82 (0.74-0.90) in men, 0.70 (0.62-0.79) in former smokers, and 0.86 (0.75-1.00) in non-smokers. Conclusion:Higher foliate levels can decrease lung cancer risk in men and former smokers. Especially, the protective effect was highest in former smokers compared in non-smokers and current smokers. Based on these facts, folate fortification programs to reduce lung cancer risk would be focused on former smokers in men. And some epidemiological studies are needed to provide a hypothesis to explain the sex differences in the association between folate and lung cancer risk.

Is natural (6S)-5-methyltetrahydrofolic acid as effective as synthetic folic acid in increasing serum and red blood cell folate concentrations during pregnancy? A proof-of-concept pilot study

BackgroundNorth American health authorities recommend 0.4 mg/day folic acid before conception and throughout pregnancy to reduce the risk of neural tube defects. Folic acid is a synthetic form of folate that must be reduced by dihydrofolate reductase and then further metabolized. Recent evidence suggests that the maximal capacity for this process is limited and unmetabolized folic acid has been detected in the circulation. The biological effects of unmetabolized folic acid are unknown. A natural form of folate, (6S)-5-methyltetrahydrofolic acid (Metafolin®), may be a superior alternative because it does not need to be reduced in the small intestine. Metafolin® is currently used in some prenatal multivitamins; however, it has yet to be evaluated during pregnancy.Methods/designThis double-blind, randomized trial will recruit 60 pregnant women aged 19–42 years. The women will receive either 0.6 mg/day folic acid or an equimolar dose (0.625 mg/day) of (6S)-5-methyltetrahydrofolic acid for 16 weeks. The trial will be initiated at 8–21 weeks’ gestation (after neural tube closure) to reduce the risk of harm should (6S)-5-methyltetrahydrofolic acid prove less effective. All women will also receive a prenatal multivitamin (not containing folate) to ensure adequacy of other nutrients. Baseline and endline blood samples will be collected to assess primary outcome measures, including serum folate, red blood cell folate and unmetabolized folic acid. The extent to which the change in primary outcomes from baseline to endline differs between treatment groups, controlling for baseline level, will be estimated using linear regression. Participants will have the option to continue supplementing until 1 week postpartum to provide a breastmilk and blood sample. Exploratory analyses will be completed to evaluate breastmilk and postpartum blood folate concentrations.DiscussionThis proof-of-concept trial is needed to obtain estimates of the effect of (6S)-5-methyltetrahydrofolic acid compared to folic acid on circulating biomarkers of folate status during pregnancy. These estimates will inform the design of a definitive trial which will be powered to assess whether (6S)-5-methyltetrahydrofolic acid is as effective as folic acid in raising blood folate concentrations during pregnancy. Ultimately, these findings will inform folate supplementation policies for pregnant women.Trial registrationClinicalTrials.gov, ID: NCT04022135. Registered on 14 July 2019.

Association of serum folate and vitamin B12 with pre-neoplastic cervical lesions.

Diet and lifestyle play an important role in etiology of various tumors. Serum concentration of folate and vitamin B12may be associated with carcinogenesis since they are involved in DNA methylation and nucleotide synthesis. However, the role of these micronutrients on development of cervical cancer is still controversial. Thus, the aim of this study was to analyze the association of lower status of folate and vitamin B12 with the risk of pre-neoplastic cervical lesions. Our sample group was divided in Control group (n=120) - women with normal cytology, and Case groups (n=57) - women presenting Atypical Squamous Cells of Undetermined Significance (ASC-US, n=21), Low Grade Squamous Intraepithelial Lesion (LSIL; n=16), and High-Grade lesions (n=20). We obtained cervical samples for cytology analysis and HPV detection, and blood samples for evaluation of serum concentration of folate and vitamin B12. No difference of serum folate was observed among Cases and Control groups. On the other hand, women with High-Grade lesions presented significant lower median concentration of vitamin B12 if compared to another groups. Then, we observed increased risk of High-Grade lesions among participants with low vitamin B12 levels was observed in relation to women that presented high levels of the micronutrient and from Control group [OR (95% CI): 2.09 (0.65-6.76), p=0.216], ASC-US [OR (95% CI): 3.15 (0.82-12.08), p=0.095], and LSIL [OR (95% CI): 3.10 (0.76-12.70), p=0.116]. Low concentration of vitamin B12 was associated with an increased risk of High-Grade cervical lesions. Besides, we did not observe any difference of serum folate among women with normal cytology and women with pre-neoplastic cervical lesions.

Bacterial fecal microbiota is only minimally affected by a standardized weight loss plan in obese cats

BackgroundResearch in humans and mice suggests that obesity influences the abundance and diversity of gastrointestinal (GI) microbiota, and that an “obese microbiome” influences energy metabolism and fat storage in the host. Microbiota membership and composition have been previously assessed in healthy cats. However, research investigating the effects of obesity and weight loss on the cat’s fecal microbiota is limited. Therefore, this study’s objective was to evaluate differences in fecal microbial abundance and biodiversity, as well as serum cobalamin and folate concentrations in obese cats, before and after weight loss, and compare to lean cats.Fourteen lean and 17 obese healthy client-owned cats were fed a veterinary therapeutic weight loss food at maintenance energy requirement for 4 weeks. At the end of week 4, lean cats finished the study, whereas obese cats continued with a 10-week weight loss period on the same food, fed at individually-tailored weight loss energy requirements. Body weight and body condition score were recorded every 2 weeks throughout the study. At the end of each period, a fecal sample and food-consumption records were obtained from the owners, and serum cobalamin and folate concentrations were analysed. DNA was extracted from fecal samples, polymerase chain reaction (PCR) was performed, and products were sequenced using next-generation sequencing (Illumina MiSeq).ResultsNo significant differences in the relative abundance of taxa and in biodiversity indices were observed between cats in either group (P > 0.05 for all tests). Nevertheless, some significantly enriched taxa, mainly belonging to Firmicutes, were noted in linear discriminant analysis effect size test in obese cats before weight loss compared to lean cats. Serum cobalamin concentrations were significantly higher in lean compared to obese cats both before and after weight loss. Serum folate concentrations were higher in obese cats before weight loss compared to after.ConclusionsThe association between feline obesity and the fecal bacterial microbiota was demonstrated in enriched taxa in obese cats compared to lean cats, which may be related to enhanced efficiency of energy-harvesting. However, in obese cats, the fecal microbial abundance and biodiversity were only minimally affected during the early phase of a standardized weight loss plan.

Maternal folate levels during pregnancy and children's neuropsychological development at 2 years of age.

To explore the relationship between maternal folate levels during pregnancy and children's neuropsychological development at 2 years of age. In the birth cohort MKFOAD, maternal serum folate concentrations at 12-14, 22-26, and 34-36 weeks of gestation were measured, as well as red blood cell (RBC) folate at 12-14 weeks. Neurodevelopment of 2-year-old children was assessed by Gesell Development Scale (GDS), which contained subscales of gross motor, fine motor, language, adaptive behavior, and social behavior. Linear regression models were applied to investigate the association of maternal folate levels with children's developmental quotients (DQs). One hundred and eighty singleton children participated the GDS assessment, of whom 97 (53.9%) were boys. Median RBC folate concentration was 1002.8 (IQR = 577.6) nmol L-1 in early pregnancy and median serum folate concentrations were, respectively, 33.9 (IQR = 9.2) nmol L-1, 26.3 (IQR = 14.3) nmol L-1, and 26.7 (IQR = 18.9) nmol L-1. Maternal serum folate concentration in late pregnancy was significantly associated with children's language development, where language DQ increases by 3.1 (95% CI 0.6, 5.5) for every 10 nmol L-1 increment of serum folate concentration. And maternal serum folate in early pregnancy was significantly associated with children's fine motor development, with 2.0 (95% CI 0.1, 4.0) DQ decrease for 10 nmol L-1 increase of serum folate. Maternal serum folate in late pregnancy was significantly associated with children's language development at age 2, which supports the importance of remaining folic acid supplementation across the entire gestation. However, maternal serum folate in early pregnancy was also inversely associated with children's fine motor development.

Effects of Short‐term Folic Acid Supplementation on Brachial Artery Endothelial Function in Habitually Trained and Untrained Postmenopausal Women

BackgroundExercise‐mediated increases in blood flow, a known nitric oxide (NO) stimulus, is a key signal in adaptations to exercise training, including augmented endothelial function. However, habitually endurance trained postmenopausal women (PMW) demonstrate similar brachial artery endothelial function as untrained PMW, suggesting the vascular adaptations to exercise training are mitigated. Folic acid (FA), a B‐vitamin, increases endothelium‐derived NO production. We tested the hypothesis that short‐term FA supplementation would augment endothelial function in association with increased circulating NO levels in endurance trained and untrained PMW, but that trained PMW would demonstrate greater vascular improvements.MethodsTwo groups of healthy, normotensive, age‐matched (57±1 years; overall mean±SEM), habitually endurance trained (n=12; VO2peak 40±1 ml/kg/min; PMWtr) and untrained (n=12; VO2peak 29±1 ml/kg/min; PMWun) PMW volunteered for the study (Table 1). Brachial artery endothelial function was assessed using flow‐mediated dilation (FMD) before and after 4‐weeks of FA supplementation (5mg/day). Blood pressure (BP) was assessed using an automated device. Primary outcome measures included: FMD% (percentage change from baseline diameter to peak diameter), shear rate (area under the curve from post‐occlusion cuff release to peak diameter; SRAUC), and FMD% adjusted for SRAUC (FMD/SRAUC). Blood samples were also obtained and analyzed for total serum folate, plasma nitrite, and asymmetric dimethylarginine (ADMA), an inhibitor of flow mediated‐induced NO and vasodilation.ResultsBaselineBetween‐groups, cardiorespiratory fitness was higher (p&lt;0.05) and body mass index lower (p&lt;0.05) in PMWtr (Table 1). Brachial artery measures, BP and blood biomarkers did not differ (p&gt;0.05; Tables 1 and 2).Post‐FAWithin‐groups, serum folate concentration was increased (p&lt;0.05), and plasma ADMA unaltered (p&gt;0.05) in both groups. Plasma nitrite concentration was increased (p&lt;0.05) in PMWtr only. FMD% and SRAUC were increased (p&lt;0.05) in PMWun only. FMD/SRAUC was augmented (p&lt;0.05) in both groups. Between‐groups, SRAUC was higher (p&lt;0.05) in PMWun. Plasma nitrite (p&gt;0.05) and FMD/SRAUC (p&gt;0.05) did not differ between groups.ConclusionsHabitually endurance trained PMW demonstrate similar endothelial function, circulating nitrite, and ADMA concentrations as their untrained counterparts. Four weeks of FA supplementation augmented vascular function, specifically FMD/SRAUC, in both groups, but did not influence ADMA. Nitrite concentration was increased post‐FA in trained PMW only. These findings suggest that in PMW: i) habitual endurance training does not modulate vascular function nor circulating levels of ADMA or nitrite; ii) FA may, in the face of estrogen deficiency, augment vascular responsiveness to shear stress, but that habitual endurance training does not further augment this responsiveness.Support or Funding InformationThe research was funded by Loughborough University and supported by NIHR Leicester Research Centre Group characteristics PMWun (n=12) PMWtr (n=12) Age (years) 57±1 57±1 Height (cm) 164±1 166±2 Weight (kg) 62±2 59±2 BMI (kg/m2) 23±1 21±1 † VO2peak (ml/kg/min) 29±1 40±1 † Heart rate (beats/min) 58±2 55±2 Systolic BP (mmHg) 118±3 113±2 Diastolic BP (mmHg) 76±2 73±2 MAP (mmHg) 90±2 86±2 All values are mean±SEM BMI, body mass index; VO2peak, peak oxygen uptake; BP, blood pressure; MAP, mean arterial pressure †Significant between group differences, p&lt;0.05 Brachial artery responses and blood biomarker concentrations pre‐ and post‐folic acid PMWun (n=12) PMWtr (n=12) Pre‐FA Post‐FA Pre‐FA Post‐FA Dbase (mm) 3.15±0.11 3.12±0.13 3.29±0.08 3.34±0.09 Dpeak (mm) 3.26±0.11 3.26±0.13 3.43±0.09 3.49±0.10 FMD (%) 3.53±0.33 4.65±0.50 * 4.21±0.40 4.53±0.40 SRAUC (a.u) 5969±623 6899±462 † * 5885±371 5236±228 FMD/SRAUC (a.u) 6.33±0.74 6.80±0.64 * 7.45±0.81 8.81±0.87 * TTP (secs) 36.8±3.2 40.2±2.5 38.5±3.5 36.4±2.0 Folate (ng/ml) 7.9±0.8 20±0 * 10.5±1.0 20±0 * Nitrite (nM) 72.9±9.7 65.5±9.1 57.9±7.1 92.3±15.2 * ADMA (μmol/L) 0.41±0.05 0.42±0.05 0.53±0.08 0.48±0.07 All values are mean±SEM. Dbase, baseline brachial artery diameter; Dpeak, peak brachial artery diameter; FMD, flow mediated dilation; TTP, time to Dpeak; SRAUC shear rate area under the curve from cuff‐release to Dpeak; FMD/SRAUC, FMD normalised to SRAUC; ADMA, asymmetric dimethylarginine †Between groups, within condition p&lt;0.05 *Within‐groups, pre‐ vs post‐FA, p&lt;0.05

Serum homocysteine and folate concentrations in early pregnancy and subsequent events of adverse pregnancy outcome: the Sichuan Homocysteine study

BackgroundHyperhomocysteinemia may be a risk factor for endothelial dysfunction. Folate and vitamin B12 regulate the homocysteine metabolic process. This study aimed to evaluate the associations between subsequent events of adverse pregnancy outcome and early variables of homocysteine, folate, and vitamin B12 in pregnant women.MethodsThis multicenter, retrospective, case–control study involved 563 pregnant women with adverse pregnancy outcome and 600 controls. Adverse pregnancy outcomes included one or more of the following events: preeclampsia, preterm birth, low birth weight, and stillbirth. The associations between subsequent events of adverse pregnancy outcome and early variables of homocysteine, folate, and vitamin B12; metabolic parameters; inflammatory markers; anthropometrics; and lifestyle habits at 11–12 weeks of gestation were analyzed using the logistic regression model.ResultsCompared to the lower quartile homocysteine concentrations, the upper quartile homocysteine concentrations were associated with preeclampsia, preterm birth and low birth weight. On the contrary, the lower quartile folate concentrations were associated with preeclampsia, preterm birth and low birth weight compared with the upper quartile folate concentrations. The incidence of adverse pregnancy outcome increased progressively from the first to fourth homocysteine quartiles but decreased progressively from the first to fourth folate quartiles. After adjusting for confounding factors, multivariate logistic regression analysis showed that besides systolic blood pressure, diastolic blood pressure, body mass index and age, homocysteine (IV vs I quartile, aOR 5.89, 95% CI 4.08–8.51, P < 0.001), folate (IV vs I quartile, aOR 0.35, 95% CI 0.25–0.50, P < 0.001), folate supplementation (yes vs no, aOR 0.55, 95% CI 0.35–0.86, P = 0.010) during early pregnancy were independently associated with subsequent events of adverse pregnancy outcome, and vitamin B12 was rejected. Of these, the homocysteine revealed the highest odds ratio in all risk variables, and folate showed the lowest odds ratio in all protective variables.ConclusionsHigher homocysteine concentration and lower folate level during early pregnancy were associated with adverse pregnancy outcome. However, no association was found between vitamin B12 and adverse pregnancy outcome. Supplementation with folate in early pregnancy may reduce adverse pregnancy outcome.

Circulating folate concentrations and risk of coronary artery disease: a prospective cohort study in Chinese adults and a Mendelian randomization analysis

The association between circulating folate concentrations and risk of coronary artery disease (CAD) has been evaluated in Western populations with inconsistent results; however, the observational and causal associations in Chinese populations with relatively low folate concentrations remain unclear. We aimed to examine the association of circulating folate concentrations with incident CAD in Chinese adults, and further evaluated the causal relation using Mendelian randomization (MR) analysis. We measured baseline serum folate in 1605 incident CAD cases and 1605 age- and sex-matched controls nested within the Dongfeng-Tongji (DFTJ) cohort, which recruited 27,009 individuals with a mean age of 63.6 y in 2008-2010 and followed up until the end of 2013 (mean: 4.4 y). We quantified the observational association between folate and incident CAD using conditional logistic regression models. A 2-sample MR analysis was performed using summary statistics obtained for genetic variants identified from a genome-wide association study (GWAS) of circulating folate concentrations in participants of European ancestry (n=37,341) and from the CardiogramplusC4D 1000 genomes-based GWAS meta-analysis (n=184,305). We also conducted 1-sample MR among 1545 incident CAD cases and 1444 controls with genotyping data in the DFTJ cohort. In the DFTJ cohort, higher serum folate concentrations were associated with a lower risk of CAD: the OR (95% CI) across sex-specific quartiles of folate (from lowest to highest concentrations) was 1.00 (reference), 0.78 (0.63, 0.97), 0.77 (0.61, 0.97), and 0.75 (0.60, 0.95), respectively (P-trend=0.01). In the MR analysis, the OR of CAD per SD increase in genetically predicted serum folate was 0.99 (0.82, 1.20) and 0.88 (0.59, 1.32) for European and Chinese populations, respectively. We found an inverse association between circulating folate concentrations and incident CAD among Chinese populations. However, we confirmed that there was no genetic evidence to support the causal relation in both European and Chinese populations.

Association between body mass index and folate insufficiency indicative of neural tube defects risk among nonpregnant women of childbearing age in the United States, NHANES, 2007-2010.

Maternal folate status and obesity are known risk factors for neural tube defects (NTD) in the offspring. We examined the association between body mass index (BMI) categories and blood folate concentrations, specifically, red blood cell (RBC) folate concentrations indicative of NTD risk among nonpregnant women of child-bearing age (20-44 years) in the United States. We used data from 2007 to 2010 US National Health and Nutrition Examination Survey (NHANES). Overweight, obesity, and strata within obesity were examined. Serum and RBC folate concentrations were examined as continuous and categorical variables. RBC folate concentrations were grouped indicating high (≤585 nmol/L) and elevated risk (586-747 nmol/L) for NTDs. Unadjusted and adjusted prevalence odds ratios (aPOR) and their 95% confidence intervals (CI) were estimated using logistic regression. Of the 30,878 participants, 25.6% were overweight, 32.7% obese, and 32.3% had RBC folate concentration indicating NTD risk (<748 nmol/L). Overweight was not associated with RBC folate level for NTD risk; however, a marginally significant negative association was noted for overall obesity and RBC folate concentrations indicative of elevated NTD risk (aPOR = 0.76; 95% CI = 0.45, 1.00). A significant protective association was noted between Class 3 obesity (BMI ≥40 kg/m2 ) and folate concentration indicative of high NTD risk (≤585 nmol/L; aPOR = 0.46; 95% CI = 0.24, 0.89). The prevalence of RBC folate concentrations indicating elevated or high NTD risk varied by level of obesity among nonpregnant women of child-bearing age. Further studies are needed to understand the folate pathway in overweight and obese women and subsequent NTD risk in their offspring.

Assessment of folate and cobalamin concentrations in relation to their dependent intracellular metabolites in serum of pigs between 6 and 26 weeks of age

Folate (vitamin B9) and cobalamin (vitamin B12) play an important role in amino acid metabolism, nucleic acid synthesis, and methyl group transfer. Two intracellular enzymes, methionine synthase and methylmalonyl-CoA mutase, are folate and/or cobalamin-dependent, respectively. At the cellular level, a lack of folate and cobalamin leads to accumulation of serum homocysteine (HCY) and a lack of cobalamin leads to increased methylmalonic acid (MMA) concentrations. Altered serum HCY and MMA concentrations can influence amino acid metabolism and nucleic acid synthesis in pigs. Therefore, we aimed to evaluate serum folate, cobalamin, HCY, and MMA concentrations in postweaning pigs between 6 and 26 weeks of age. Serum samples from 12 pigs collected at week 6, 7, 8, 9, 10, 14, 18, 22, and 26 as part of an unrelated study were analyzed. Serum folate (p < .0001), cobalamin (p = .0001), HCY (p < .0001), and MMA (p < .0001) concentrations differed significantly during the postweaning period between 6 and 26 weeks of age; with significantly higher serum HCY (at weeks 6 and 7 compared to weeks 9, 14, 18, 22, and 26) and MMA concentrations (at weeks 6, 7, and 8 compared to weeks 14, 18, 22, and 26) and an overall decrease of serum MMA concentrations from week 6 to week 14 in the pigs studied. This study suggests age-dependent changes in intracellular folate- and cobalamin-dependent metabolites (i.e., HCY and MMA) in pigs between 6 and 26 weeks of age, possibly reflecting decreased availability of intracellular folate and/or cobalamin for amino acid metabolism, nucleic acid synthesis, and methyl group transfer.

Maternal and Cord Blood Folate Concentrations Are Inversely Associated with Fetal DNA Hydroxymethylation, but Not DNA Methylation, in a Cohort of Pregnant Canadian Women

Aberrancies in fetal DNA methylation programming may modify disease susceptibility of the offspring. Maternal folate status has potential to alter fetal DNA methylation. We examined the association of maternal and cord blood concentrations of folate and unmetabolized folic acid (UMFA), vitamin B-12, vitamin B-6, and choline with fetal DNA methylation and hydroxymethylation and assessed potential modifying effects of 38 fetal genetic variants in 22 genes. Nutrient blood concentrations were measured in 368 pregnant women in early pregnancy (12-16 wk of gestation) and at delivery (37-42 wk of gestation) and in cord blood. DNA methylation and hydroxymethylation in cord blood mononuclear cells were quantified by LC-MS/MS. Pearson partial correlations were used to determine the association between individual nutrients and DNA methylation and hydroxymethylation. Serum and RBC folate and plasma UMFA concentrations (primary outcomes) in early pregnancy, at delivery, and in cord blood were not significantly associated with fetal DNA methylation. In contrast, maternal RBC folate in early pregnancy (r=-0.16, P=0.04) and cord plasma UMFA (r=-0.23, P=0.004) were inversely correlated with fetal DNA hydroxymethylation. Neither maternal and cord blood concentrations of other nutrients nor fetal genotypes (secondary outcomes) were significantly associated with fetal DNA methylation or hydroxymethylation. Infants born to mothers with RBC folate concentrations in the highest quartile and serum vitamin B-12 concentrations in the lowest quartile in early pregnancy had significantly lower fetal DNA methylation and higher birth weight compared with those born to mothers with lower RBC folate and higher serum vitamin B-12 concentrations (P=0.01). Maternal and cord blood folate concentrations are associated with fetal DNA hydroxymethylation, but not DNA methylation, in a cohort of pregnant Canadian women. The observation that high folate and low vitamin B-12 maternal status in early pregnancy may be associated with decreased fetal DNA methylation and higher birth weight warrants further investigation. This trial was registered at clinicaltrials.gov as NCT02244684.

Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers

BackgroundAutism spectrum disorder (ASD) evolves from an interplay between genetic and environmental factors during prenatal development. Since identifying maternal biomarkers associated with ASD risk in offspring during early pregnancy might result in new strategies for intervention, we investigated maternal metabolic biomarkers in relation to occurrence of ASD in offspring using both univariate logistic regression and multivariate network analysis.MethodsSerum samples from 100 women with an offspring diagnosed with ASD and 100 matched control women with typically developing offspring were collected at week 14 of pregnancy. Concentrations of 62 metabolic biomarkers were determined, including amino acids, vitamins (A, B, D, E, and K), and biomarkers related to folate (vitamin B9) metabolism, lifestyle factors, as well as C-reactive protein (CRP), the kynurenine-tryptophan ratio (KTR), and neopterin as markers of inflammation and immune activation.ResultsWe found weak evidence for a positive association between higher maternal serum concentrations of folate and increased occurrence of ASD (OR per 1 SD increase: 1.70, 95% CI 1.22–2.37, FDR adjusted P = 0.07). Multivariate network analysis confirmed expected internal biochemical relations between the biomarkers. Neither inflammation markers nor vitamin D3 levels, all hypothesized to be involved in ASD etiology, displayed associations with ASD occurrence in the offspring.ConclusionsOur findings suggest that high maternal serum folate status during early pregnancy may be associated with the occurrence of ASD in offspring. No inference about physiological mechanisms behind this observation can be made at the present time because blood folate levels may have complex relations with nutritional intake, the cellular folate status and status of other B-vitamins. Therefore, further investigations, which may clarify the potential role and mechanisms of maternal blood folate status in ASD risk and the interplay with other potential risk factors, in larger materials are warranted.

Gastric and Jejunal Enteral Feeding Differently Affect Vitamin B12 Status in Subjects with Severe Motor and Intellectual Disabilities.

The absorption of vitamin B12 is a complex process involving gastric acid and intrinsic factor as the indispensable components. In this study, we have investigated the effects of the administration site in enteral feeding on vitamin B12 status in subjects with severe motor and intellectual disabilities (SMID). This is a cross-sectional study conducted from January to June 2016. Blood concentrations of vitamin B12, folate, vitamin B6, and homocysteine (Hcy) were measured in a total of 82 subjects (38 men, 44 women). Also, nutrients intake was assessed. Subjects with enteral feeding (EF) had significantly higher intakes of vitamin B12, folate, and vitamin B6 than those with oral ingestion (OI). Serum folate and vitamin B6 concentrations in subjects with EF were significantly higher than those with OI. Among the EF subjects, serum vitamin B12 concentration was significantly higher in those fed with gastric tube than those fed with jejunal tube in spite of similar vitamin B12 intakes. No significant difference was observed between the two groups regarding the circulating concentrations of folate, vitamin B6, or Hcy. Although each administration route has its own benefit, gastric tube is advantageous in the absorption of vitamin B12.

Exposure to Toxic Heavy Metals Can Influence Homocysteine Metabolism?

Background: Homocysteine is a sulfur amino acid whose metabolism is activated in two pathways: remethylation to methionine, which requires folate and vitamin B12, and transsulfuration to cystathionine, which needs pyridoxal-5’-phosphate. High homocysteine level increases the risk of developing heart disease, stroke, peripheral vascular diseases, and cognitive impairment. Some evidence showed that exposure to these metals increased plasma homocysteine levels. Methods: A systematic review was carried out to clarify the relationship between homocysteine blood levels and exposure to toxic heavy metals (Lead, Cadmium, Mercury, and Chromium). Results: The results of this systematic review indicate that exposure to Pb, Cr, Cd, and Hg is connected with nonphysiological homocysteine levels or vitamin B12 and folate serum concentrations. Conclusions: These findings reinforce the importance of involvement in exposure to heavy metals in homocysteine metabolism. This supports the role of blood metals as potential upstream modifiable risk factors to prevent the development of other established risk factors as hyperhomocysteinemia.

Multi-Micronutrient Fortified Rice Improved Serum Zinc and Folate Concentrations of Cambodian School Children. A Double-Blinded Cluster-Randomized Controlled Trial.

Background: Within Cambodia, micronutrient deficiencies continue to be prevalent in vulnerable groups, such as women and children. Fortification of staple foods such as rice could be a promising strategy for Cambodia to improve micronutrient status. Objective: Our objective was to investigate the impact of multiple-micronutrient fortified rice (MMFR), distributed through a World Food Program school-meals program (WFP-SMP) on serum zinc concentrations and folate status in a double-blind, cluster-randomized, placebo-controlled trial. Methods: Sixteen schools were randomly assigned to receive one of three different types of extruded-fortified rice (UltraRice Original (URO), UltraRice New (URN), or NutriRice) or unfortified rice (placebo) six days a week for six months. A total of 1950 schoolchildren (6–16 years old) participated in the study. Serum zinc (all groups) and folate (only in NutriRice and placebo group) concentrations were assessed from morning non-fasting antecubital blood samples and were measured at three time points (baseline and after three and six months). Results: After six months of intervention, serum zinc concentrations were significantly increased in all fortified rice group compared to placebo and baseline (0.98, 0.85 and 1.40 µmol/L for URO, URN and NutriRice, respectively) (interaction effect: p < 0.001 for all). Children in the intervention groups had a risk of zinc deficiencies of around one third (0.35, 039, and 0.28 for URO, URN, and NutriRice, respectively) compared to the placebo (p < 0.001 for all). The children receiving NutriRice had higher serum folate concentrations at endline compared to children receiving normal rice (+2.25 ng/mL, p = 0.007). Conclusions: This study showed that the high prevalence of zinc and folate deficiency in Cambodia can be improved through the provision of MMFR. As rice is the staple diet for Cambodia, MMFR should be considered to be included in the school meal program and possibilities should be explored to introduce MMFR to the general population.