Genetic Variation: Impact on Folate (and Choline) Bioefficacy

2010 ◽  
Vol 80 (45) ◽  
pp. 319-329 ◽  
Author(s):  
Allyson A. West ◽  
Marie A. Caudill
Keyword(s):  
Carbon Metabolism ◽  
Genetic Variants ◽  
Plasma Homocysteine ◽  
Water Soluble ◽  
Gene Interactions ◽  
Dietary Folate ◽  
Methyl Donors ◽  
Common Genetic Variants ◽  
One Carbon Metabolism ◽  
The Impact

Folate and choline are water-soluble micronutrients that serve as methyl donors in the conversion of homocysteine to methionine. Inadequacy of these nutrients can disturb one-carbon metabolism as evidenced by alterations in circulating folate and/or plasma homocysteine. Among common genetic variants that reside in genes regulating folate absorptive and metabolic processes, homozygosity for the MTHFR 677C > T variant has consistently been shown to have robust effects on status markers. This paper will review the impact of genetic variants in folate-metabolizing genes on folate and choline bioefficacy. Nutrient-gene and gene-gene interactions will be considered along with the need to account for these genetic variants when updating dietary folate and choline recommendations.

scholarly journals The Impact of Natural Dietary Compounds and Food-Borne Mycotoxins on DNA Methylation and Cancer

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2004 ◽  
Author(s):  
Terisha Ghazi ◽  
Thilona Arumugam ◽  
Ashmika Foolchand ◽  
Anil A. Chuturgoon
Keyword(s):  
Dna Methylation ◽  
Bioactive Compounds ◽  
Epigenetic Modification ◽  
Bioactive Molecules ◽  
Methyl Donors ◽  
Food Borne ◽  
One Carbon Metabolism ◽  
Aberrant Dna Methylation ◽  
Methylation Patterns ◽  
The Impact

Cancer initiation and progression is an accumulation of genetic and epigenetic modifications. DNA methylation is a common epigenetic modification that regulates gene expression, and aberrant DNA methylation patterns are considered a hallmark of cancer. The human diet is a source of micronutrients, bioactive molecules, and mycotoxins that have the ability to alter DNA methylation patterns and are thus a contributing factor for both the prevention and onset of cancer. Micronutrients such as betaine, choline, folate, and methionine serve as cofactors or methyl donors for one-carbon metabolism and other DNA methylation reactions. Dietary bioactive compounds such as curcumin, epigallocatechin-3-gallate, genistein, quercetin, resveratrol, and sulforaphane reactivate essential tumor suppressor genes by reversing aberrant DNA methylation patterns, and therefore, they have shown potential against various cancers. In contrast, fungi-contaminated agricultural foods are a source of potent mycotoxins that induce carcinogenesis. In this review, we summarize the existing literature on dietary micronutrients, bioactive compounds, and food-borne mycotoxins that affect DNA methylation patterns and identify their potential in the onset and treatment of cancer.

scholarly journals Allosteric inhibition of MTHFR prevents futile SAM cycling and maintains nucleotide pools in one-carbon metabolism

2020 ◽  
Vol 295 (47) ◽  
pp. 16037-16057 ◽  
Author(s):  
Muskan Bhatia ◽  
Jyotika Thakur ◽  
Shradha Suyal ◽  
Ruchika Oniel ◽  
Rahul Chakraborty ◽  
...  
Keyword(s):  
Carbon Metabolism ◽  
Methylenetetrahydrofolate Reductase ◽  
Isotope Labeling ◽  
Redox Homeostasis ◽  
Regulatory Region ◽  
Regulatory Control ◽  
Growth Defect ◽  
Transsulfuration Pathway ◽  
One Carbon Metabolism ◽  
The Impact

Methylenetetrahydrofolate reductase (MTHFR) links the folate cycle to the methionine cycle in one-carbon metabolism. The enzyme is known to be allosterically inhibited by SAM for decades, but the importance of this regulatory control to one-carbon metabolism has never been adequately understood. To shed light on this issue, we exchanged selected amino acid residues in a highly conserved stretch within the regulatory region of yeast MTHFR to create a series of feedback-insensitive, deregulated mutants. These were exploited to investigate the impact of defective allosteric regulation on one-carbon metabolism. We observed a strong growth defect in the presence of methionine. Biochemical and metabolite analysis revealed that both the folate and methionine cycles were affected in these mutants, as was the transsulfuration pathway, leading also to a disruption in redox homeostasis. The major consequences, however, appeared to be in the depletion of nucleotides. 13C isotope labeling and metabolic studies revealed that the deregulated MTHFR cells undergo continuous transmethylation of homocysteine by methyltetrahydrofolate (CH3THF) to form methionine. This reaction also drives SAM formation and further depletes ATP reserves. SAM was then cycled back to methionine, leading to futile cycles of SAM synthesis and recycling and explaining the necessity for MTHFR to be regulated by SAM. The study has yielded valuable new insights into the regulation of one-carbon metabolism, and the mutants appear as powerful new tools to further dissect out the intersection of one-carbon metabolism with various pathways both in yeasts and in humans.

Genetic Variants in One-Carbon Metabolism Pathway Predict Survival Outcomes of Early-Stage Non-Small Cell Lung Cancer

Oncology ◽  
2020 ◽  
Vol 98 (12) ◽  
pp. 897-904
Author(s):  
Sook Kyung Do ◽  
Sun Ha Choi ◽  
Shin Yup Lee ◽  
Jin Eun Choi ◽  
Hyo-Gyoung Kang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Carbon Metabolism ◽  
Genetic Variants ◽  
Early Stage ◽  
Small Cell ◽  
Survival Outcomes ◽  
Small Cell Lung ◽  
Metabolism Pathway ◽  
One Carbon Metabolism ◽  
The One

<b><i>Background:</i></b> This study was conducted to investigate the association between genetic variants in one-carbon metabolism and survival outcomes of surgically resected non-small cell lung cancer (NSCLC). <b><i>Methods:</i></b> We genotyped 41 potentially functional variants of 19 key genes in the one-carbon metabolism pathway among 750 NSCLC patients who underwent curative surgery. The association between genetic variants and overall survival (OS)/disease-free survival (DFS) were analyzed. <b><i>Results:</i></b> Among the 41 single-nucleotide polymorphisms (SNPs) analyzed, 4 SNPs (<i>MTHFD1L</i> rs6919680T&#x3e;G and rs3849794T&#x3e;C, <i>MTR</i> rs2853523C&#x3e;A, and <i>MTHFR</i> rs4846049G&#x3e;T) were significantly associated with survival outcomes. <i>MTHFD1L</i> rs6919680T&#x3e;G and <i>MTR</i> rs2853523C&#x3e;A were significantly associated with better OS (adjusted hazard ratio [aHR] = 0.73, 95% confidence interval [CI] = 0.54–0.99, <i>p</i> = 0.04) and worse OS (aHR = 2.14, 95% CI = 1.13–4.07, <i>p</i> = 0.02), respectively. <i>MTHFD1L</i> rs3849794T&#x3e;C and <i>MTHFR</i> rs4846049G&#x3e;T were significantly associated with worse DFS (aHR = 1.41, 95% CI = 1.08–1.83, <i>p</i> = 0.01; and aHR = 1.97, 95% CI = 1.10–3.53, <i>p</i> = 0.02, respectively). When the patients were divided according to histology, the associations were significant only in squamous cell carcinoma (SCC), but not in adenocarcinoma (AC). In SCC, <i>MTHFD1L</i> rs6919680T&#x3e;G and <i>MTR</i> rs2853523C&#x3e;A were significantly associated with better OS (aHR = 0.64, 95% CI = 0.41–1.00, <i>p</i> = 0.05) and worse OS (aHR = 2.77, 95% CI = 1.11–6.91, <i>p</i> = 0.03), respectively, and <i>MTHFD1L</i> rs3849794T&#x3e;C and <i>MTHFR</i> rs4846049G&#x3e;T were significantly associated with worse DFS (aHR = 1.73, 95% CI = 1.17–2.56, <i>p</i> = 0.01; and aHR = 2.78, 95% CI = 1.12–6.88, <i>p</i> = 0.03, respectively). <b><i>Conclusions:</i></b> Our results suggest that the genetic variants in the one-carbon metabolism pathway could be used as biomarkers for predicting the clinical outcomes of patients with early-stage NSCLC.

scholarly journals Flaxseed Increases Animal Lifespan and Reduces Ovarian Cancer Severity by Toxically Augmenting One-Carbon Metabolism

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5674
Author(s):  
William C. Weston ◽  
Karen H. Hales ◽  
Dale B. Hales
Keyword(s):  
Liver Function ◽  
Carbon Metabolism ◽  
Vitamin B6 ◽  
Ovarian Tumor ◽  
Tumor Metastasis ◽  
Plasma Homocysteine ◽  
Elevated Plasma ◽  
Polyamine Biosynthesis ◽  
Reduced Body ◽  
One Carbon Metabolism

We used an LC-MS/MS metabolomics approach to investigate one-carbon metabolism in the plasma of flaxseed-fed White Leghorn laying hens (aged 3.5 years). In our study, dietary flaxseed (via the activity of a vitamin B6 antagonist known as “1-amino d-proline”) induced at least 15-fold elevated plasma cystathionine. Surprisingly, plasma homocysteine (Hcy) was stable in flaxseed-fed hens despite such highly elevated cystathionine. To explain stable Hcy, our data suggest accelerated Hcy remethylation via BHMT and MS-B12. Also supporting accelerated Hcy remethylation, we observed elevated S-adenosylmethionine (SAM), an elevated SAM:SAH ratio, and elevated methylthioadenosine (MTA), in flaxseed-fed hens. These results suggest that flaxseed increases SAM biosynthesis and possibly increases polyamine biosynthesis. The following endpoint phenotypes were observed in hens consuming flaxseed: decreased physiological aging, increased empirical lifespan, 9–14% reduced body mass, and improved liver function. Overall, we suggest that flaxseed can protect women from ovarian tumor metastasis by decreasing omental adiposity. We also propose that flaxseed protects cancer patients from cancer-associated cachexia by enhancing liver function.

scholarly journals B Vitamins and Cognitive Performance in Older Adults: Review

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
J. L. Reay ◽  
M. A. Smith ◽  
L. M. Riby
Keyword(s):  
Cognitive Function ◽  
Carbon Metabolism ◽  
Optimal Dose ◽  
Epidemiological Studies ◽  
B Vitamins ◽  
Therapeutic Window ◽  
Vitamin Therapy ◽  
One Carbon Metabolism ◽  
B Vitamin ◽  
The Impact

A copious amount of scientific scrutiny has been dedicated to documenting typical and atypical human ageing, with a substantial body of work focusing upon the impact of lifestyle choices. One such lifestyle choice is that of diet and, in particular, micronutrient ingestion. Epidemiological studies have reported positive associations between B vitamin status and cognitive function, including negative associations between biological markers (i.e., homocysteine) of dysregulated one-carbon metabolism and cognitive function. This has led to a surge of randomised control trials (RCTs) investigations into B vitamin therapy. However, results have continuingly failed to show beneficial behavioural effects. Despite this, results reliably show treatment-related increases in B vitamin level and decreases in homocysteine level—both of which have been identified as risk factors for atypical ageing. In this paper we argue that it would be premature to conclude that B vitamin therapy has no potential and that more research is needed to systematically investigate the optimal dose, the therapeutic “window,” and individual differences in therapy responders and nonresponders. We start with a brief look at one-carbon metabolism and then consider the evidence from epidemiological studies and RCTs in relation to three specific B vitamins: folic acid (B9), pyridoxine (B6), and cobamides (B12).

scholarly journals Integration of rare large-effect expression variants improves polygenic risk prediction

2020 ◽  
Author(s):  
Craig Smail ◽  
Nicole M. Ferraro ◽  
Matthew G. Durrant ◽  
Abhiram S. Rao ◽  
Matthew Aguirre ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Rare Variants ◽  
Complex Trait ◽  
Risk Scores ◽  
Multiple Traits ◽  
Polygenic Risk ◽  
Common Genetic Variants ◽  
Using Data ◽  
The Uk ◽  
The Impact

SummaryPolygenic risk scores (PRS) aim to quantify the contribution of multiple genetic loci to an individual’s likelihood of a complex trait or disease. However, existing PRS estimate genetic liability using common genetic variants, excluding the impact of rare variants. We identified rare, large-effect variants in individuals with outlier gene expression from the GTEx project and then assessed their impact on PRS predictions in the UK Biobank (UKB). We observed large deviations from the PRS-predicted phenotypes for carriers of multiple outlier rare variants; for example, individuals classified as “low-risk” but in the top 1% of outlier rare variant burden had a 6-fold higher rate of severe obesity. We replicated these findings using data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) biobank and the Million Veteran Program, and demonstrated that PRS across multiple traits will significantly benefit from the inclusion of rare genetic variants.

scholarly journals Paraquat Exposure Increases Oxidative Stress Within the Dorsal Striatum of Male Mice With a Genetic Deficiency in One-carbon Metabolism

2019 ◽  
Vol 169 (1) ◽  
pp. 25-33 ◽  
Author(s):  
Nafisa M Jadavji ◽  
Lauren K Murray ◽  
Joshua T Emmerson ◽  
Chris A Rudyk ◽  
Shawn Hayley ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Carbon Metabolism ◽  
Methylenetetrahydrofolate Reductase ◽  
Memory Function ◽  
Dorsal Striatum ◽  
Cell Loss ◽  
Human Populations ◽  
Mthfr Polymorphism ◽  
One Carbon Metabolism ◽  
The Impact

Abstract Paraquat is an herbicide that is commonly used worldwide. Exposure to paraquat results in Parkinson’s disease (PD)-like symptoms including dopaminergic cell loss. Nutrition has also been linked in the pathogenesis of PD, such as reduced levels of folic acid, a B-vitamin, and component of one-carbon metabolism. Within one-carbon metabolism, methylenetetrahydrofolate reductase (MTHFR) catalyzes the irreversible conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. A polymorphism in MTHFR (677 C&→T) has been reported in 5%–15% of North American and European human populations. The MTHFR polymorphism is also prevalent in PD patients. The goal of this study was to investigate the impact of paraquat-induced PD-like pathology in the context of reduced levels of MTHFR. Three-month-old male Mthfr+/− mice, which model the MTHFR polymorphism observed in humans, were administered intraperitoneal injections of paraquat (10 mg/kg) or saline 6 times over 3 weeks. At the end of paraquat treatment, motor and memory function were assessed followed by collection of brain tissue for biochemical analysis. Mthfr+/– mice treated with paraquat showed impaired motor function. There was increased microglial activation within the substantia nigra (SN) of Mthfr+/− mice treated with paraquat. Additionally, all Mthfr+/− mice that were treated with paraquat showed increased oxidative stress within the dorsal striatum, but not the SN. The present results show that paraquat exposure increases PD-like pathology in mice deficient in one-carbon metabolism.

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