Should vitamin B12 status be considered in assessing risk of neural tube defects?
Ontology highlight
ABSTRACT:
SUBMITTER: Molloy AM
PROVIDER: S-EPMC5887889 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
Publications
Should vitamin B<sub>12</sub> status be considered in assessing risk of neural tube defects?
Annals of the New York Academy of Sciences 20180129 1
There is a strong biological premise for including vitamin B<sub>12</sub> with folic acid in strategies to prevent neural tube defects (NTDs), due to the closely interlinked metabolism of these two vitamins. For example, reduction of B<sub>12</sub> deficiency among women of reproductive age could enhance the capacity of folic acid to prevent NTDs by optimizing the cellular uptake and utilization of natural folate cofactors. Vitamin B<sub>12</sub> might also have an independent role in NTD preven ...[more]
Similar Datasets
Project description:BackgroundWomen of reproductive age (WRA) are a high-risk population for anemia and micronutrient deficiencies. However, there are few representative population-level data from India, which could help inform evidence-based recommendations and policy.ObjectiveTo conduct a population-based biomarker survey of anemia and vitamin B-12 and folate status in WRA as part of a periconceptional surveillance program in southern India.MethodsParticipants were WRA (15-40 y) who were not pregnant or lactating. Whole blood (n = 979) was analyzed for hemoglobin via a Coulter counter (Coulter HMX). Plasma, serum, and RBCs were processed and stored at -80°C or less until batch analysis. Vitamin B-12 concentrations were measured via chemiluminescence; RBC and serum folate concentrations were evaluated via microbiological assay. Anemia and severe anemia were defined as hemoglobin <12.0 g/dL and <8.0 g/dL, respectively. Vitamin B-12 deficiency and insufficiency were defined as total vitamin B-12 <148 pmol/L and <221 pmol/L, respectively. Folate deficiency and insufficiency were defined as RBC folate <305 nmol/L and <748 nmol/L. A previously developed Bayesian model was used to predict neural tube defect (NTD) prevalence per 10,000 births.ResultsA total of 41.5% of WRA had anemia and 3.0% had severe anemia. A total of 48.3% of WRA had vitamin B-12 deficiency and 74.3% had vitamin B-12 insufficiency. The prevalence of RBC folate deficiency was 7.6%, and 79.3% of WRA had RBC folate <748 nmol/L, the threshold for optimal NTD prevention. Predicted NTD prevalence per 10,000 births based on RBC folate concentrations was 20.6 (95% uncertainty interval: 16.5-25.5).ConclusionsThe substantial burden of anemia, vitamin B-12 deficiency, and RBC folate insufficiency in WRA in this setting suggests an opportunity for anemia and birth defects prevention. Findings will directly inform the development of a randomized trial for anemia and birth defects prevention in southern India.This study was registered at clinicaltrials.gov as NCT04048330.
| S-EPMC8128722 | biostudies-literature
Project description:Susceptibility to neural tube defects (NTDs), such as anencephaly and spina bifida is influenced by genetic and environmental factors including maternal nutrition. Maternal periconceptional supplementation with folic acid significantly reduces the risk of an NTD-affected pregnancy, but does not prevent all NTDs, and "folic acid non-responsive" NTDs continue to occur. Similarly, among mouse models of NTDs, some are responsive to folic acid but others are not. Among nutritional factors, inositol deficiency causes cranial NTDs in mice while supplemental inositol prevents spinal and cranial NTDs in the curly tail (Grhl3 hypomorph) mouse, rodent models of hyperglycemia or induced diabetes, and in a folate-deficiency induced NTD model. NTDs also occur in mice lacking expression of certain inositol kinases. Inositol-containing phospholipids (phosphoinositides) and soluble inositol phosphates mediate a range of functions, including intracellular signaling, interaction with cytoskeletal proteins, and regulation of membrane identity in trafficking and cell division. Myo-inositol has been trialed in humans for a range of conditions and appears safe for use in human pregnancy. In pilot studies in Italy and the United Kingdom, women took inositol together with folic acid preconceptionally, after one or more previous NTD-affected pregnancies. In nonrandomized cohorts and a randomized double-blind study in the United Kingdom, no recurrent NTDs were observed among 52 pregnancies reported to date. Larger-scale fully powered trials are needed to determine whether supplementation with inositol and folic acid would more effectively prevent NTDs than folic acid alone. Birth Defects Research 109:68-80, 2017. © 2016 The Authors Birth Defects Research Published by Wiley Periodicals, Inc.
| S-EPMC5353661 | biostudies-literature
Project description:Background:Vitamin B12 is an essential micronutrient in humans needed for health maintenance. Deficiency of vitamin B12 has been linked to dietary, environmental and genetic factors. Evidence for the genetic basis of vitamin B12 status is poorly understood. However, advancements in genomic techniques have increased the knowledge-base of the genetics of vitamin B12 status. Based on the candidate gene and genome-wide association (GWA) studies, associations between genetic loci in several genes involved in vitamin B12 metabolism have been identified. Objective:The objective of this literature review was to identify and discuss reports of associations between single-nucleotide polymorphisms (SNPs) in vitamin B12 pathway genes and their influence on the circulating levels of vitamin B12. Methods:Relevant articles were obtained through a literature search on PubMed through to May 2017. An article was included if it examined an association of a SNP with serum or plasma vitamin B12 concentration. Beta coefficients and odds ratios were used to describe the strength of an association, and a P?<?0.05 was considered as statistically significant. Two reviewers independently evaluated the eligibility for the inclusion criteria and extracted the data. Results:From 23 studies which fulfilled the selection criteria, 16 studies identified SNPs that showed statistically significant associations with vitamin B12 concentrations. Fifty-nine vitamin B12-related gene polymorphisms associated with vitamin B12 status were identified in total, from the following populations: African American, Brazilian, Canadian, Chinese, Danish, English, European ancestry, Icelandic, Indian, Italian, Latino, Northern Irish, Portuguese and residents of the USA. Conclusion:Overall, the data analyzed suggests that ethnic-specific associations are involved in the genetic determination of vitamin B12 concentrations. However, despite recent success in genetic studies, the majority of identified genes that could explain variation in vitamin B12 concentrations were from Caucasian populations. Further research utilizing larger sample sizes of non-Caucasian populations is necessary in order to better understand these ethnic-specific associations.
| S-EPMC5801754 | biostudies-literature
Project description:Investigations of maternal caffeine intake and neural tube defects (NTDs) have not considered genetic influences. Caffeine metabolism gene effects were examined in the National Birth Defects Prevention Study.Average daily caffeine was summed from self-reported coffee, tea, soda, and chocolate intake for mothers of 768 NTD cases, and 4143 controls delivered from 1997 to 2002. A subset of 306 NTD and 669 control infants and their parents were genotyped for CYP1A2*1F, NAT2 481C>T, and NAT2 590G>A. CYP1A2*1F was classified by fast or slow oxidation status, and NAT2 variants were categorized into rapid or slow acetylation status. Case-control logistic regression analyses, family-based transmission/disequilibrium tests and log-linear analyses, and hybrid log-linear analyses were conducted to produce odds ratios (ORs) or relative risks (RRs) and 95% confidence intervals (CIs) for caffeine intake and maternal and infant gene variants, and to examine interaction effects.NTDs were independently associated with infant slow NAT2 acetylator status (RR, 2.00; 95% CI, 1.10-3.64) and maternal CYP1A2*1F fast oxidation status (OR, 1.49; 95% CI, 1.10-2.03). Mothers who consumed caffeine, oxidized CYP1A2*1F quickly, and acetylized NAT2 slowly had a nonsignificantly elevated estimated risk for an NTD-affected pregnancy (OR, 3.10; 95% CI, 0.86-11.21). Multiplicative interaction effects were observed between maternal caffeine and infant CYP1A2*1F fast oxidizer status (p(interaction) = 0.03).The association identified between maternal CYP1A2*1F fast oxidation status and NTDs should be examined further in the context of the other substrates of CYP1A2. Maternal caffeine and its metabolites may be associated with increased risk for NTD-affected pregnancies in genetically susceptible subgroups.
| S-EPMC2917796 | biostudies-literature
Project description:Genetic variants in MTHFD1 (5,10-methylenetetrahydrofolate dehydrogenase/5,10-methenyltetrahydrofolate cyclohydrolase/ 10-formyltetrahydrofolate synthetase), an important folate metabolic enzyme, are associated with a number of common diseases, including neural tube defects (NTDs). This study investigates the promoter of the human MTHFD1 gene in a bid to understand how this gene is controlled and regulated. Following a combination of in silico and molecular approaches, we report that MTHFD1 expression is controlled by a TATA-less, Initiator-less promoter and transcription is initiated at multiple start sites over a 126 bp region. We confirmed the presence of three database polymorphisms (dbSNP) by direct sequencing of the upstream region (rs1076991 C > T, rs8010584 G > A, rs4243628 G > T), with a fourth (dbSNP rs746488 A > T) not found to be polymorphic in our population and no novel polymorphisms identified. We demonstrate that a common SNP rs1076991 C > T within the window of transcriptional initiation exerts a significant effect on promoter activity in vitro. We investigated this SNP as a potential risk factor for NTDs in a large homogenous Irish population and determined that it is not an independent risk factor, but, it does increase both case (chi (2) = 11.06, P = 0.001) and maternal (chi (2) = 6.68, P = 0.01) risk when allele frequencies were analysed in combination with the previously identified disease-associated p.R653Q (c.1958 G > A; dbSNP rs2236225) polymorphism. These results provide the first insight into how MTHFD1 is regulated and further emphasise its importance during embryonic development.
| S-EPMC2732995 | biostudies-literature
Project description:BACKGROUND:Women with a previous neural tube defect (NTD)-affected pregnancy are recommended to consume 4,000??g daily folic acid (FA) for prevention (10 times the general-population recommendation). Protection from doses between 400 and 4,000??g for this and other higher risk groups is unclear. METHODS:In the case-control Slone Birth Defects Study (1988-2015), we examined the associations between periconceptional FA doses and NTDs among four higher risk groups: NTD family history, periconceptional antiepileptic drug exposure (AED), pregestational diabetes, and prepregnancy obesity. Mothers completed standardized interviews about pregnancy events and exposures. FA categorizations were based on (a) supplements only and (b) supplements and diet ("total folate"). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) (adjusted for age and study center) using logistic regression. RESULTS:Cases and controls included: 45 and 119 with family history, 25 and 108 with AED exposure, 12 and 63 with pregestational diabetes, 111 and 1,243 with obesity. Daily FA supplementation was associated with lower NTD risk compared to no supplementation (adjusted ORs were 0.33 [95% CI 0.13, 0.76] for family history, 0.31 [0.09, 0.95] for AED exposure, 0.25 [0.04, 1.05] for pregestational diabetes, 0.65 [0.40, 1.04] for obesity). Though estimates were imprecise, as total folate increased stronger point estimates were observed, notably among family history. No mothers with a prior NTD-affected pregnancy supplemented with 4,000??g. CONCLUSIONS:Our findings reinforce that all women of childbearing potential should consume at least 400??g FA/day to protect against NTDs. Higher risk groups may benefit from higher doses.
| S-EPMC7186568 | biostudies-literature
Project description:Neural tube defects (NTDs) are common, severe congenital malformations whose causation involves multiple genes and environmental factors. Although more than 200 genes are known to cause NTDs in mice, there has been rather limited progress in delineating the molecular basis underlying most human NTDs. Numerous genetic studies have been carried out to investigate candidate genes in cohorts of patients, with particular reference to those that participate in folate one-carbon metabolism. Although the homocysteine remethylation gene MTHFR has emerged as a risk factor in some human populations, few other consistent findings have resulted from this approach. Similarly, attention focused on the human homologues of mouse NTD genes has contributed only limited positive findings to date, although an emerging association between genes of the non-canonical Wnt (planar cell polarity) pathway and NTDs provides candidates for future studies. Priorities for the next phase of this research include: (i) larger studies that are sufficiently powered to detect significant associations with relatively minor risk factors; (ii) analysis of multiple candidate genes in groups of well-genotyped individuals to detect possible gene-gene interactions; (iii) use of high throughput genomic technology to evaluate the role of copy number variants and to detect 'private' and regulatory mutations, neither of which have been studied to date; (iv) detailed analysis of patient samples stratified by phenotype to enable, for example, hypothesis-driven testing of candidates genes in groups of NTDs with specific defects of folate metabolism, or in groups of fetuses with well-defined phenotypes such as craniorachischisis.
| S-EPMC2758708 | biostudies-literature
Project description:BackgroundIt is controversial whether B12 deficiency causes dementia or B12 treatment can prevent dementia.ObjectiveTo assess associations between low plasma (P-)B12 levels, B12 treatment, and risk of Alzheimer's disease (AD; primary outcome) and all-cause or vascular dementia (secondary outcomes).MethodsWe conducted a population-based cohort study using Danish registry data to assess associations between low P-B12 levels, high-dose injection or oral B12 treatment, and risk of dementia (study period 2000-2013). The primary P-B12 cohort included patients with a first-time P-B12 measurement whose subsequent B12 treatment was recorded. The secondary B12 treatment cohort included patients with a first-time B12 prescription and P-B12 measurement within one year before this prescription. For both cohorts, patients with low P-B12 levels (<200 pmol/L) were propensity score-matched 1:1 with patients with normal levels (200-600 pmol/L). We used multivariable Cox regression to compute 0-15-year hazard ratios for dementia.ResultsFor low P-B12 and normal P-B12 level groups, we included 53,089 patients in the primary P-B12 cohort and 13,656 patients in the secondary B12 treatment cohort. In the P-B12 cohort, hazard ratios for AD centered around one, regardless of follow-up period or treatment during follow-up. In the B12 treatment cohort, risk of AD was unaffected by low pre-treatment P-B12 levels, follow-up period and type of B12 treatment. Findings were similar for all-cause and vascular dementia.ConclusionWe found no associatio1n between low P-B12 levels and dementia. Associations were unaffected by B12 treatment. Results do not support routine screening for B12 deficiency in patients with suspected dementia.
| S-EPMC7990402 | biostudies-literature
Project description:Neural tube defects (NTDs) are the most common congenital defects of the central nervous system among neonates and the folate status during pregnancy was considered as the most important etiopathogenesis of NTDs. Besides, methionine synthase (MTR) gene and methionine synthase reductase (MTRR) gene were folate metabolism involved genes and had been investigated in several previous studies with inconsistent results. Hence, we aimed to explore the association of 4 selected single-nucleotide polymorphisms (SNPs) on MTRR/MTR gene and the susceptibility of NTDs in a Chinese population.Seven SNPs were selected from HapMap databases with Haploview 4.2 software. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to genotype the polymorphisms from blood samples of 165 NTDs patients and 280 healthy controls. The correlation between these SNPs and NTDs risk was tested by Student t test and Chi-square test by STATA 11.0 software. Furthermore, we performed a meta-analysis of relevant studies to investigate the association between the SNPs MTRR 66A>G and MTR 2756A>G and the susceptibility of NTDs.An increased risk of NTDs was verified to be significantly associated with MTRR 66A>G (G allele vs. A allele: OR = 1.36 (1.03-1.80), P = 0.028; GG + AG vs. AA: OR = 1.60 (1.05-2.43), P = 0.027) and MTR 2756A>G (G allele vs. A allele: OR = 1.45 (1.06-1.98), P = 0.021; GG + AG vs. AA: OR = 1.51 (1.02-2.23), P = 0.038) in our study. However, the other SNPs in our analysis showed no significant association with NTDs risk (all P > 0.05). Furthermore, the result of the meta-analysis supported the association between MTRR 66A>G and NTDs risk (G allele vs. A allele: OR = 1.32, 95% CI = 1.09-1.61, GG + GA vs. AA: OR = 1.49, 95% CI = 1.06-2.09, GG vs. AA: OR = 1.61, 95% CI = 1.04-2.49).Our study confirmed that the MTRR 66A>G and MTR 2756A>G were significantly associated with the increased NTDs risk in a Chinese population. The further meta-analysis enhance that MTRR 66A>G was connected with the susceptibility of NTDs widely. Further investigations based on more detailed stratification were recommended.
| S-EPMC4616500 | biostudies-literature
Project description:Single-gene analyses indicate that maternal genes associated with metabolic conditions (e.g., obesity) may influence the risk of neural tube defects (NTDs). However, to our knowledge, there have been no assessments of maternal-fetal metabolic gene-gene interactions and NTDs. We investigated 23 single nucleotide polymorphisms among 7 maternal metabolic genes (ADRB3, ENPP1, FTO, LEP, PPARG, PPARGC1A, and TCF7L2) and 2 fetal metabolic genes (SLC2A2 and UCP2). Samples were obtained from 737 NTD case-parent triads included in the National Birth Defects Prevention Study for birth years 1999-2007. We used a 2-step approach to evaluate maternal-fetal gene-gene interactions. First, a case-only approach was applied to screen all potential maternal and fetal interactions (n = 76), as this design provides greater power in the assessment of gene-gene interactions compared to other approaches. Specifically, ordinal logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for each maternal-fetal gene-gene interaction, assuming a log-additive model of inheritance. Due to the number of comparisons, we calculated a corrected p-value (q-value) using the false discovery rate. Second, we confirmed all statistically significant interactions (q < 0.05) using a log-linear approach among case-parent triads. In step 1, there were 5 maternal-fetal gene-gene interactions with q < 0.05. The "top hit" was an interaction between maternal ENPP1 rs1044498 and fetal SLC2A2 rs6785233 (interaction OR = 3.65, 95% CI: 2.32-5.74, p = 2.09×10(-8), q=0.001), which was confirmed in step 2 (p = 0.00004). Our findings suggest that maternal metabolic genes associated with hyperglycemia and insulin resistance and fetal metabolic genes involved in glucose homeostasis may interact to increase the risk of NTDs.
| S-EPMC4394735 | biostudies-literature