Interplay among the Variants of One Carbon Metabolism, Methylenetetrahydrofolate Reductase Polymorphisms and Lung Cancer

Introduction: Folates perform an integral task in DNA synthesis, methylationand repair. Methylenetetrahydrofolate Reductase (MTHFR) potrays a key part in the metabolism of folate and regulates the equilibrium between the various forms of folate for DNA synthesis and DNA methylation. MTHFR irrevocably transforms 5,10 methylenetetrahydrofolate to 5-methyltetrahydrofolate, the principal circulating folate and the carbon donor for remethylation processes. MTHFR is vastly polymorphic in the general population. Materials and Methods: It was a case-control study conducted during March 2010 to September 2011 in the Department of Pulmonary Medicine in collaboration with the Department of Biochemistry at Government Medical College and Hospital, Chandigarh, to see whether any association exists between the variants of one carbon metabolism, MTHFR polymorphisms (C677T and A1298C), and lung cancer. Twenty biopsy proven lung cancer patients and 20 age and sex matched cancer-free controls were selected. Results: The mean serum folate in cases was higher (12.84 ng/mL±7.527 ng/mL) as compared to controls (4.46 ng/mL±1.346 ng/mL), suggesting that high levels of serum folate are associated with lung cancer. There was no significant variance in the levels of vitamin B12 and plasma homocysteine between cases and controls. No MTHFR polymorphism C677T was seen in the blood and the bronchial biopsy samples of all cases as well as blood samples of all the controls. The MTHFR polymorphism A1298C was present in the blood as well as bronchial biopsy samples of cases as well as blood of controls. Thus, in the present study, there was no relation of this polymorphism with lung cancer. Conclusion: Polymorphisms in MTHFR may contribute to lung cancer. More research on the basis of cellular and molecular mechanisms of lung cancer is urgently needed to aid in understanding of pathogenesis of the disease.

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

Toxicological Sciences ◽

10.1093/toxsci/kfz034 ◽

2019 ◽

Vol 169 (1) ◽

pp. 25-33 ◽

Cited By ~ 2

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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Effects of Periconceptional Multivitamin Supplementation on Folate and Homocysteine Levels Depending on Genetic Variants of Methyltetrahydrofolate Reductase in Infertile Japanese Women

Nutrients ◽

10.3390/nu13041381 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1381

Author(s):

Keiji Kuroda ◽

Takashi Horikawa ◽

Yoko Gekka ◽

Azusa Moriyama ◽

Kazuki Nakao ◽

...

Keyword(s):

Folic Acid ◽

Methylenetetrahydrofolate Reductase ◽

Homocysteine Level ◽

Folic Acid Supplementation ◽

Serum Folate ◽

Folate Level ◽

Multivitamin Supplementation ◽

Mthfr Polymorphisms ◽

Mthfr Genotype ◽

Multivitamin Supplements

Methylenetetrahydrofolate reductase (MTHFR) has various polymorphisms, and the effects of periconceptional folic acid supplementation for decreasing neural tube defects (NTDs) risk differ depending on the genotypes. This study analyzed the effectiveness of multivitamin supplementation on folate insufficiency and hyperhomocysteinemia, depending on MTHFR polymorphisms. Of 205 women, 72 (35.1%), 100 (48.8%) and 33 (16.1%) had MTHFR CC, CT and TT, respectively. Serum folate and homocysteine levels in women with homozygous mutant TT were significantly lower and higher, respectively, than those in women with CC and CT. In 54 women (26.3% of all women) with a risk of NTDs, multivitamin supplementation containing folic acid and vitamin D for one month increased folate level (5.8 ± 0.9 to 19.2 ± 4.0 ng/mL, p < 0.0001) and decreased the homocysteine level (8.2 ± 3.1 to 5.8 ± 0.8 nmol/mL, p < 0.0001) to minimize the risk of NTDs in all women, regardless of MTHFR genotype. Regardless of MTHFR genotype, multivitamin supplements could control folate and homocysteine levels. Tests for folate and homocysteine levels and optimal multivitamin supplementation in women with risk of NTDs one month or more before pregnancy should be recommended to women who are planning a pregnancy.

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Supplemental one‐carbon metabolism related B vitamins and lung cancer risk in the Women's Health Initiative

International Journal of Cancer ◽

10.1002/ijc.32913 ◽

2020 ◽

Vol 147 (5) ◽

pp. 1374-1384 ◽

Cited By ~ 2

Author(s):

Theodore M. Brasky ◽

Roberta M. Ray ◽

Sandi L. Navarro ◽

Jeannette M. Schenk ◽

Alison M. Newton ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Risk ◽

Women's Health ◽

Carbon Metabolism ◽

Lung Cancer Risk ◽

B Vitamins ◽

Women's Health Initiative ◽

Health Initiative ◽

One Carbon Metabolism ◽

The Women’S Health Initiative

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Non-Association of Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms with Homocysteine Levels, Venous or Arterial Thromboses in 1,141 North-Central Appalachian Patients

Cancer and Clinical Oncology ◽

10.5539/cco.v5n2p21 ◽

2016 ◽

Vol 5 (2) ◽

pp. 21

Author(s):

Farhad Khimani ◽

Peter Perrotta ◽

Gerry Hobbs ◽

Thomas Hogan

Keyword(s):

Risk Assessment ◽

Patient Population ◽

Methylenetetrahydrofolate Reductase ◽

Plasma Homocysteine ◽

Minimal Cost ◽

Frequency Pattern ◽

Mthfr Polymorphism ◽

Mthfr Polymorphisms ◽

North Central ◽

Central Appalachia

Objectives: MTHFR polymorphism testing has been used by clinicians for thrombophilia risk assessment. We questioned the utility of such testing.Methods: 1,141 patients age 18 and above had MTHFR testing for both C677T and A1298C polymorphisms, 2006 through 2012. Available plasma homocysteine levels were obtained and ICD-9 billing codes were grouped to identify venous or arterial clots in these patients.Results: 901 women and 240 men were tested; median age in women was 33 years (range 18-86); median age in men was 47 years (range 18-83). County of residence mapping confirmed that this MTHFR tested population was from north-central Appalachia. Only 144 (13%) of the 1,141 patients had no polymorphism at either the C677T or the A1298C locus; only 4 patients (0.4%) had 3 or more polymorphisms; 993 patients (87%) had either one or two polymorphisms. We found polymorphism frequency pattern similar in both sexes. Although men had higher homocysteine levels, MTHFR polymorphisms did not associate with homocysteine levels in either sex. In 901 women tested, the ICD-9 coded incidence of arterial clots was 20%, and of venous clots was 21%; in 240 men tested, the incidence of arterial clots was 48% and of venous clots was 40%. MTHFR polymorphisms did not associate with arterial or venous clots in either sex. Based on CPT billing codes, a minimal cost estimate was $137,000 for performing these 1,141 MTHFR tests.Conclusions: MTHFR testing was costly and did not add useful information during thrombophilia evaluation in this patient population.

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Association of One-Carbon Metabolism-Related Vitamins (Folate, B6, B12), Homocysteine and Methionine With the Risk of Lung Cancer: Systematic Review and Meta-Analysis

Frontiers in Oncology ◽

10.3389/fonc.2018.00493 ◽

2018 ◽

Vol 8 ◽

Cited By ~ 12

Author(s):

Jia Yang ◽

Hongjia Li ◽

Haibin Deng ◽

Zhongqi Wang

Keyword(s):

Lung Cancer ◽

Systematic Review ◽

Carbon Metabolism ◽

Meta Analysis ◽

One Carbon Metabolism

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

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015129 ◽

2020 ◽

Vol 295 (47) ◽

pp. 16037-16057 ◽

Cited By ~ 1

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.

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Long-Term, Supplemental, One-Carbon Metabolism–Related Vitamin B Use in Relation to Lung Cancer Risk in the Vitamins and Lifestyle (VITAL) Cohort

Journal of Clinical Oncology ◽

10.1200/jco.2017.72.7735 ◽

2017 ◽

Vol 35 (30) ◽

pp. 3440-3448 ◽

Cited By ~ 44

Author(s):

Theodore M. Brasky ◽

Emily White ◽

Chi-Ling Chen

Keyword(s):

Lung Cancer ◽

Cancer Risk ◽

Carbon Metabolism ◽

Lung Cancer Risk ◽

Hazard Ratio ◽

B Vitamins ◽

Vitamin B ◽

Supplement Use ◽

One Carbon Metabolism

Purpose Inconsistent findings have been reported of a link between the use of one-carbon metabolism–related B vitamins and lung cancer risk. Because of the high prevalence of supplemental vitamin B use, any possible increased association warrants further investigation. We examined the association between long-term use of supplemental B vitamins on the one-carbon metabolism pathway and lung cancer risk in the Vitamins and Lifestyle (VITAL) cohort, which was designed specifically to look at supplement use relative to cancer risk. Methods A total of 77,118 participants of the VITAL cohort, 50 to 76 years of age, were recruited between October 2000 and December 2002 and included in this analysis. Incident, primary, invasive lung cancers (n = 808) were ascertained by prospectively linking the participants to a population-based cancer registry. The 10-year average daily dose from individual and multivitamin supplements were the exposures of primary interest. Results Use of supplemental vitamins B6, folate, and B12 was not associated with lung cancer risk among women. In contrast, use of vitamin B6 and B12 from individual supplement sources, but not from multivitamins, was associated with a 30% to 40% increase in lung cancer risk among men. When the 10-year average supplement dose was evaluated, there was an almost two-fold increase in lung cancer risk among men in the highest categories of vitamin B6 (> 20 mg/d; hazard ratio, 1.82; 95% CI, 1.25 to 2.65) and B12 (> 55µg/d; hazard ratio, 1.98; 95% CI, 1.32 to 2.97) compared with nonusers. For vitamin B6 and B12, the risk was even higher among men who were smoking at baseline. In addition, the B6 and B12 associations were apparent in all histologic types except adenocarcinoma, which is the type less related to smoking. Conclusion This sex- and source-specific association provides further evidence that vitamin B supplements are not chemopreventive for lung cancer and may be harmful.

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

Oncology ◽

10.1159/000509658 ◽

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

Background: 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). Methods: 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. Results: Among the 41 single-nucleotide polymorphisms (SNPs) analyzed, 4 SNPs (MTHFD1L rs6919680T>G and rs3849794T>C, MTR rs2853523C>A, and MTHFR rs4846049G>T) were significantly associated with survival outcomes. MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (adjusted hazard ratio [aHR] = 0.73, 95% confidence interval [CI] = 0.54–0.99, p = 0.04) and worse OS (aHR = 2.14, 95% CI = 1.13–4.07, p = 0.02), respectively. MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.41, 95% CI = 1.08–1.83, p = 0.01; and aHR = 1.97, 95% CI = 1.10–3.53, p = 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, MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (aHR = 0.64, 95% CI = 0.41–1.00, p = 0.05) and worse OS (aHR = 2.77, 95% CI = 1.11–6.91, p = 0.03), respectively, and MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.73, 95% CI = 1.17–2.56, p = 0.01; and aHR = 2.78, 95% CI = 1.12–6.88, p = 0.03, respectively). Conclusions: 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.

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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

British Journal Of Nutrition ◽

10.1017/s0007114507801073 ◽

2008 ◽

Vol 99 (2) ◽

pp. 379-389 ◽

Cited By ~ 32

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.

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

Frontiers in Neurology ◽

10.3389/fneur.2021.683275 ◽

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 < 0.001), and patients presenting the TT genotype exhibited higher serum Hcy levels than patients with the CC (P < 0.001) or CT (P < 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 < 0.001; vs. CT: P < 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 < 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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