Folate and Vitamin B12-Related Biomarkers in Relation to Brain Volumes.
ABSTRACT: We investigated cross-sectional associations between circulating homocysteine, folate, biomarkers of vitamin B12 status and brain volumes. We furthermore compared brain volumes of participants who received daily folic acid and vitamin B12 supplementation with participants who did not.Participants of the B-PROOF study (n = 2919) were assigned to 400 µg folic acid and 500 µg vitamin B12, or a placebo. After two years of intervention, T?-weighted magnetic resonance imaging (MRI) scans were made in a random subsample (n = 218) to obtain grey and white matter volume, and total brain volume (TBV). Plasma homocysteine, serum folate, vitamin B12, holotranscobalamin, and methylmalonic acid concentrations were measured.Multiple linear regression analyses showed inverse associations between plasma homocysteine with TBV (? = -0.91, 95% CI -1.85-0.03; p = 0.06) and between serum folate and TBV (? = -0.20, 95% CI -0.38, -0.02; p = 0.03). No significant associations were observed for serum vitamin B12 and holotranscobalamin. Fully adjusted ANCOVA models showed that the group that received B-vitamins had a lower TBV (adjusted mean 1064, 95% CI 1058-1069 mL) than the non-supplemented group (1072, 95% CI 1067-1078 mL, p = 0.03).Results were contradictory, with higher Hcy levels associated with lower TBV, but also with higher folate levels associated with lower TBV. In addition, the lack of a baseline measurement withholds us from giving recommendations on whether folic acid and vitamin B12 supplementation will be beneficial above and beyond normal dietary intake for brain health.
Project description:BACKGROUND:Maternal serum concentrations of folate, homocysteine, and vitamin B12 have been associated with pre-eclampsia. Nevertheless, reported studies involve limited number of cases to reliably assess the nature of these associations. Our aim was to examine the relation of these three biomarkers with pre-eclampsia risk in a large Colombian population. MATERIALS AND METHODS:Design: A case-control study. Setting: Cases of pre-eclampsia and healthy pregnant controls were recruited at the time of delivery from eight different Colombian cities between 2000 and 2012. Population or Sample: 2978 cases and 4096 controls were studied. Maternal serum concentrations of folate, homocysteine, and vitamin B12 were determined in 1148 (43.6%) cases and 1300 (31.7%) controls. Also, self-reported folic acid supplementation was recorded for 2563 (84%) cases and 3155 (84%) controls. Analysis: Adjusted odds ratios (OR) for pre-eclampsia were estimated for one standard deviation (1SD) increase in log-transformed biomarkers. Furthermore, we conducted analyses to compare women that reported taking folic acid supplementation for different periods during pregnancy. Main Outcomes Measures: Odds ratio for pre-eclampsia. RESULTS:After adjusting for potential confounders in logistic regression models, the OR for pre-eclampsia was 0.80 (95% CI: 0.72, 0.90) for 1SD increase in log-folate, 1.16 (95%CI: 1.05, 1.27) for 1SD increase in log-homocysteine, and 1.10 (95%CI: 0.99, 1.22) for 1SD increase in log-vitamin B12. No interactions among the biomarkers were identified. Women who self-reported consumption of folic acid (1 mg/day) throughout their pregnancy had an adjusted OR for pre-eclampsia of 0.86 (95%CI: 0.67, 1.09) compared to women that reported no consumption of folic acid at any point during pregnancy. CONCLUSIONS:Maternal serum concentrations of folate were associated as a protective factor for pre-eclampsia while concentrations of homocysteine were associated as a risk factor. No association between maternal vitamin B12 concentrations and preeclampsia was found.
Project description:Folate, and its synthetic form folic acid, function as donor of one-carbon units and have been, together with other B-vitamins, implicated in programming of epigenetic processes such as DNA methylation during early development. To what extent regulation of DNA methylation can be altered via B-vitamins later in life, and how this relates to health and disease, is not exactly known. The aim of this study was to identify effects of long-term supplementation with folic acid and vitamin B12 on genome-wide DNA methylation in elderly subjects. This project was part of a randomized, placebo-controlled trial on effects of supplemental intake of folic acid and vitamin B12 on bone fracture incidence (B-PROOF study). Participants with mildly elevated homocysteine levels, aged 65-75 years, were randomly assigned to take 400 µg folic acid and 500 µg vitamin B12 per day or a placebo during an intervention period of two years. DNA was isolated from buffy coats, collected before and after intervention, and genome-wide DNA methylation was determined in 87 participants (n=44 folic acid/vitamin B12, n=43 placebo) using the Infinium HumanMethylation450 BeadChip. After intervention with folic acid and vitamin B12, 162 (versus 14 in the placebo group) of the 431,312 positions were differentially methylated as compared to baseline. Comparisons of the DNA methylation changes in the participants receiving folic acid and vitamin B12 versus placebo, revealed one single differentially methylated position (cg19380919) with a borderline statistical significance. However, based on the analyses of differentially methylated regions (DMRs) consisting of multiple positions, we identified 6 regions that differed statistically significantly between the intervention and placebo group. Pronounced changes were found for regions in the DIRAS3, ARMC8 and NODAL genes, implicated in carcinogenesis and early embryonic development. Furthermore, serum levels of folate and vitamin B12 or plasma homocysteine were related to DNA methylation of 173, 425 and 11 regions, respectively. Interestingly, for several members of the developmental HOX genes, DNA methylation was related to serum levels of folate. Long-term supplementation with folic acid and vitamin B12 in elderly subjects resulted in effects on DNA methylation of several genes, among which genes implicated in developmental processes. Overall design: A randomized, placebo-controlled intervention trial was used to study the effects of long-term supplementation (2 year) with folic acid (400 µg/day) and vitamin B12 (500 µg/day) on DNA methylation in elderly subjects. This entry contains the DNA methylation data of DNA isolated from buffy coats collected before and after the intervention with folic acid / vitamin B12 or placebo.
Project description:Both taking folic acid-containing vitamins around conception and consuming food fortified with folic acid have been reported to reduce omphalocele rates. Genetic factors are etiologically important in omphalocele as well; our pilot study showed a relationship with the folate metabolic enzyme gene methylenetetrahydrofolate reductase (MTHFR). We studied 169 non-aneuploid omphalocele cases and 761 unaffected, matched controls from all New York State births occurring between 1998 and 2005 to look for associations with single nucleotide polymorphisms (SNPs) known to be important in folate, vitamin B12, or choline metabolism. In the total study population, variants in the transcobalamin receptor gene (TCblR), rs2232775 (p.Q8R), and the MTHFR gene, rs1801131 (c.1298A>C), were significantly associated with omphalocele. In African-Americans, significant associations were found with SNPs in genes for the vitamin B12 transporter (TCN2) and the vitamin B12 receptor (TCblR). A SNP in the homocysteine-related gene, betaine-homocysteine S-methyltransferase (BHMT), rs3733890 (p.R239Q), was significantly associated with omphalocele in both African-Americans and Asians. Only the TCblR association in the total population remained statistically significant if Bonferroni correction was applied. The finding that transcobalamin receptor (TCblR) and transporter (TCN2) SNPs and a BHMT SNP were associated with omphalocele suggests that disruption of methylation reactions, in which folate, vitamin B12, and homocysteine play critical parts, may be a risk factor for omphalocele. Our data, if confirmed, suggest that supplements containing both folic acid and vitamin B12 may be beneficial in preventing omphaloceles.
Project description:Homocysteine-lowering nutrients may have preventive/ameliorative roles in depression.To test whether long-term B-vitamin/folate supplementation reduces depression risk.Participants were 4331 women (mean age 63.6 years), without prior depression, from the Women's Antioxidant and Folic Acid Cardiovascular Study - a randomised controlled trial of cardiovascular disease prevention among 5442 women. Participants were randomly assigned to receive a combination of folic acid (2.5 mg/d), vitamin B6 (50 mg/d) and vitamin B12 (1 mg/d) or a matching placebo. Average treatment duration was 7 years. The outcome was incident depression, defined as self-reported physician/clinician-diagnosed depression or clinically significant depressive symptoms.There were 524 incident cases. There was no difference between active v. placebo groups in depression risk (adjusted relative risk 1.02, 95% CI 0.86-1.21, P = 0.81), despite significant homocysteine level reduction.Long-term, high-dose, daily supplementation with folic acid and vitamins B6 and B12 did not reduce overall depression risk in mid-life and older women.
Project description:Whey protein isolate (WPI) is high in vitamin B12 and folate. These and other related markers (holotranscobalamin, methylmalonic acid and homocysteine) have been linked with cognitive health. This study explored the efficacy of WPI for improving cognitive function via delivery of vitamin B12. Moderately vitamin B12-deficient participants aged between 45 and 75 years (n = 56) were recruited into this randomised controlled crossover trial. Participants (55% female) consumed 50 g whey (WPI; active) or soy protein isolate (SPI; control) for eight weeks. Following a 16-week washout phase, they consumed the alternative supplement. Consumption of WPI significantly improved active B12 and folate status but did not result in direct improvements in cognitive function. However, there was evidence of improvement in reaction time (p = 0.02) and reasoning speed (p = 0.04) in the SPI condition for females. Additional analyses showed that changes in active B12, HcY and folate measures during WPI treatment correlated with improvements in cognitive function (all p < 0.05). Results indicate that WPI itself did not result in improved cognitive function but some evidence of benefit of SPI for females was found. However, consistent with previous research, we present further evidence of a role for active B12, HcY and folate in supporting cognitive improvement in adults with low B vitamin status.
Project description:<h4>Objectives</h4>Deficiencies of vitamin B12 and folate are associated with delayed development and neurological manifestations. The objective of this study was to measure the effect of daily supplementation of vitamin B12 and/or folic acid on development in young North Indian children.<h4>Methods</h4>In a randomized, double blind trial, children aged six to 30 months, received supplement with placebo or vitamin B12 and/or folic acid for six months. Children were allocated in a 1:1:1:1 ratio in a factorial design and in blocks of 16. We measured development in 422 children by the Ages and Stages Questionnaire 3rd ed. at the end of the intervention.<h4>Results</h4>Compared to placebo, children who received both vitamin B12 and folic acid had 0.45 (95% CI 0.19, 0.73) and 0.28 (95% CI 0.02, 0.54) higher SD-units in the domains of gross motor and problem solving functioning, respectively. The effect was highest in susceptible subgroups consisting of stunted children, those with high plasma homocysteine (> 10 ?mol/L) or in those who were younger than 24 at end study. With the exception of a significant improvement on gross motor scores by vitamin B12 alone, supplementation of either vitamin alone had no effect on any of the outcomes.<h4>Conclusion</h4>Our findings suggest that supplementation of vitamin B12 and folic acid benefit development in North Indian Children.<h4>Trial registration</h4>ClinicalTrials.gov NCT00717730.
Project description:Homocysteinemia may play an etiologic role in the pathogenesis of type 2 diabetes by promoting oxidative stress, systemic inflammation, and endothelial dysfunction. We investigated whether homocysteine-lowering treatment by B vitamin supplementation prevents the risk of type 2 diabetes.The Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a randomized, double-blind, placebo-controlled trial of 5,442 female health professionals aged > or = 40 years with a history of cardiovascular disease (CVD) or three or more CVD risk factors, included 4,252 women free of diabetes at baseline. Participants were randomly assigned to either an active treatment group (daily intake of a combination pill of 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12) or to the placebo group.During a median follow-up of 7.3 years, 504 women had an incident diagnosis of type 2 diabetes. Overall, there was no significant difference between the active treatment group and the placebo group in diabetes risk (relative risk 0.94 [95% CI 0.79-1.11]; P = 0.46), despite significant lowering of homocysteine levels. Also, there was no evidence for effect modifications by baseline intakes of dietary folate, vitamin B6, and vitamin B12. In a sensitivity analysis, the null result remained for women compliant with their study pills (0.92 [0.76-1.10]; P = 0.36).Lowering homocysteine levels by daily supplementation with folic acid and vitamins B6 and B12 did not reduce the risk of developing type 2 diabetes among women at high risk for CVD.
Project description:Folate and its synthetic form folic acid function as donor of one-carbon units and have been, together with other B-vitamins, implicated in programming of epigenetic processes such as DNA methylation during early development. To what extent regulation of DNA methylation can be altered via B-vitamins later in life, and how this relates to health and disease, is not exactly known. The aim of this study was to identify effects of long-term supplementation with folic acid and vitamin B12 on genome-wide DNA methylation in elderly subjects. This project was part of a randomized, placebo-controlled trial on effects of supplemental intake of folic acid and vitamin B12 on bone fracture incidence (B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF) study). Participants with mildly elevated homocysteine levels, aged 65-75 years, were randomly assigned to take 400 ?g folic acid and 500 ?g vitamin B12 per day or a placebo during an intervention period of 2 years. DNA was isolated from buffy coats, collected before and after intervention, and genome-wide DNA methylation was determined in 87 participants (n?=?44 folic acid/vitamin B12, n?=?43 placebo) using the Infinium HumanMethylation450 BeadChip.After intervention with folic acid and vitamin B12, 162 (versus 14 in the placebo group) of the 431,312 positions were differentially methylated as compared to baseline. Comparisons of the DNA methylation changes in the participants receiving folic acid and vitamin B12 versus placebo revealed one single differentially methylated position (cg19380919) with a borderline statistical significance. However, based on the analyses of differentially methylated regions (DMRs) consisting of multiple positions, we identified 6 regions that differed statistically significantly between the intervention and placebo group. Pronounced changes were found for regions in the DIRAS3, ARMC8, and NODAL genes, implicated in carcinogenesis and early embryonic development. Furthermore, serum levels of folate and vitamin B12 or plasma homocysteine were related to DNA methylation of 173, 425, and 11 regions, respectively. Interestingly, for several members of the developmental HOX genes, DNA methylation was related to serum levels of folate.Long-term supplementation with folic acid and vitamin B12 in elderly subjects resulted in effects on DNA methylation of several genes, among which genes implicated in developmental processes.
Project description:PURPOSE:We compare the effect of 8-week oral supplementation with cyano-B12 (currently used in vitamin pills) and hydroxo-B12 (predominant form in the diet) in a population with nutritional vitamin B12 deficiency. METHODS:Fifty-one healthy Indian adults with baseline serum cobalamin < 200 pmol/L were supplied for 8 weeks with daily oral supplements of 3-µg cyano-B12 (n = 15), 3-µg hydroxo-B12 (n = 16), or a placebo (n = 20). Blood at baseline, and each following week, was examined for total cobalamin, holotranscobalamin, methylmalonic acid, and homocysteine. RESULTS:The study groups did not differ at baseline and were characterized by [median (range)] serum cobalamin [128 (68-191) pmol/L], holotranscobalamin [16 (6-41) pmol/L], methylmalonic acid [0.8 (0.3-1.7) µmol/L], homocysteine [17.9 (8.5-100.9) µmol/L], and a combined indicator of B12 status 4cB12 of - 1.65 (- 0.64 to - 4.07). The group supplemented with cyano-B12 showed a higher increase in total serum cobalamin than the group treated with hydroxo-B12, while other biomarkers changed comparably in the two groups. After 8 weeks of treatment, the biomarker values of the supplemented groups (pooled) differed significantly from the placebo group. Yet, the vitamin B12 status was still poor [cobalamin: 168 (87-302) pmol/L; holotranscobalamin: 19 (8-45) pmol/L; methylmalonic acid: 0.7 (0.2-1.7) µmol/L; homocysteine: 17.2 (2.6-96.8) µmol/L; 4cB12 = - 1.34 (- 0.33 to - 3.3)]. CONCLUSION:8-week supplementation with 3-µg cyano-B12 elevated serum cobalamin more than 3 µg hydroxo-B12, but all other biomarkers changed similarly in both groups. Supplementation with 3 µg vitamin B12 did not reverse the low status in individuals with nutritional vitamin B12 deficiency. CLINICAL TRIAL REGISTRY OF INDIA:REF/2017/02/013343.