scholarly journals Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels

2019 ◽  
Vol 20 (15) ◽  
pp. 3754 ◽  
Author(s):  
Coppedè ◽  
Stoccoro ◽  
Tannorella ◽  
Gallo ◽  
Nicolì ◽  
...  
Keyword(s):  
Carbon Metabolism ◽  
Healthy Subjects ◽  
Metabolic Disorders ◽  
Tandem Repeats ◽  
Methylenetetrahydrofolate Reductase ◽  
High Resolution Melting ◽  
Human Disorders ◽  
One Carbon Metabolism ◽  
Inborn Defects ◽  
The One

Methylenetetrahydrofolate reductase (MTHFR) is a pivotal enzyme in the one-carbon metabolism, a metabolic pathway required for DNA synthesis and methylation reactions. MTHFR hypermethylation, resulting in reduced gene expression, can contribute to several human disorders, but little is still known about the factors that regulate MTHFR methylation levels. We performed the present study to investigate if common polymorphisms in one-carbon metabolism genes contribute to MTHFR methylation levels. MTHFR methylation was assessed in peripheral blood DNA samples from 206 healthy subjects with methylation-sensitive high-resolution melting (MS-HRM); genotyping was performed for MTHFR 677C>T (rs1801133) and 1298A>C (rs1801131), MTRR 66A>G (rs1801394), MTR 2756A>G (rs1805087), SLC19A1 (RFC1) 80G>A (rs1051266), TYMS 28-bp tandem repeats (rs34743033) and 1494 6-bp ins/del (rs34489327), DNMT3A -448A>G (rs1550117), and DNMT3B -149C>T (rs2424913) polymorphisms. We observed a statistically significant effect of the DNMT3B -149C>T polymorphism on mean MTHFR methylation levels, and particularly CT and TT carriers showed increased methylation levels than CC carriers. The present study revealed an association between a functional polymorphism of DNMT3B and MTHFR methylation levels that could be of relevance in those disorders, such as inborn defects, metabolic disorders and cancer, that have been linked to impaired DNA methylation.

scholarly journals Duality of Tocopherol Isoforms and Novel Associations with Vitamins Involved in One-Carbon Metabolism: Results from an Elderly Sample of the LifeLines Cohort Study

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 580
Author(s):  
Camilo G. Sotomayor ◽  
Isidor Minović ◽  
Manfred L. Eggersdorfer ◽  
Ineke J. Riphagen ◽  
Martin H. de Borst ◽  
...  
Keyword(s):  
Vitamin E ◽  
Carbon Metabolism ◽  
Serum Vitamin ◽  
Elderly Subjects ◽  
Vitamin Supplement ◽  
Total Lipids ◽  
Metabolism Pathway ◽  
Age Related ◽  
One Carbon Metabolism ◽  
The One

Whether the affinity of serum vitamin E with total lipids hampers the appropriate assessment of its association with age-related risk factors has not been investigated in epidemiological studies. We aimed to compare linear regression-derived coefficients of the association of non-indexed and total lipids-indexed vitamin E isoforms with clinical and laboratory characteristics pertaining to the lipid, metabolic syndrome, and one-carbon metabolism biological domains. We studied 1429 elderly subjects (non-vitamin supplement users, 60–75 years old, with low and high socioeconomic status) from the population-based LifeLines Cohort and Biobank Study. We found that the associations of tocopherol isoforms with lipids were inverted in total lipids-indexed analyses, which may be indicative of overcorrection. Irrespective of the methods of standardization, we consistently found positive associations of α-tocopherol with vitamins of the one-carbon metabolism pathway and inverse associations with characteristics related to glucose metabolism. The associations of γ-tocopherol were often opposite to those of α-tocopherol. These data suggest that tocopherol isoforms and one-carbon metabolism are related, with beneficial and adverse associations for α-tocopherol and γ-tocopherol, respectively. Whether tocopherol isoforms, or their interplay, truly affect the one-carbon metabolism pathway remains to be further studied.

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.

Maternal vitamin D deficiency impact on LCPUFA and pregnancy outcome associated with alterations in the one carbon metabolism

2020 ◽  
Author(s):  
Anindita A. Nandi ◽  
Nisha S. Wadhwani ◽  
Karuna N. Randhir ◽  
Shweta D. Madiwale ◽  
Juilee S. Deshpande ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Pregnancy Outcome ◽  
Carbon Metabolism ◽  
Maternal Vitamin ◽  
One Carbon Metabolism ◽  
The One

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 Gene expression profiles of the one-carbon metabolism pathway

2009 ◽  
Vol 36 (5) ◽  
pp. 277-282 ◽  
Author(s):  
Yin Leng Lee ◽  
Xinran Xu ◽  
Sylvan Wallenstein ◽  
Jia Chen
Keyword(s):  
Gene Expression ◽  
Carbon Metabolism ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Metabolism Pathway ◽  
One Carbon Metabolism ◽  
The One

scholarly journals Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway

2009 ◽  
Vol 18 (23) ◽  
pp. 4677-4687 ◽  
Author(s):  
Aditi Hazra ◽  
Peter Kraft ◽  
Ross Lazarus ◽  
Constance Chen ◽  
Stephen J. Chanock ◽  
...  
Keyword(s):  
Carbon Metabolism ◽  
Metabolism Pathway ◽  
Genome Wide ◽  
One Carbon Metabolism ◽  
The One

scholarly journals Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, intakes of folate and related B vitamins and colorectal cancer: a case–control study in a population with relatively low folate intake

2008 ◽  
Vol 99 (2) ◽  
pp. 379-389 ◽  
Author(s):  
Linda Sharp ◽  
Julian Little ◽  
Nigel T. Brockton ◽  
Seonaidh C. Cotton ◽  
Lindsey F. Masson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Carbon Metabolism ◽  
Methylenetetrahydrofolate Reductase ◽  
Case Control Study ◽  
Case Control ◽  
B Vitamins ◽  
Folate Intake ◽  
Vitamin B ◽  
One Carbon Metabolism ◽  
Control Study

Folate is key in one-carbon metabolism, disruption of which can interfere with DNA synthesis, repair, and methylation. Efficient one-carbon metabolism requires other B vitamins and the optimal activity of enzymes including 5,10-methylenetetrahydrofolate reductase (MTHFR). We report a population-based case–control study of folate intake, related dietary factors andMTHFRpolymorphisms (C677T, A1298C) and colorectal cancer in a population with relatively high colorectal cancer incidence and relatively low folate intake. A total of 264 cases with histologically confirmed incident colorectal cancer and 408 controls participated. There was no clear trend in risk with reported intakes of total, or dietary, folate, riboflavin, vitamin B12or vitamin B6, nor were there interactions between folate intake and the other B vitamins or alcohol. For C677T, risk decreased with increasing variant alleles (multivariate OR for CTv.CC = 0·77 (95 % CI 0·52, 1·16); OR for TTv.CC = 0·62 (95 % CI 0·31, 1·24)), which, although not statistically significant, was consistent with previous studies. For A1298C, compared with AA subjects, CC subjects had modest, non-significant, reduced risk (multivariate OR = 0·81 (95 % CI 0·45, 1·49)). There were significant interactions between total folate and C677T (P = 0·029) and A1298C (P = 0·025), and total vitamin B6and both polymorphisms (C677T,P = 0·016; A1298C,P = 0·033), although the patterns observed differed from previous studies. Seen against the setting of low folate intake, the results suggest that the role of folate metabolism in colorectal cancer aetiology may be more complex than previously thought. Investigation of particular folate vitamers (for example, tetrahydrofolate, 5,10-methylenetetrahydrofolate) may help clarify carcinogenesis pathways.

scholarly journals Genetic Polymorphisms in Enzymes Involved in One-Carbon Metabolism and Anti-epileptic Drug Monotherapy on Homocysteine Metabolism in Patients With Epilepsy

2021 ◽  
Vol 12 ◽  
Author(s):  
Shaofang Zhu ◽  
Guanzhong Ni ◽  
Lisen Sui ◽  
Yiran Zhao ◽  
Xiaoxu Zhang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Carbon Metabolism ◽  
Methylenetetrahydrofolate Reductase ◽  
Folate Receptor ◽  
Linear Regression Analysis ◽  
Elevated Serum ◽  
Anti Epileptic Drug ◽  
Independent Risk Factors ◽  
One Carbon Metabolism ◽  
Patients With Epilepsy

Aims: To investigate the effects of single nucleotide polymorphisms (SNPs) in genes of one-carbon metabolism (OCM) related enzymes and anti-epileptic drug (AED) monotherapy on homocysteine (Hcy) metabolism in patients with epilepsy, and to further explore specific SNPs that may increase patients' susceptibility to the effects of AEDs on the Hcy imbalance.Method: This case-control study analyzed 279 patients with epilepsy, including patients receiving monotherapy with valproate (VPA) (n = 53), oxcarbazepine (OXC) (n = 71), lamotrigine (LTG) (n = 55), or levetiracetam (LEV) (n = 35) and patients who had not taken any AEDs (controls, n = 65) for at least 6 months. Serum levels of vitamin B12 (vit B12), folate (FA) and Hcy were measured, and 23 SNPs in 13 genes of OCM-related enzymes were genotyped in all patients.Results: Methylenetetrahydrofolate reductase (MTHFR) rs1801133 was associated with elevated serum Hcy levels in patients with epilepsy (P &lt; 0.001), and patients presenting the TT genotype exhibited higher serum Hcy levels than patients with the CC (P &lt; 0.001) or CT (P &lt; 0.001) genotype. A subsequent multiple linear regression analysis showed that AED monotherapy with VPA (vs. control: P = 0.023) or OXC (vs. control: P = 0.041), and genotypes of MTHFR rs1801133 TT (vs. CC: P &lt; 0.001; vs. CT: P &lt; 0.001), transcobalamin 2 (TCN2) rs1801198 CC (vs. GC: P = 0.039) and folate receptor 1 (FOLR1) rs2071010 AA (vs. GA: P = 0.031) were independent risk factors for higher Hcy levels. In the subgroup analysis of patients taking OXC, we found that patients with genotypes of MTHFR rs1801133 TT (vs. CC: P = 0.001; vs. CT: P &lt; 0.001) and TCN2 rs1801198 CC (vs. GC: P = 0.021; vs. GG: P = 0.018) exhibited higher serum Hcy levels.Conclusions: VPA, OXC, and genotypes of MTHFR rs1801133 TT, TCN2 rs1801198 CC, and FOLR1 rs2071010 AA are all independent risk factors for elevated Hcy levels in patients with epilepsy. Moreover, genotypes of MTHFR rs1801133 TT and TCN2 rs1801198 CC may increase patients' susceptibility to the effect of OXC on disrupting Hcy homeostasis.

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