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Previous studies show that B vitamins and homocysteine (Hcy) may be associated with mental disorders, but the accurate causal relationship remains unclear. This study aimed to elucidate the potential causal relationship of serum B vitamins and Hcy levels with five common mental disorders through a two-sample Mendelian randomization (MR) study. In this MR analysis, 50 single-nucleotide polymorphisms (SNPs)-13 related to folate, 17 to vitamin B6, 8 to vitamin B12 and 12 to Hcy-were obtained from a large-scale Genome-Wide Association Studies (GWAS) database and employed as instrumental variables (IVs). The MR analyses were conducted using the inverse variance weighted (IVW), weighted median (WM), MR-Egger methods and sensitivity analyses were further performed to test the robustness. This MR study found a suggestive causal relationships between serum vitamin B12 levels and the risk of anxiety disorders (odds ratio (OR): 1.34, 95% confidence interval (CI): 1.01-1.78, p = 0.046) and bipolar affective disorders (OR: 1.85, 95% CI: 1.16-2.96, p = 0.010). However, folate, vitamin B6 and Hcy levels may not be causally associated with the risk of mental disorders. In conclusion, this study reveals that elevated serum vitamin B12 levels might suggestively increase the risk of anxiety and bipolar affective disorders, even though horizontal pleiotropy cannot be completely eliminated. The potential implications of our results warrant validation in larger GWAS based on diverse populations.

Objective: Previous observational studies have identified a correlation between elevated plasma homocysteine (Hcy) levels and polycystic ovary syndrome (PCOS). This study aimed to determine whether a causal relationship exists between Hcy and PCOS at the genetic level., Methods: A two-sample Mendelian Randomization (TSMR) study was implemented to assess the genetic impact of plasma levels of Hcy, folate, vitamin B12, and vitamin B6 on PCOS in individuals of European ancestry. Independent single nucleotide polymorphisms (SNPs) associated with Hcy (n=12), folate (n=2), vitamin B12 (n=10), and vitamin B6 (n=1) at genome-wide significance levels ( P <5×10 -8 ) were selected as instrumental variables (IVs). Data concerning PCOS were obtained from the Apollo database. The primary method of causal estimation was inverse variance weighting (IVW), complemented by sensitivity analyses to validate the results., Results: The study found no genetic evidence to suggest a causal association between plasma levels of Hcy, folate, vitamin B12, vitamin B6, and PCOS. The effect sizes, determined through random-effect IVW, were as follows: Hcy per standard deviation increase, OR = 1.117, 95%CI: (0.842, 1.483), P = 0.442; folate per standard deviation increase, OR = 1.008, CI: (0.546, 1.860), P = 0.981; vitamin B12 per standard deviation increase, OR = 0.978, CI: (0.808, 1.185), P = 0.823; and vitamin B6 per standard deviation increase, OR = 0.967, CI: (0.925, 1.012), P = 0.145. The fixed-effect IVW results for each nutrient exposure and PCOS were consistent with the random-effect IVW findings, with additional sensitivity analyses reinforcing these outcomes., Conclusion: Our findings indicate no causal link between Hcy, folate, vitamin B12, vitamin B6 levels, and PCOS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Su, Li, Xia, Huang and Chen.)

The role of haem in the activity of cystathionine β-synthase (CBS) is reviewed and a hypothesis postulating multiple effects of haem on enzyme activity under conditions of haem excess or deficiency is proposed, with implications for some therapies of acute hepatic porphyrias. CBS utilises both haem and pyridoxal 5'-phosphate (PLP) as cofactors. Although haem does not participate directly in the catalytic process, it is vital for PLP binding to the enzyme and potentially also for CBS stability. Haem deficiency can therefore undermine CBS activity by impairing PLP binding and facilitating CBS degradation. Excess haem can also impair CBS activity by inhibiting it via CO resulting from haem induction of haem oxygenase 1 (HO 1), and by induction of a functional vitamin B6 deficiency following activation of hepatic tryptophan 2,3-dioxygenase (TDO) and subsequent utilisation of PLP by enhanced kynurenine aminotransferase (KAT) and kynureninase (Kynase) activities. CBS inhibition results in accumulation of the cardiovascular risk factor homocysteine (Hcy) and evidence is emerging for plasma Hcy elevation in patients with acute hepatic porphyrias. Decreased CBS activity may also induce a proinflammatory state, inhibit expression of haem oxygenase and activate the extrahepatic kynurenine pathway (KP) thereby further contributing to the Hcy elevation. The hypothesis predicts likely changes in CBS activity and plasma Hcy levels in untreated hepatic porphyria patients and in those receiving hemin or certain gene-based therapies. In the present review, these aspects are discussed, means of testing the hypothesis in preclinical experimental settings and porphyric patients are suggested and potential nutritional and other therapies are proposed., (© 2021 The Author(s).)

The central position of methionine (Met) in protein metabolism indicates the importance of this essential amino acid for growth and maintenance of lean body mass. Therefore, Met might be a tempting candidate for supplementation. However, because Met is also the precursor of homocysteine (Hcy), a deficient intake of B vitamins or excessive intake of Met may result in hyperhomocysteinemia (HHcy), which is a risk factor for cardiovascular disease. This review discusses the evidence generated in preclinical and clinical studies on the importance and potentially harmful effects of Met supplementation and elaborates on potential clinical applications of supplemental Met with reference to clinical studies performed over the past 20 y. Recently acquired knowledge about the NOAEL (no observed adverse effect level) of 46.3 mg · kg-1 · d-1 and the LOAEL (lowest observed adverse effect level) of 91 mg · kg-1 · d-1 of supplemented Met will guide the design of future studies to further establish the role of Met as a potential (safe) candidate for nutritional supplementation in clinical applications., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Objective: To evaluate the effect of folate and vitamin B 12 levels on pregnancy progression and outcomes., Methods: The present study is a prospective follow up study of 100 pregnant women. Biochemical investigations (plasma homocysteine, folate, and vitamin B 12 levels) were performed on all pregnant women in first, second, and third trimesters. Nonparametric tests were used to compare the differences in median levels and odds ratio analysis for the assessment of the risk between the selected biomarkers and adverse pregnancy progression and outcomes., Results: The pregnant women at their first antenatal care visit were found to be predominantly folate replete (97%) and vitamin B 12 deficient (60%). Hyperhomocysteinemia in first and second trimesters was found to pose more than 3-fold increased risk for adverse pregnancy outcomes (P = .006 and .0002, respectively). Low birth weight (LBW) was found to be the most common adverse pregnancy outcome (52%), and was significantly associated with vitamin B 12 deficiency in the first and second trimesters (82%, P < .0001; 71.4%, P = .04, respectively)., Conclusion: The vitamin B 12 deficiency is more common among Indian pregnant women as compared to folate deficiency. Hyperhomocysteinemia is an independent risk factor for pregnancy complications. Vitamin B 12 deficiency in first and second trimesters is associated with LBW babies., (© 2020 Wiley Periodicals, Inc.)

Background: Diet may influence vascular function through elevated homocysteine (Hcy) concentrations. However the relationship between dietary patterns (DP), characterised by Hcy and its associated nutrients is unknown., Objective: To identify a DP characterised by plasma Hcy, dietary folate and dietary vitamin B12, and examine its associations with two markers of vascular function: carotid intima-media thickness (cIMT) and pulse wave velocity (PWV)., Methods: 1562 participants of the MRC National Survey of Health and Development (NSHD), a British birth cohort, with dietary data measured at least once between 36 and 60-64 years, and cIMT or PWV measured at 60-64 years were included. DPs were derived using reduced rank regression with three intermediate variables: 1) plasma Hcy (μmol/L) 2) folate intake (μg/1000 kcal) 3) vitamin B12 intake (μg/1000 kcal). Multiple regression models assessed associations between the derived DP z-scores and vascular function adjusting for dietary misreporting, socioeconomic position, BMI, smoking, physical activity and diabetes., Results: A DP explaining the highest amount of shared variation (4.5%) in plasma Hcy, dietary folate and dietary vitamin B12 highly correlated with folate (r = 0.96), moderately correlated with vitamin B12 (r = 0.27), and weakly correlated with Hcy (r = 0.10). This "high B-vitamin" DP (including folate) was characterised by high intakes of vegetables, fruit and low fibre breakfast cereal, and low intakes of processed meat, white bread, sugar and preserves. No associations were observed between DP z-scores and vascular function at any time point following adjustment for covariates., Conclusion: This study explored a specific hypothesised pathway linking diet to vascular function. Although we found no consistent evidence for an association between a high B-vitamin DP and vascular function, we did observe an association with CRP and triglycerides in secondary analyses. Further analyses using strongly correlated and biologically relevant intermediate variables are required to refine investigations into diet and CVD in longitudinal cohort data., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Mental health disorders are major contributors to disease burden in older people. Deficient status of folate and the metabolically related B vitamins may be implicated in these conditions. This study aimed to investigate folate, vitamin B 12 , vitamin B 6 , and riboflavin in relation to depression and anxiety in aging and also considered the role of fortified foods as a means of optimizing B-vitamin status and potentially reducing the risk of these mental health disorders., Design: The Trinity Ulster Department of Agriculture (TUDA) aging study was a cross-sectional cohort study., Setting and Participants: Community-dwelling adults (n = 5186; ≥60 years) recruited from 2 jurisdictions within the island of Ireland from 2008 to 2012., Measures: Depression and anxiety were assessed using the Centre for Epidemiological Studies Depression (CES-D) and the Hospital Anxiety and Depression (HAD) scales, respectively. The following B-vitamin biomarkers were measured: red blood cell folate, serum total vitamin B 12 , plasma pyridoxal-5-phosphate (PLP; vitamin B 6 ), and erythrocyte glutathione reductase activation coefficient (EGRac; riboflavin)., Results: Biomarker values in the lowest 20% of status for folate (odds ratio [OR] 1.79; 95% CI 1.23-2.61), vitamin B 6 (OR 1.45, 95% CI 1.01-2.06), or riboflavin (OR 1.56, 95% CI 1.10-2.00), but not vitamin B 12 , were each associated with an increased risk of depression (CES-D score ≥16). Correspondingly, B vitamin-fortified foods if consumed daily were associated with a reduced risk of depression (OR 0.54, 95% CI 0.41-0.70). A deficient status of vitamin B 6 (OR 1.73, 95% CI 1.07-2.81), but not other vitamins, was associated with increased anxiety., Conclusions/implications: Better B-vitamin status may have a role in impacting positively on mental health in older adults. Regular intake of fortified foods can provide a means of optimizing B-vitamin status and thus could contribute to reducing depression. If confirmed by a randomized trial, these results may have implications for nutrition and mental health policy, and thus quality of life, in older people., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Background: Imbalance of homocysteine (Hcy) metabolism links with several pathologies; nevertheless, it is poorly characterized in pediatric populations. This study investigated the impact of age on plasma concentrations of Hcy and relevant biomarkers along with correspondent genotype interactions., Methods: A healthy pediatric cohort aged 9 ( n = 195) and 17 ( n = 128) years old (yo) was studied. Immunoassays and GC-MS-SIM-mode quantified plasma levels of Hcy and biomarkers. PCR-RFLP or quantitative-PCR assays assessed common variations in related genes., Results: Age impacted on levels of Hcy and metabolic markers: older children presented with the lowest folates and total-cobalamin (tCbl), while with the highest Hcy concentrations, whereas methylmalonic acid (MMA) and holotranscobalamin (Holo-TC) levels remained similar in 9-yo and 17-yo children. The relationships between B-vitamins and metabolic markers were also dependent on age. Only in the older children, MMA correlated with tCbl and Holo-TC, and MMA levels were markedly higher in the 17-yo subjects presenting with the lowest quartiles of Holo-TC concentrations. Lastly, age also impacted on the correlations between genotype and biomarkers. In the 17-yo group, however not in the 9-yo children, tHcy differed between MTHFR 677 genotypes, with subjects who had the MTHFR 677TT genotype displaying the highest tHcy concentrations., Conclusions: Age impacts on the Hcy metabolism dynamics in a pediatric population.

Vitamin B deficiency in patients with inflammatory bowel disease (IBD) is well-documented; however, few studies have explored genomic damage in patients with IBD using the cytokinesis-block micronucleus cytome (CBMN-Cyt) assay. This study investigated the frequency of micronuclei (MNi) using the CBMN-Cyt assay and the level of vitamin B in patients with IBD. This prospective study was conducted in 15 patients with ulcerative colitis, 15 patients with Crohn's disease, and 30 healthy controls from one tertiary hospital. Serum vitamin B and homocysteine levels were measured, and the MNi status was analyzed using the CBMN-Cyt assay. The patients with IBD showed significantly lower serum pyridoxine levels and significantly higher homocysteine levels than controls. The frequencies of binucleated cells (BNCs) with MNi, nucleoplasmic bridges (NPBs), and nuclear buds (Nbuds) were 8.5 [5.8-13.5], 1.0 [0.0-1.9], and 5.4 [4.3-7.4] for the IBD group, and 5.9 [4.8-7.7], 0.2 [0.0-1.0], and 3.5 [2.9-5.4] for the control group (P =  0.011, P =  0.010, and P =  0.002), respectively. This study suggests that patients with IBD have increased frequencies of MNi and decreased levels of pyridoxine than healthy controls., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Hemodialysis (HD) with dialysis adequacy could increase the excretion of B vitamins (folate, vitamin B 6 , and B 12 ) and raise the plasma level of homocysteine. Here we determined the associations of plasma homocysteine with B vitamins in patients with HD adequacy or inadequacy., Methods: We recruited 68 patients who had received HD treatments (three times a week, 4 h each). Based on the individual's hemogram and quarterly urea reduction rate (Kt/V), patients were pooled into one of the following two groups: the first group with dialysis adequacy (Kt/V > 1.2, n = 48) and the second with dialysis inadequacy (Kt/V ≤ 1.2, n = 20). We also recorded the anthropometric date of each patient and their biochemical data and dietary intakes. Plasma levels of homocysteine, cysteine, folate, pyridoxal 5'-phosphate (PLP), and vitamin B 12 were measured twice, once before and once after HD., Results: The plasma levels of homocysteine, cysteine, folate, PLP, and vitamin B 12 dropped significantly at the end of HD. The plasma levels of vitamin B 12 were negatively correlated with the plasma levels of homocysteine, both pre- and post-HD, and in both groups regardless of dialysis adequacy or inadequacy. In contrast, plasma levels of folate and PLP were not correlated with homocysteine at both pre- or post-HD in both groups., Conclusions: The plasma level of vitamin B 12 , but not folate or vitamin B 6 , was negatively correlated with that of homocysteine both before and after HD treatment, and regardless of dialysis adequacy or inadequacy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: This post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial) assessed the individual variation in total homocysteine (tHcy)-lowering response after an average 4.5 years of 0.8 mg daily folic acid therapy in Chinese hypertensive adults and evaluated effect modification by methylenetetrahydrofolate reductase ( MTHFR ) C677T genotypes and serum folate levels., Approach and Results: This analysis included 16 413 participants from the CSPPT, who were randomly assigned to 2 double-blind treatment groups: either 10-mg enalapril+0.8-mg folic acid or 10-mg enalapril, daily and had individual measurements of serum folate and tHcy levels at baseline and exit visits and MTHFR C677T genotypes. Mean baseline tHcy levels were comparable between the 2 treatment groups (14.5±8.5 versus 14.4±8.1 μmol/L; P =0.561). After 4.5 years of treatment, mean tHcy levels were reduced to 12.7±6.1 μmol/L in the enalapril+folic acid group, but almost stayed the same in the enalapril group (14.4±7.9 μmol/L, group difference: 1.61 μmol/L; 11% reduction). More importantly, tHcy lowering varied by MTHFR genotypes and serum folate levels. Compared with CC and CT genotypes, participants with the TT genotype had a more prominent L-shaped curve between tHcy and serum folate levels and required higher folate levels (at least 15 ng/mL) to eliminate the differences in tHcy by genotypes., Conclusions: Compared with CC or CT, tHcy in the TT group manifested a heightened L-shaped curve from low to high folate levels, but this difference in tHcy by genotype was eliminated when plasma folate levels reach ≈15 ng/mL or higher. Our data raised the prospect to tailor folic acid therapy according to individual MTHFR C677T genotype and folate status., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885., (© 2018 American Heart Association, Inc.)

Folic acid (FA) supplementation reduces the elevated serum homocysteine (Hcy) concentrations. [6 S]-5-methyltetrahydrofolate ([6 S]-5-MTHF) is an alternative to FA due to possible advantages, that is, no masking cobalamin deficiency. The study aim was to evaluate the effectiveness of [6 S]-5-MTHF in relations to FA supplementation in reducing the serum Hcy. Healthy volunteers, aged 50-65, had normal serum folate and did not use supplements with B-vitamins for 6 months. Forty subjects were divided into two groups: receiving 400 μg/d FA or the equimolar amount of [6 S]-5-MTHF. Blood was collected at baseline and after 4 weeks. In both groups, a significant decrease in the mean Hcy level after intervention period was observed. Supplementation with [6 S]-5-MTHF was slightly less effective, but not significantly, in Hcy lowering than FA (p = .243 between the groups), that is, by 7.8% and 13.4%, respectively. The [6 S]-5-MTHF was shown to be an adequate alternative to FA in reducing Hcy concentrations.

Background: Functional (metabolic) markers of B-vitamin status, including plasma total homocysteine (tHcy) for folate and plasma methylmalonic acid (MMA) for vitamin B-12, suffer from moderate sensitivity and poor specificity. Ratios of metabolites belonging to the same pathway may have better performance characteristics. Objective: We evaluated the ratios of tHcy to total cysteine (tCys; Hcy:Cys), tHcy to creatinine (Hcy:Cre), and tHcy to tCys to creatinine (Hcy:Cys:Cre) as functional markers of B-vitamin status represented by a summary score composed of folate, cobalamin, betaine, pyridoxal 5'-phosphate (PLP), and riboflavin concentrations measured in plasma. Methods: Cross-sectional data were obtained from a cohort of patients with stable angina pectoris (2994 men and 1167 women) aged 21-88 y. The relative contribution of the B-vitamin score, age, sex, smoking, body mass index, and markers of renal function and inflammation to the variance of the functional B-vitamin markers was calculated by using multiple linear regression. Results: Compared with tHcy alone, Hcy:Cys, Hcy:Cre, and Hcy:Cys:Cre all showed improved sensitivity and specificity for detecting plasma B-vitamin status. Improvements in overall performance ranged from 4-fold for Hcy:Cys to ∼8-fold for Hcy:Cys:Cre and were particularly strong in subjects with the common 5,10-methylenetetrahydrofolate reductase (MTHFR) 677CC genotype. Conclusions: Ratios of tHcy to tCys and/or creatinine showed a severalfold improvement over tHcy alone as functional markers of B-vitamin status in Norwegian coronary angiography screenees. The biological rationale for these ratios is discussed in terms of known properties of enzymes involved in the catabolism of homocysteine and synthesis of creatine and creatinine., Competing Interests: 2: Author disclosures: A Ulvik, S Hustad, A McCann, Ø Midttun, O Nygård, and PM Ueland, no conflicts of interest., (© 2017 American Society for Nutrition.)

Background/objectives: Observationally, homocysteine is positively associated with ischemic heart disease (IHD) and unhealthy lipids; folate and vitamin B12, which reduce homocysteine, are associated with lower IHD risk and healthy lipids. Randomized controlled trials have shown no benefits of folate and vitamin B12 for IHD. To clarify the role of these potential targets of intervention in IHD we assessed how genetically determined homocysteine, folate and vitamin-B12-affected IHD and lipids., Subjects/methods: Separate-sample instrumental variable analysis with genetic instruments, that is, Mendelian randomization, was used to obtain unconfounded estimates (based on strongly related single-nucleotide polymorphisms (SNPs)) using CARDIoGRAMplusC4D, a large coronary artery disease/myocardial infarction (CAD/MI) case (n=64 374)-control (n=130 681) study with extensive genotyping, and the Global Lipids Genetics Consortium Results (n=196 475)., Results: Homocysteine was unrelated to CAD/MI (odds ratio (OR) 1.07 per log-transformed s.d., 95% confidence interval (CI) 0.96 to 1.19) based on 14 SNPs, as was folate (OR 1.18 per s.d., 95% CI 0.80 to 1.75) based on rs153734, and vitamin B12 (OR 0.98 per log-transformed s.d., 95% CI 0.85 to 1.14) based on rs602662, rs9473555, rs526934 and rs11254363. Homocysteine and folate were not clearly associated with lipids, vitamin B12 was associated with higher inverse normal transformed low-density lipoprotein cholesterol (0.07, 95% CI 0.02 to 0.12) and triglycerides (0.05, 95% CI 0.004 to 0.09)., Conclusions: Our findings do not corroborate the observed positive association of homocysteine or negative associations of folate and vitamin B12 with CAD/MI. Vitamin B12 might be associated with an unfavorable lipid profile.

Objectives: Diet has been recognised as a crucial factor influencing fetal and maternal health. Adequate levels of substances such as homocysteine, folate and vitamin B 12 have been associated with a higher rate of success in infertility treatments. Few data, however, are available on the average levels of micronutrients in the blood of reproductive-aged women, and specific values for adequate levels are not available. The aim of this cross-sectional study was to measure levels of folate, homocysteine and selected vitamins and minerals in women attending the infertility unit of an academic hospital for in vitro fertilisation (IVF)., Methods: Fasting venous blood samples were taken in the morning during routine screening before IVF in order to measure: serum folate, red blood cell (RBC) folate, total plasma homocysteine, vitamin B 12 , vitamin A, vitamin E, serum iron and serum ferritin., Results: Among 269 women aged 37 ± 4 years, only 69% and 44% showed adequate levels of homocysteine and vitamin B 12 , respectively. Serum folate was appropriate in 78% of the study participants, but only a minority (12%) had a concentration of RBC folate regarded as optimal for the prevention of fetal neural tube defects. Serum levels of vitamin A, vitamin E, iron and ferritin were, however, appropriate in the vast majority of participants (>80%)., Conclusion: Folate levels were largely inadequate among women attending an infertility clinic for IVF. Vitamin B 12 levels were also found to be inadequate.

Increase in serum homocysteine is shown to be a potential risk factor for cognitive impairment. Evidence suggests that vitamin B supplementation may reduce cognitive decline by lowering the homocysteine levels. The current meta-analysis evaluated the efficacy of folic acid along with vitamin B12 and/or B6 in lowering homocysteine, thereby attenuating cognitive decline in elderly patients with Alzheimer disease or dementia. Randomized controlled trials (RCTs) comparing the efficacy of folate and B vitamin supplementation in patients with cognitive decline secondary to Alzheimer disease or dementia were identified using the keywords, "homocysteine, hyper-homocysteinemia, B vitamin, vitamin B6, B12, folic acid, cognitive, Alzheimer's disease, and dementia." The outcome measures analyzed were the Mini-Mental State Examination (MMSE) score and serum homocysteine. Of the 77 studies identified, 4 RCTs were included in the current meta-analysis. The baseline characteristics, age, and gender distribution of patients among the 2 groups (supplement vs placebo) were comparable. The results reveal that the intervention group achieved significantly greater reduction in homocysteine levels than the control (pooled difference in means = -3.625, 95% confidence interval [CI] = -5.642 to -1.608, P < .001). However, no significant difference in MMSE (pooled difference in means = 0.027, 95% CI = -0.518 to 0.573, P = 0.921) was observed between the groups. Taken together, vitamin B supplementation was effective in reducing serum homocysteine levels. However, it did not translate into cognitive improvement, indicating that the existing data on vitamin B-induced improvement in cognition by lowering homocysteine levels are conflicting.

Cognitive decline is one of the major causes of disability in older people. A high level of homocysteine, a byproduct of vitamin B, has been linked to brain atrophy, which itself is a precursor to cognitive decline leading to dementia and Alzheimer's disease. In addition, a low level of vitamin B is often noted in patients with dementia and Alzheimer's disease and its supplementation has been shown to improve memory and to slow the progress of brain atrophy. This information may aid in the use of vitamin B as a preventative measure against severe cognitive decline, and thus reduce the onset of conditions such as dementia and Alzheimer's disease., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Chronic arsenic toxicity is a serious environmental health problem across the world. Bangladesh and India (particularly the state of West Bengal) are the worst affected countries with such problem. The present study reports plasma-aminothiols (p-aminothiols) like L-cysteine (L-Cys), cysteinyl glycine (Cys-gly), total homocysteine (t-Hcy) and glutathione (GSH) status, and the inverse relationship of t-Hcy with B-vitamins (B1, B6, B9 and B12) in arsenic exposed population of West Bengal, India. Reverse phase HPLC was used to measure p-aminothiols and serum B-vitamins in different arsenic exposed population. Arsenic in drinking water and urine were measured by flow injection analysis system - Atomic Absorption Spectrometry (FIAS-AAS) and Transversely heated graphite atomizer (THGA-AAS) techniques, respectively. Water arsenic exposure was >50 µg/L in 50% population, of which majority (33.58%) belong to the range of >50-500 µg/L and more than 8% were even >1000 µg/L. Urine arsenic (µg/g creatinine) levels increased with arsenic exposure. The variability among p-aminothiols was also observed with higher exposure to arsenic in drinking water. A significant difference between exposed and control population was noticed for plasma L-Cys. The difference of B-vitamins between the population exposed to <50 and >50 µg/L arsenic in drinking water was also found to be significant. B9 and B12 deficiency with increased consumption of arsenic in water corroborates the anemic conditions commonly observed among arsenic exposed population. The aminothiol status indicated oxidative stress in exposed population. This study demonstrated progressive increase in plasma t-Hcy as well as inverse relationships of serum B-vitamins with increased water arsenic concentration.

Background and Objective: The increased mortality risk of hyperhomocysteinaemia in diabetes may be mitigated by dietary quality., Methods and Study Design: The Nutrition and Health Survey in Taiwan of 1999-2000 for elders formed this prospective cohort. Baseline health status, diet and anthropometry were documented and plasma homocysteine and biomarkers for B vitamins measured. Participants without diabetes (n=985) were referent for those who had diabetes or developed diabetes until 2006 (n=427). The effect of homocysteine on mortality risk during 1999-2008 was evaluated., Results: Men, smokers and those with poorer physical function had higher homocysteine, but less so with diabetes. Diabetes incidence was unrelated to homocysteine. In hyperhomocysteinaemia (>=15 vs <15 μmol/L), those with diabetes had an adjusted hazard ratio (HR) (95% CI) for mortality of 1.71 (1.18-2.46); p for interaction between homocysteine and diabetes was 0.005. Without diabetes, but with hyperhomocysteinaemia and a low dietary diversity score (DDS <=4 of 6), where the joint mortality hazard for the greater DDS, (>4) and lower homocysteine (<15) was referent, the HR was 1.80 (1.27-2.54) with significant interaction (p=0.008); by contrast, there was no joint effect with diabetes. The contribution of DDS to mortality mitigation in hyperhomocysteinaemia could not be explained by B group vitamins, even though plasma folate was low in hyperhomocysteinaemic participants. With hyperhomocysteinaemia, heart failure was a major cause of death., Conclusions: In non-diabetic hyperhomocysteinaemia, a more diverse diet increases survival prospects independent of B group vitamins, but not in hyperhomocysteinaemic diabetes where the cardiomyopathy may be less responsive.

Objective: To evaluate the usefulness of serial determinations of asymmetric dimethylarginine (ADMA) and homocysteine (Hcy) concentrations during pregnancy to predict pre-eclampsia, taking into account maternal obesity and B vitamin status., Design: Longitudinal study., Setting: Two obstetric referral hospitals., Sample: Two hundred and fifty-two of 411 women invited to participate in the study., Methods: The women made monthly visits from ≤20 weeks of gestation until delivery for measurements of plasma ADMA, Hcy, and vitamins B6 , B12, and folic acid, and for the recording of clinical information., Main Outcome Measure: Early elevations in plasma ADMA and Hcy related to the development of pre-eclampsia., Results: Of the 252 women who completed the study, 179 had no complications, 49 developed pre-eclampsia, and 24 presented with complications other than pre-eclampsia. ADMA and Hcy increased gradually throughout pregnancy in the pre-eclampsia group, independent of maternal B-vitamin status and obesity, but remained constant in women with no complications. Relative to the preceding month, ADMA and Hcy levels increased 1 month prior to the onset of pre-eclampsia: 124 ± 27 nmol (P < 0.001) and 1177 ± 278 nmol (P = 0.001), respectively, in the pre-eclampsia group. The group of women with no complications did not show any significant changes. Increases of 80 nmol ADMA and 1000 nmol Hcy at 1 month prior to the onset of pre-eclampsia demonstrated the best potential for prediction., Conclusions: Increased ADMA and Hcy levels precede clinical manifestations of pre-eclampsia. Therefore, serial determinations of their concentrations may be helpful in identifying women at risk., Tweetable Abstract: Increased ADMA and Hcy precede clinical pre-eclampsia and may identify women at risk., (© 2015 Royal College of Obstetricians and Gynaecologists.)

This study explored the effects of four-week multi-vitamin and mineral (MVM) supplementation on mood and neurocognitive function in healthy, young adults. Fifty-eight healthy adults, 18-40 years of age (M = 25.82 years, SD = 4.87) participated in this randomised, double-blind, placebo-controlled trial, in which mood and blood biomarkers were assessed at baseline and after four weeks of supplementation. Compared to placebo, MVM supplementation was associated with significantly lowered homocysteine and increased blood B-vitamin levels (p < 0.01). MVM treatment was also associated with significantly improved mood, as measured by reduced scores on the "depression-dejection" subscale of the Profile of Mood States (p = 0.018). These findings suggest that the four weeks of MVM supplementation may have beneficial effects on mood, underpinned by elevated B-vitamins and lowered homocysteine in healthy young adults.

Oxidative stress induced interactions between fatty acid (FA) and one-carbon metabolism may be involved in co-occurrence of major depressive disorder (MDD) and cardiovascular disease (CVD), which have been scarcely studied together. In 137 recurrent MDD-patients vs. 73 age- and sex-matched healthy controls, we simultaneously measured key components of one-carbon metabolism in plasma (homocysteine, folate, vitamins B6 and B12), and of FA-metabolism in red blood cell membranes [main polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA) and structural FA-indices (chain length, unsaturation, peroxidation)]. Results show significant positive associations of folate with EPA, DHA, and the peroxidation index, which were similar in patients and controls. After correction for confounders, these associations were lost except for EPA. Associations between B-vitamins and FA-parameters were non-significant, but also similar in patients and controls. Homocysteine and DHA were significantly less negatively associated in patients than in controls. In conclusion, these data indicate similarities but also differences in associations between parameters of one-carbon and FA-metabolism in recurrent MDD patients vs. controls, which may reflect differences in handling of oxidative stress. Further research should test the consequences of these differences, particularly the premature development of CVD in MDD., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: The only treatment for celiac disease is the gluten-free diet. Few studies have assessed the nutritional adequacy of this diet, especially of B vitamins related to homocysteine metabolism. The aim of this study was to assess the nutritional status and serum concentrations of B vitamins involved in homocysteine metabolism, and to determine whether the dietary intake of these vitamins are meeting Dietary Reference Intakes in celiac patients., Methods: A cross-sectional study enrolled a total of 20 celiac patients (36.3 ± 13.7 years old; 65% women), following strict gluten-free diet (GFD) and 39 healthy controls matched by sex and age. The dietary intake was assessed by 3-day food records, and serum concentrations of homocysteine and vitamins B6, B12, and folate were determined after overnight fasting. Comparisons between the two groups were performed by Student's t test or Mann-Whitney U-test, for continuous variables. Pearson's chi-square test or Fisher's exact test was used for categorical variables. An alpha level of 5% were considered significant., Results: Celiac patients had lower serum folate concentrations (7.7 ± 3.5 ng/mL, P < 0.05) than controls. All celiac patients had folate intake below the Estimated Average Requirement (EAR) (130.8 ± 53.6 μg/d). However, only a small proportion of celiac patients had hyperhomocysteinemia., Conclusions: Celiac patients treated with GFD presented inadequacy of dietary folate intake and low-serum concentrations of folate, suggesting that more attention should be given to the quality of the nutrients offered by the GFD, as it constitutes a lifelong treatment.

Hyperhomocysteinemia is a recognized risk factor for cognitive decline and incident dementia in older adults. Two recent reports addressed the cumulative epidemiological evidence for this association but expressed conflicting opinions. Here, the evidence is reviewed in relation to Sir Austin Bradford Hill's criteria for assessing "causality," and the latest meta-analysis of the effects of homocysteine-lowering on cognitive function is critically examined. The meta-analysis included 11 trials, collectively assessing 22,000 individuals, that examined the effects of B vitamin supplements (folic acid, vitamin B12, vitamin B6) on global or domain-specific cognitive decline. It concluded that homocysteine-lowering with B vitamin supplements has no significant effect on cognitive function. However, careful examination of the trials in the meta-analysis indicates that no conclusion can be made regarding the effects of homocysteine-lowering on cognitive decline, since the trials typically did not include individuals who were experiencing such decline. Further definitive trials in older adults experiencing cognitive decline are still urgently needed., (© The Author(s) 2015. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Preeclampsia is a pregnancy-related pathological condition triggered by an abnormal placentation which produces endothelial dysfunction (ED). ED, in turn, is associated with an increase in homocysteine (hcy) and asymmetric dimethylarginine (ADMA); these molecules are also increased when some of the B-vitamins are deficient. It is unclear whether increases in hcy and ADMA during preeclampsia are the result of ED, or the consequence of a B-vitamin deficiency., Objective: To evaluate hcy, ADMA, folic acid (FA), vitamin B6 and B2 concentrations in patients with preeclampsia., Methods: In a cross-sectional design 19 patients with severe preeclamp- sia (preeclampsia) and 57 with normal pregnancy (no-preeclampsia), paired by gestational age and body mass index, were studied. Plasma hcy, ADMA, FA and vitamins B6 and B12 were determined. Non-parametric statistics was used for between-groups comparisons and regression analyses to evaluate interactions among molecules., Results: 72% of women were vitamin B deficient, 40% were deficient of B12 and 4% of FA. Preeclamptic patients presented hcy and ADMA concentrations higher than no-preeclamptic ones. Inferential analyses demonstrated that: hcy and ADMA are increased during preeclampsia independently from vitamins blood concentration; that the risk for pre- eclampsia is associated with high hcy but not with vitamins deficiency; and that the ratio L-arginine:ADMA decreases the preeclampsia risk., Conclusion: In patients with preeclampsia, increases of hcy and ADMA are associated with ED, but not with deficiency of the vitamins involved in their metabolism.

Nutrition is one of the most important modifiable factors involved in the development and maintenance of good bone health. Calcium and Vitamin D have confirmed and established roles in the maintenance of proper bone health. However, other nutritional factors could also be implicated. This review will explore the emerging evidence of the supporting role of certain B Vitamins as modifiable factors associated with bone health. Individuals with high levels of homocysteine (hcy) exhibit reduced bone mineral density (BMD), alteration in microarchitecture and increased bone fragility. The pathophysiology caused by high serum homocysteine is not completely clear regarding fractures, but it may involve factors, such as bone mineral density, bone turnover, bone blood flow and collagen cross-linking. It is uncertain whether supplementation with B Vitamins, such as folate, Vitamin B1, and Vitamin B6, could decrease hip fracture incidence, but the results of further clinical trials should be awaited before a conclusion is drawn.

Background: We aimed to study the effect of long-term supplementation of B-vitamins on folate forms in serum and whole blood (WB) in elderly German subjects., Methods: 59 participants (mean age 67 years) were randomized to daily receive either vitamin D3 (1200 IU), folic acid (500 μg), vitamin B12 (500 μg), vitamin B6 (50 mg), and calcium carbonate (456 mg) or vitamin D3 plus calcium carbonate. Serum and WB folate forms were measured before and after 6 and 12 months., Results: B-vitamins supplementation for 6 months led to higher concentrations of 5-methyltetrahydrofolate (5-methylTHF) in serum (mean 49.1 vs. 19.6 nmol/L) and WB (1332 vs. 616 nmol/L). Also non-methyl-folate concentrations in serum and WB were higher after 6 months with B-vitamins supplementation. Unmetabolized folic acid (UFA) increased after supplementation. tHcy concentration was lowered after 1 year of B-vitamin supplementation (mean 13.1 vs. 9.6 μmol/L). A stronger reduction of tHcy after 1 year was found in participants who had baseline level >12.5 μmol/L (mean 17.0 vs. 11.9 μmol/L) compared to those with baseline tHcy lower than this limit (mean 9.1 vs. 7.4 μmol/L). In contrast, the increases in serum and WB 5-methylTHF were comparable between the two groups., Conclusions: One year B-vitamins supplementation increased the levels of 5-methylTHF and non-methyl-folate in serum and WB, normalized tHcy, but caused an increase in the number of cases with detectable UFA in serum. Lowering of tHcy was predicted by baseline tHcy, but not by baseline serum or WB 5-methylTHF.

Objectives: Vitamin B-12 and n-3 polyunsaturated fatty acids (PUFA) decrease blood homocysteine (Hcy) concentrations. However, the combined effect of these nutrients on Hcy and ferritin, and C-reactive protein is limited and inconclusive. The objective was to examine the synergistic effect of vitamin B-12 in combination of n-3 PUFA on plasma Hcy, ferritin, and other biochemical markers., Methods: In a randomized controlled trial, thirty eligible subjects were randomly divided into three groups, and assigned to receive 1000 μg of vitamin B-12, 2 g fish oil, or 1000 μg vitamin B-12 and 2 g fish oil, respectively, for 8 weeks. Plasma phospholipids (PL) fatty acids and biochemical markers were determined. This study was registered under ClinicalTrials.gov Identifier: NCT01762072., Results: Plasma PL 20:5n-3, 22:6n-3 and n-3 PUFA was increased after 4 and 8 week supplementation of fish oil, and vitamin B-12+fish oil. Plasma concentrations of triacylglycerol, uric acid, C-reactive protein, and ferritin were significantly decreased after 4 and 8 week supplementation of fish oil, and vitamin B-12+fish oil. In all groups, significant changes in plasma Hcy were observed during the study period. Vitamin B-12, fish oil, and vitamin B-12+fish oil supplementation lowered plasma Hcy concentrations by 22%, 19%, and 39%, respectively., Conclusions: The combination of vitamin B-12 and fish oil has a synergistic effect on lowering plasma concentrations of Hcy.

Purpose: Guanidinoacetic acid (GAA) is an intermediate in the biosynthesis of creatine (Cr), yet its use in human nutrition is limited due to a lack of a clear understanding of its' dose-response effect. Thus, the purpose of this study was to investigate the effect of three different dosages of GAA (1.2, 2.4 and 4.8 g/day) administered for 6 weeks on serum and urinary variables related to GAA metabolism., Methods: Forty-eight healthy volunteers participated in the randomized, placebo-controlled, double-blind, repeated-measure study. At baseline, after 1, 2, 4 and 6 weeks, participants provided both fasting blood samples and 24-h urine., Results: GAA intervention significantly increased serum and urinary GAA, Cr and creatinine as compared to placebo (P < 0.05). Differences were found for serum GAA and Cr responses between the three GAA dosages, with high-dose GAA resulting in a greater increase (P < 0.05) in the plasma concentration of both variables as compared to other GAA dosages. In GAA groups, fasting plasma total homocysteine (T-Hcy) increased by 3.5 μmol/L on average at post-administration, yet no dose-response differences were found between trials. Serum B vitamins were not affected by either placebo or GAA intervention (P > 0.05)., Conclusion: Results indicate that low-to-high dosages of exogenous GAA can increase serum concentrations of Cr and T-Hcy while not depleting the B vitamins pool available for remethylation of homocysteine., Clinical Trial Registration: ClinicalTrials.gov, identification number NCT01133899.

Background: Lead (Pb) exposure may influence the plasma concentration of homocysteine, a one-carbon metabolite associated with cardiovascular and neurodegenerative diseases. Little is known about the associations between Pb and homocysteine over time, or the potential influence of dietary factors., Objectives: We examined the longitudinal association of recent and cumulative Pb exposure with homocysteine concentrations and the potential modifying effect of dietary nutrients involved in one-carbon metabolism., Methods: In a subcohort of the Veterans Affairs (VA) Normative Aging Study (1,056 men with 2,301 total observations between 1993 and 2011), we used mixed-effects models to estimate differences in repeated measures of total plasma homocysteine across concentrations of Pb in blood and tibia bone, assessing recent and cumulative Pb exposure, respectively. We also assessed effect modification by dietary intake and plasma concentrations of folate, vitamin B6, and vitamin B12., Results: An interquartile range (IQR) increment in blood Pb (3 μg/dL) was associated with a 6.3% higher homocysteine concentration (95% CI: 4.8, 7.8%). An IQR increment in tibia bone Pb (14 μg/g) was associated with a 3.7% higher homocysteine (95% CI: 1.6, 5.6%), which was attenuated to 1.5% (95% CI: -0.5, 3.6%) after adjusting for blood Pb. For comparison, a 5-year increase in time from baseline was associated with a 5.7% increase in homocysteine (95% CI: 4.3, 7.1%). The association between blood Pb and homocysteine was significantly stronger among participants with estimated dietary intakes of vitamin B6 and folate below (vs. above) the study population medians, which were similar to the U.S. recommended dietary allowance intakes., Conclusions: Pb exposure was positively associated with plasma homocysteine concentration. This association was stronger among men with below-median dietary intakes of vitamins B6 and folate. These findings suggest that increasing intake of folate and B6 might reduce Pb-associated increases in homocysteine, a risk factor for cardiovascular disease and neurodegeneration.

Introduction: Available data on plasma homocysteine level in patients with nephrotic syndrome (NS) are controversial with increased, decreased and unchanged values reported. Therefore, plasma homocysteine and serum B vitamins in Nigerian children with NS were assessed in this study., Methods: Fasting blood samples were analysed for plasma homocysteine, serum folate and B vitamins in 42 children with NS and 42 age and sex-matched healthy controls in this case control study. Data were compared between NS and control using t test and Chi square. Relationships were tested with regression analysis with p set at 0.05., Results: Prevalence of hyperhomocysteinaemia, low folate and cyanocobalamin in NS was 57.1%, 14.3% and 9.5% respectively. The mean homocysteine level was significantly higher in NS than control (11.3±2.6 µmol/L versus 5.5±2.3 µmol/L). Also, NS had lower folate and cyanocobalamin than control: 9.1±3.9 ng/mL versus 11.2±3.1 ng/dL and 268.5±95.7 pg/mL versus 316±117.2 pg/mL respectively. Weak but significant correlation between homocysteine and serum albumin (r = 0.347), folate (r = -0.607) and vitamin B12 (r = -0.185) were found in the NS group. Significant relationship was also found between homocysteine and vitamin B12 (ß = -0.64, 95% CI = -1.20, -0.08) after controlling for folate and vitamin B6 levels., Conclusion: Clinically important hyperhomocysteinaemia and low B vitamins occur in Nigerian children with nephrotic syndrome. This data suggest that potential usefulness of folate and vitamin B supplementation for reducing high homocysteine levels in nephrotic syndrome need to be further investigated.

Colorectal adenomas are considered to be precursors of colorectal cancer. B-vitamins (i.e., folate, vitamin B(6) and B(12)) are involved in homocysteine metabolism and play an important role as coenzymes in 1-carbon metabolism, which is thought to have a critical role in the progression of colorectal polyps. The purpose of this study was to examine the effects of B-vitamins and homocysteine on the risk of developing colorectal polyps. Forty-eight participants with colorectal polyps [29 adenomatous polyps (AP), 19 hyperplastic polyps (HP)], and 96 age- and sex-matched healthy controls were recruited. Fasting blood was drawn from each participant to measure hematological parameters, plasma pyridoxal 5'-phosphate (PLP), serum folate and vitamin B(12), and plasma homocysteine. Participants with AP and HP had significantly higher plasma homocysteine levels than did healthy controls. There was no significant difference in serum folate and vitamin B(12) and plasma PLP among the 3 groups. B-vitamins had no significant effect on the risk of colorectal polyps. However, participants with higher plasma homocysteine [odds ratio (OR) = 1.87, 95% confidence interval (CI) = 1.13, 3.08) level exhibited significantly increased risk of colorectal polyps after adjusting for potential confounders. Plasma homocysteine was a strong predictor of the risk of colorectal polyps in participants with adequate B-vitamins status.

Background: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Riboflavin is involved in myelin formation in nerve cells. Riboflavin is a precursor of flavin adenine D-nucleotide (FAD), which is a coenzyme of methylene tetrahydrofolate reductase (MTHFR), which is an important enzyme for remethylation of homocysteine. Riboflavin supplementation has been shown to affect the serum levels of homocysteine in healthy volunteers. The aim of the present study was to test the effect of riboflavin supplementation on the status and disability of patients with MS and whether this effect could be mediated by serum homocysteine levels., Materials and Methods: This was a randomized, double-blind, controlled trial in which 29 MS patients with a mean age of 33 were tested with riboflavin, and the placebo group, with a mean age of 31, received either riboflavin supplementation (10 mg) or the placebo daily for six months. Disability, measured by the Expanded Disability Status Scale (EDSS) scores, erythrocyte glutathione reductase activity coefficient (EGRAC), and serum homocysteine levels were measured before and after the study., Results: The mean ± SD of EDSS score was significantly decreased in both groups over the six months of the study (2.3 ± 0.7 vs. 1.6 ± 0.6 for the riboflavin group and 2.8 ± 1.1 vs. 2.3 ± 1.3 for the placebo groups. The comparison across both groups yielded a non-significant change (P = 0.001 and 0.02, respectively). No significant differences were observed between the two groups in terms of EGRAC, riboflavin deficiency levels by EGRAC category, and serum homocysteine levels before and after the study., Conclusion: Riboflavin supplementation (10 mg/day) to patients with MS does not improve disability status. It appears that this effect is not related to serum homocysteine levels.

Hyperhomocysteinemia and cognitive impairment both predict mortality and partly because of dietary associations. We have hypothesized that for, nutritional reasons, homocysteine and cognition may act jointly to determine elder survival. In a Nutrition and Health Survey in Taiwan (1999-2000), some 1412 representative elderly were followed up for mortality up to 10 years. Cognition was assessed by the Short Portable Mental Status Questionnaire. Food and B vitamin intakes with their biomarkers, and plasma homocysteine, were measured at baseline. The possible effects of cognition on homocysteine-associated mortality were ascertained with Cox proportional-hazards models. Homocysteine was higher in those who were older, male, and single, consumed less fish and tea, and with alcohol and smoking. In models adjusted for these variables, when homocysteine exceeded 14.5 μmol/L, mortality was 1.80-fold more than when <9.3 μmol/L (hazard ratio [HR], 1.80; 95% confidence interval [95% CI], 1.20-2.71). P for trend was 0.002 and interactive with sex (P < .002). However, these homocysteine-mortality associations were dependent on cognition (P = .03); adjustment for food intake or nutrient status made little difference. Homocysteine did not predict cognitive impairment (adjusted OR, 1.40; 95% CI = 0.50-3.93). Vitamins B(1), B(2), and B(6) accounted somewhat for cognitive impairment. Cognition predicted mortality, fully adjusted for available covariates and also for homocysteine (HR, 3.66; 95% CI, 1.64-8.20) but interactively with homocysteine. Thus, the B-group vitamin insufficiency and cognitive impairment associations with premature mortality are confirmed. Yet cognition is inter-related with homocysteine in its association with survival in ways not detectably altered by foods or food-derived vitamins., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: To evaluate the association between plasma total homocysteine (tHcy) levels, serum folic acid, vitamin B(12) and vitamin B(6) levels, methylenetetrahydrofolate reductase (MTHFR) C677T genotype and risk of primary open-angle glaucoma (POAG)., Clinical Relevance: There are conflicting reports on the association of Hcy, folic acid, vitamin B(12), vitamin B(6), MTHFR, and risk of POAG. We conducted this meta-analysis to derive a more precise estimation of the association., Methods: Pertinent articles were identified through a systematic search of the EMBASE and Medline databases. Results were pooled using meta-analytic methods. The main outcome measure included tHcy, folic acid, vitamin B(12) and vitamin B(6) levels, and MTHFR C677T genotype., Results: Twelve studies were eligible for Hcy, 6 studies for folic acid, 6 studies for vitamin B(12), 3 studies for vitamin B(6), and 10 studies for MTHFR. The combined results showed that plasma tHcy levels in POAG were 2.05 μmol/L (95% confidence interval [CI], 0.63-3.47) higher than in controls. There was no difference between serum folic acid, vitamin B(6), and vitamin B(12) levels in POAG and controls. The weighted mean difference with 95% CI were 0.34 μmol/L (-0.37 to 1.05), 2.75 μmol/L (-3.68 to 9.18), and 0.97 μmol/L (-30.45 to 32.40), respectively. The MTHFR 677TT genotype was not associated with the risk of POAG (odds ratio, 1.10; 95% CI, 0.83-1.47)., Conclusions: We found that POAG is associated with elevated plasma tHcy levels, but not serum folic acid, vitamin B(12), vitamin B(6) levels, or MTHFR C677T genotype., Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Aim: Endothelial dysfunction is a marker for development and progression of atherosclerosis. Statin therapy improves endothelial function in cardiovascular patients by reducing LDL-cholesterol and by pleiotropic effects. B-group vitamin supplementation restores endothelial function mainly by reducing homocysteine-induced oxidative stress. Thus, we evaluated the effect of rosuvastatin, B-group vitamins and their combination on endothelial function in high-risk cardiovascular patients., Methods: Thirty-six patients with cardiovascular disease were randomly, double-blinded assigned to either rosuvastatin 10 mg (group R, n = 18) or vitamin supplementation consisting of folic acid 1 mg, vitamin B12 0.4 mg, and B6 10 mg (group V, n = 18) for 6 weeks. After 6 weeks all patients received rosuvastatin and vitamin supplementation in combination for additional 6 weeks. Endothelial function was assessed by flow-mediated vasodilation (FMD) at baseline and after 6- and 12-week treatment., Results: At baseline, FMD, plasma lipids, vitamins, and homocysteine were comparable between both groups. After 6 weeks, FMD improved in both groups (from 4.4 ± 1.6 to 6.9 ± 1.4% group R, P= 0.0004 and from 4.9 ± 1.8 to 6.4 ± 1.8% group V, P= 0.0002). This improvement in FMD was mainly associated with a decrease of plasma lipids in group R and a decrease of homocysteine in group V. After 12 weeks, the combined therapy with rosuvastatin and vitamins further improved FMD to the normal range in 26/33 patients compared to 5/36 at baseline (P < 0.0001)., Conclusions: In conclusion, both treatments, rosuvastatin and B-group vitamin supplementation, improved endothelial function in high-risk cardiovascular patients. The combination of both therapies had an additive effect on endothelial function suggesting different mechanisms of action., (© 2011 Blackwell Publishing Ltd.)

Objective: We assessed serum homocysteine (tHcy) and folate concentrations among US adolescents before and after fortification of cereal-grain products with folic acid, and associations with demographic, behavioural and physiological factors., Design: Observational study conducted among participants of a randomized trial., Setting: The Child and Adolescent Trial for Cardiovascular Health (CATCH) study., Subjects: Adolescents (n 2445) in grades 8 (pre-fortification, mean age 14 years) and 12 (post-fortification, mean age 18 years)., Results: Average serum concentrations of tHcy, folate and vitamin B6 increased by 17 %, 16 % and 14 %, respectively, while serum concentrations of vitamin B12 decreased by 11 % post-fortification. Folic acid fortification provided, on average, an additional intake of 118 μg folate/d. Male sex (P < 0.0001) and white race (P = 0.0008) were associated with significantly greater increases in tHcy concentration, while increases in BMI (P = 0.006) and serum folate concentration (P < 0.0001) were associated with significant decreases in tHcy concentration. Female sex (P < 0.0001), non-smoking (P < 0.0001), use of multivitamins (P < 0.0001) and higher dietary intake of folate (P = 0.001) were associated with significantly greater increases in serum folate concentrations. From grade 8 to grade 12, the upward age trend in serum tHcy concentration was uninterrupted in its course (P > 0.50); whereas serum folic acid concentration showed a downward trend that incurred a discrete jump upward (17 % higher; P < 0.0001) with fortification. These trends differed significantly for males v. females (P < 0.001 for interaction)., Conclusions: Fortification had a significant impact on improving folate status but not serum tHcy concentrations among US adolescents.

Background & Aims: Elevated circulating fasting total homocysteine (tHcy) concentration is associated with an increased risk of occlusive vascular disease in adults. Important determinants of tHcy levels are folate, vitamin B(12) and vitamin B(6). This study aimed to investigate age, gender, and body mass as determinants of folate, vitamin B(12) and tHcy levels in Arab older children and adolescents and to propose population, gender and age-specific reference ranges for these biomarkers., Methods & Results: 774 (316 boys, 458 girls) healthy 10-19 yr olds attending secondary schools in Kuwait were assessed for anthropometry and fasting blood levels of Hcy, folate and vitamin B(12). The mean (95% CI) serum levels of tHcy, folate and vitamin B(12) were respectively 6.57 μmol/L (6.42-6.73), 16.0 ng/ml (15.6-16.3) and 354.3 pg/ml (343.0-365.7). Boys had significantly higher tHcy and folate concentrations than the girls, although vitamin B(12) levels were greater in the latter. Folate and vitamin B(12) levels decreased significantly with age, while correspondingly, tHcy levels increased, with mean values (μmol/L) for boys (6.71; 8.25) and girls (5.36; 6.67) aged 10-14 yr and 14-19 yr respectively. Bivariate and multivariate analyses with adjustment for confounders such as age, gender, need for dietary control and socio-demographic variables indicated that the independent determinants of levels of tHcy were age, gender and body mass., Conclusion: There is an age-related increase in tHcy in adolescents reflecting decreased levels of folate and vitamin B(12), with the suggestion that age-related reference ranges for these biomarkers be used. These observations may have implications for prevention of future atherogenic disease., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Hyperhomocysteinemia might be at least partially due to compromised B vitamin status in critically ill patients and has been linked with critical illness. This study was conducted to examine the association between plasma homocysteine with B vitamins and clinical outcomes in critically ill surgical patients., Methods: Thirty-two patients in the surgical intensive care unit (SICU) were enrolled. Disease severity (Acute Physiology and Chronic Health Evaluation II score), hematological values, serum and erythrocyte folate, serum vitamin B₁₂, plasma, and erythrocyte pyridoxal 5'-phosphate (PLP) were determined within 24 hours of admission and again after 7 days., Results: The prevalence of hyperhomocysteinemia in the patients was either 46.9% (plasma homocysteine ≥12 µmol/L) or 31.3% (plasma homocysteine ≥15 µmol/L) on day 1 in the SICU and increased to 62.5% (plasma homocysteine ≥12 µmol/L) and 37.5% (plasma homocysteine ≥15 µmol/L) on day 7 after admission to the SICU. Plasma homocysteine, serum folate, and vitamin B₁₂ significantly increased by day 7, whereas plasma and erythrocyte PLP remained constant throughout the study. Plasma homocysteine was not correlated with serum folate and vitamin B₁₂. However, plasma and erythrocyte PLP on day 1 were adversely associated with day 1 levels of plasma homocysteine after adjusting for potential confounders. Plasma homocysteine on day 1 or changes (Δ day 7-day 1) did not show any association with clinical outcomes., Conclusions: Lower plasma PLP might be a significant factor for increased plasma homocysteine in critically ill surgical patients. The association between plasma homocysteine and clinical outcomes was not found.

Objective: To evaluate the effects on anencephaly risk of the interaction between the maternal profile of folate, vitamin B12 and homocysteine and the 677C→T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR)., Design: Case-control study paired (1:1) on maternity clinic, date of birth and state of residence. Cases of anencephaly were identified using the Registry of the Mexican Neural Tube Defect Epidemiological Surveillance System. Case and control mothers were selected from the same maternity departments. All mothers completed a structured questionnaire and blood samples were obtained to determine the MTHFR 677C→T polymorphism and biochemical profile., Setting: Mexico, Puebla and Guerrero states, Mexico., Subjects: A total of 151 mothers of cases and controls were enrolled from March 2000 to February 2001. We had complete information on biochemical profile and MTHFR C677T polymorphism for ninety-eight mothers of cases and ninety-one mothers of controls., Results: The adjusted models show that the risk of anencephaly in mothers with 677TT genotype was reduced by 18 % (OR = 0·82; 95 % CI 0·72, 0·94) for each 1 ng/ml increment in serum folate. In terms of tertiles, mothers with 677TT genotype with serum folate levels in the upper tertile (>14·1 ng/ml) had a 95 % lower risk to have a child with anencephaly than mothers with serum folate levels in the first and second tertiles (P trend = 0·012)., Conclusions: Our data agree with the hypothesis of a gene-nutrient interaction between MTHFR 677C→T polymorphism and folate status. We observed a protective effect on anencephaly risk only in mothers with 677TT genotype as serum folate levels increased.

Background: The aim of this meta-analysis is to explore the relationship between plasma total homocysteine (tHcy) levels, serum folic acid, vitamin B12 and vitamin B6 levels, methylenetetrahydrofolate reductase (MTHFR) C677T genotype and risk of pseudoexfoliation glaucoma (PEXG)., Methods: A systematic search of EMBASE and PubMed of relevant articles was carried out for all published articles. Main outcome measures included the calculation of plasma tHcy levels, serum folic acid, vitamin B12, and vitamin B6 levels mean difference and odds ratios (OR) of MTHFR C677T genotype between cases and controls., Results: There were 14 studies for tHcy (485 cases and 456 controls), five studies for folic acid (188 cases and 189 controls), six studies for vitamin B12 (199 cases and 225 controls), three studies for vitamin B6 (128 cases and 130 controls) and eight studies for MTHFR (479 cases and 661 controls). Overall, the mean plasma tHcy levels in cases was 3.38 umol/l (95% confidence intervals (CI): 2.35-4.42) higher than in controls. Serum folic acids, but not vitamin B12 and vitamin B6 levels, was significantly lower in cases than in controls; the weighted mean differences with 95% CI were -1.50 umol/l (-2.53, -0.46), -36.29 umol/l (-81.27, 8.68) and -0.60 umol/l (-2.55, 1.35) respectively. There was no evidence of association between the MTHFR C677T genotype and PEXG (OR = 1.28, 95% CI: 0.85, 1.93)., Conclusions: PEXG is associated with elevated plasma tHcy and low serum folic acid levels, but not serum vitamin B12, vitamin B6 levels, and MTHFR C677T genotype.

Background: Homocysteine is a risk factor for Alzheimer's disease. In the first report on the VITACOG trial, we showed that homocysteine-lowering treatment with B vitamins slows the rate of brain atrophy in mild cognitive impairment (MCI). Here we report the effect of B vitamins on cognitive and clinical decline (secondary outcomes) in the same study., Methods: This was a double-blind, single-centre study, which included participants with MCI, aged ≥ 70 y, randomly assigned to receive a daily dose of 0.8 mg folic acid, 0.5 mg vitamin B(12) and 20 mg vitamin B(6) (133 participants) or placebo (133 participants) for 2 y. Changes in cognitive or clinical function were analysed by generalized linear models or mixed-effects models., Results: The mean plasma total homocysteine was 30% lower in those treated with B vitamins relative to placebo. B vitamins stabilized executive function (CLOX) relative to placebo (P = 0.015). There was significant benefit of B-vitamin treatment among participants with baseline homocysteine above the median (11.3 µmol/L) in global cognition (Mini Mental State Examination, P < 0.001), episodic memory (Hopkins Verbal Learning Test-delayed recall, P = 0.001) and semantic memory (category fluency, P = 0.037). Clinical benefit occurred in the B-vitamin group for those in the upper quartile of homocysteine at baseline in global clinical dementia rating score (P = 0.02) and IQCODE score (P = 0.01)., Conclusion: In this small intervention trial, B vitamins appear to slow cognitive and clinical decline in people with MCI, in particular in those with elevated homocysteine. Further trials are needed to see if this treatment will slow or prevent conversion from MCI to dementia., (Copyright © 2011 John Wiley & Sons, Ltd.)

Folate and vitamin B12 are involved in homocysteine metabolism and are critical to the methylation of DNA. We aimed to assess plasma vitamin B12 (pB12), plasma folate (pFol), and red cell folate (rcFol) in women and their infants during pregnancy and after birth. Maternal biomarkers were tested as predictors of infant biomarkers, including plasma homocysteine (pHcy), at age 6 months. Participants (n = 153) were recruited at the John Hunter Hospital, Australia. Maternal fasting blood samples were collected at 20 and 36 weeks gestation, and at 14 and 27 weeks postpartum. Fifty healthy, term infants provided non-fasting samples at age 6 months. Plasma homocysteine data were available for 16 infants at age 6 months. Maternal pB12 concentrations fell by 16% from 20 to 36 weeks gestation, but had recovered by 14 weeks postpartum. Maternal rcFol concentrations fell by 31% from 20 weeks gestation to 27 weeks postpartum. Infants breastfed at 6 months had lower pB12 (median 159 vs. 402 pmol/L, n = 23 vs. 18, P < 0.01) and folate (median folate z-score -0.58 vs. 0.85, n = 23 vs. 17, P < 0.01), and higher pHcy (median 11.9 vs. 7.3 μmol/L, n = 8 vs. 6, P < 0.01), than those on infant formula. Maternal pregnancy pFol, but not pB12, inversely predicted infant pHcy, after adjustment for the infant's current pB12 (P = 0.04). Changes in maternal B12 and folate occur during pregnancy and after birth. Infant homocysteine metabolism may be regulated through maternal folate concentrations during pregnancy and postnatal feeding.

Background: The aim of this study was to longitudinally study serum homocysteine levels in patients with Crohn's disease (CD) and ulcerative colitis (UC) in relation to disease activity and B vitamin status., Methods: In all, 98 consecutive adult patients (age 25-55 years) with CD (n = 70) and UC (n = 28) were enrolled and assessed at three timepoints over 1 year., Results: There were no significant differences in levels of homocysteine, B vitamins, or dietary intake by disease type, disease activity, or across visits. 13% of all inflammatory bowel disease (IBD) patients had elevated homocysteine at least once during the study. Nine patients with CD had fluctuating homocysteine levels during the study but these were inconsistent, ranging from within normal range to elevated levels in any individual. Six of these nine patients were persistently in remission. 30% of all IBD patients had vitamin B6 deficiency, 11% had vitamin B12 deficiency, and one patient (CD) had folate deficiency. All vitamins showed a significant correlation between intake and serum levels (B6; r = 0.46, P < 0.001, B12; r = 0.42, P < 0.001, and folate; r = 0.26, P = 0.008). There was an inverse relationship between serum homocysteine in the blood and serum vitamin B12 (r = -0.241, P = 0.017)., Conclusions: Serum homocysteine was mostly normal in patients with IBD and changed minimally over time. There was no association between disease activity and elevation of serum homocysteine. 30% of patients have vitamin B6 deficiency but vitamin B6 is not associated with elevated homocysteine. The routine measurement of homocysteine is not warranted., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

Background and Aim: Maternal nutrition is an important determinant of the duration of pregnancy and fetal growth, and thereby influences pregnancy outcome. Folic acid and vitamin B(12) are involved in one-carbon metabolism and are reported to underlie intrauterine programming of adult diseases., Methods: In the present study, the levels of folate, vitamin B(12) and homocysteine were measured in mothers delivering preterm (PT; gestation <37 weeks; n = 67), those delivering preterm due to preeclampsia (PT-PE; n = 49) and women delivering at term (control group; n = 76)., Results: Increased vitamin B(12) and homocysteine levels (p < 0.05 for both) were seen in the PT-PE and PT groups as compared to the controls. In addition, reduced folate levels (p < 0.05) were observed in the PT group. A negative association of maternal plasma homocysteine with birth weight was seen in the idiopathic preterm group., Conclusions: Altered maternal micronutrients and resultant increased homocysteine concentrations exist in women delivering preterm. These alterations may also be partly associated with other factors such as undiagnosed inflammatory conditions or inadequate placentation in some women. Since these micronutrients play an important role in epigenetic regulation of vital genes involved in the fetal programming of adult diseases, further studies need to be undertaken to understand their role in preterm deliveries., (Copyright © 2012 S. Karger AG, Basel.)

Recent reports have demonstrated elevated serum homocysteine (Hcy) levels in children receiving valproic acid (VPA) therapy. Elevated Hcy levels might play a potential role in the resistance to antiepileptic drugs, and might lead to an increased risk for a vascular disease. It has been reported that elevated total homocysteine (tHcy) levels are associated with elevated asymmetric dimethylarginine (ADMA) levels, which are factors that may be better indicators of endothelial dysfunction compared to serum homocysteine levels, because they are less sensitive to changes, such as fasting status, physical activity, and other factors. In this study, we aim to evaluate serum ADMA, Hcy, lipid, folate, and vitamin B₁₂ levels in epileptic children, receiving VPA monotherapy. Forty-four epileptic children, receiving VPA monotherapy for at least 6 months and 28 healthy children aged between 4 and 16 years, were recruited. Serum lipids, lipoproteins, folate, vitamin B₁₂, Hcy, and ADMA levels were analyzed in both study groups. Serum Hcy, ADMA, and vitamin B₁₂ levels were higher in patients than in controls (p < 0.001 for tHcy and ADMA levels; p < 0.05 for vitamin B₁₂ levels); however, serum lipid, lipoprotein, and folate levels were similar. According to the duration of epilepsy, serum tHcy, ADMA, and triglyceride (TG) levels were higher in patients with epilepsy for ≥ 2 years than in patients with epilepsy for < 2 years (p < 0.001 for serum ADMA levels, p < 0.01 for tHcy levels, and p < 0.05 for serum TG levels). Similarly, with respect to the duration of VPA therapy, serum tHcy, ADMA, and TG levels were higher in patients who had received VPA therapy for more than 2 years (p < 0.001 for serum ADMA levels, p < 0.05 for serum tHcy levels, p < 0.01 for TG levels). Serum ADMA levels were significantly higher in patients receiving VPA at the dose of 25-30 mg/kg/day than in those receiving 20 mg/kg/day (p < 0.01). In conclusion, our study found increased serum ADMA levels and increased tHcy levels in epileptic children receiving VPA monotherapy. Increased serum ADMA levels were demonstrated in epileptic children who have had a seizure history greater than 2 years, and have used VPA therapy for more than 2 years, and have received higher doses of VPA. Routine monitoring of serum ADMA and tHcy levels might have beneficial effects for patients receiving long-term VPA therapy, especially in children who have other potential risk factors for vascular diseases. Further studies are needed to investigate serum ADMA and Hcy levels, and the presence of vascular disease, as well as the potential interactions between serum ADMA levels and seizure control.

Objectives: To investigate whether gene nutrient interactions influence the risk of cognitive dysfunction among older persons., Design: We performed a cross-sectional and longitudinal study of 499 adults aged 70-79 years from the Mac Arthur Study of Successful Aging to determine the effect of apolipoprotein E (APOE) in conjunction with plasma levels of homocysteine and of the related B vitamins on multiple domains of cognitive function and cognitive decline., Results: The APOE-ε4 allele, high homocysteine, low folate, and low vitamin B6 levels were each associated with worse baseline cognitive function, and all but B6 and B12 were associated with seven year cognitive decline. There was no interaction between APOE-ε4, and homocysteine, folate, B6, or B12 in predicting baseline cognitive function (p-values: 0.12-0.94) or longitudinal decline (p-values: 0.52-0.91). Of five cognitive subtests, there was a significant interaction between the ε4 allele, low B6, and decline in correct naming response items (p=0.04)., Conclusion: B vitamin status does not influence the risk of overall cognitive dysfunction in ε4 allele affected older adults.