Vision Changes after Spaceflight Are Related to Alterations in Folate– and Vitamin B-12–Dependent One-Carbon Metabolism

ABSTRACT Background Choline plays an integral role in one-carbon metabolism in the body, but it is unclear whether genetic polymorphisms are associated with variations in plasma choline and its metabolites. Objectives This study aimed to evaluate the association of genetic variants in choline and one-carbon metabolism with plasma choline and its metabolites. Methods We analyzed data from 1423 postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. Plasma concentrations of choline, betaine, dimethylglycine (DMG), and trimethylamine N-oxide were determined in 12-h fasting blood samples collected at baseline (1993–1998). Candidate and tagging single-nucleotide polymorphisms (SNPs) were genotyped in betaine-homocysteine S-methyltransferase (BHMT), BHMT2, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (NADP+ dependent 1) (MTHFD1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Linear regression was used to derive percentage difference in plasma concentrations per variant allele, adjusting for confounders, including B-vitamin biomarkers. Potential effect modification by plasma vitamin B-12, vitamin B-6, and folate concentrations and folic-acid fortification periods was examined. Results The candidate SNP BHMT R239Q (rs3733890) was associated with lower concentrations of plasma betaine and DMG concentrations (−4.00% and −6.75% per variant allele, respectively; both nominal P < 0.05). Another candidate SNP, BHMT2 rs626105 A>G, was associated with higher plasma DMG concentration (13.0%; P < 0.0001). Several tagSNPs in these 2 genes were associated with plasma concentrations after correction for multiple comparisons. Vitamin B-12 status was a significant effect modifier of the association between the genetic variant BHMT2 rs626105 A>G and plasma DMG concentration. Conclusions Genetic variations in metabolic enzymes were associated with plasma concentrations of choline and its metabolites. Our findings contribute to the knowledge on the variation in blood nutrient concentrations in postmenopausal women.

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Betaine: a key modulator of one-carbon metabolism and homocysteine status

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2005.187 ◽

2005 ◽

Vol 43 (10) ◽

Cited By ~ 129

Author(s):

Per Magne Ueland ◽

Pål I. Holm ◽

Steinar Hustad

Keyword(s):

Carbon Metabolism ◽

Individual Variability ◽

Vitamin B ◽

Total Homocysteine ◽

Altered Metabolism ◽

One Carbon Metabolism ◽

And Gender ◽

Betaine Homocysteine Methyltransferase ◽

Plasma Total Homocysteine ◽

Homocysteine Methyltransferase

AbstractBetaine serves as a methyl donor in a reaction converting homocysteine to methionine, catalysed by the enzyme betaine-homocysteine methyltransferase. It has been used for years to lower the concentration of plasma total homocysteine (tHcy) in patients with homocystinuria, and has recently been shown to reduce fasting and in particular post-methionine load (PML) tHcy in healthy subjects.Betaine exists in plasma at concentrations of about 30μmol/L; it varies 10-fold (from 9 to 90μmol/L) between individuals, but the intra-individual variability is small. Major determinants are choline, dimethylglycine and folate in plasma, folic acid intake and gender.Recent studies have demonstrated that plasma betaine is a stronger determinant of PML tHcy than are vitamin BTo conclude, betaine status is a component of an individual's biochemical make-up with ramifications to one-carbon metabolism. Betaine status should be investigated in pathologies related to altered metabolism of homocysteine and folate, including cardiovascular disease, cancer and neural tube defects.

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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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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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B-Vitamine und Lungenkrebsrisiko

Deutsche Zeitschrift für Onkologie ◽

10.1055/s-0043-121934 ◽

2017 ◽

Vol 49 (04) ◽

pp. 195-197

Keyword(s):

Lung Cancer ◽

Cancer Risk ◽

Clin Oncol ◽

Carbon Metabolism ◽

Vitamin B6 ◽

Lung Cancer Risk ◽

Vitamin B ◽

One Carbon Metabolism

Brasky TM, White E, Cheng C-L. Long-term, supplemental, one-carbon metabolism-related vitamin B use in relation to lung cancer risk in the Vitamins and Lifestyle (VITAL) Cohort. J Clin Oncol 2017; 35: 3440–3448 Die jahrelange Einnahme von hoch dosierten Vitamin-B6- oder -B12-Einzelpräparaten ging in einer prospektiven Kohortenstudie bei älteren Männern mit einem stark erhöhten Lungenkrebsrisiko (2- bis 4-fach) einher.

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Metabolism of Mycotoxins, Intracellular Functions of Vitamin B12, and Neurological Manifestations in Patients with Chronic Toxigenic Mold Exposures. A Review

The Scientific World JOURNAL ◽

10.1100/tsw.2004.133 ◽

2004 ◽

Vol 4 ◽

pp. 736-745 ◽

Cited By ~ 1

Author(s):

Ebere C. Anyanwu ◽

Mohammed Morad ◽

Andrew W. Campbell

Keyword(s):

Carbon Metabolism ◽

Synergistic Effects ◽

Chromosome Breakage ◽

Vitamin B ◽

Neurological Manifestations ◽

Ongoing Research ◽

Normal Functions ◽

One Carbon Metabolism ◽

The One ◽

And Function

This paper evaluates the possible reasons for consistent vitamin B12deficiency in chronic toxigenic mold exposures and the synergistic relationships with the possible mycotoxic effects on one-carbon metabolism that lead to the manifestations of clinical neuropathological symptomology. Vitamins are first defined in general and the nutritional sources of vitamin B12are evaluated in particular. Since patients with chronic exposures to toxigenic molds manifest vitamin B12deficiencies, the role of mycotoxins in vitamin B12metabolism is assessed, and since vitamin B12plays important biochemical roles in one-carbon metabolism, the synergistic effects with mycotoxins on humans are reviewed. An outline of the proposed mechanism by which mycotoxins disrupt or interfere with the normal functions of vitamin B12on one-carbon metabolism is proposed. The overall functions of vitamin B12as a source of coenzymes, in intracellular recycling of methionine, in methionine synthase reaction, in the prevention of chromosome breakage, in methylation, and in maintaining a one-carbon metabolic balance are reviewed. Signs, symptoms, and clinical neurological indications of vitamin B12deficiency are also cited. By implication and derivation, it is likely that the interruption of the structure and function of vitamin B12would in turn interfere with the one-carbon metabolism leading to the neurological manifestations. This review is an attempt to formulate a basis for an ongoing research investigation on the subject.

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Matrix metalloproteinases-2, -3 and tissue inhibitors of metalloproteinases-1, -2 in placentas from preterm pregnancies and their association with one-carbon metabolites

Reproduction ◽

10.1530/rep-12-0520 ◽

2013 ◽

Vol 145 (4) ◽

pp. 401-410 ◽

Cited By ~ 13

Author(s):

Deepali Sundrani ◽

Preeti Chavan-Gautam ◽

Hemlata Pisal ◽

Savita Mehendale ◽

Sadhana Joshi

Keyword(s):

Oxidative Stress ◽

Matrix Metalloproteinases ◽

Carbon Metabolism ◽

Preterm Labor ◽

Tissue Inhibitors Of Metalloproteinases ◽

Vitamin B ◽

Tissue Inhibitors ◽

One Carbon Metabolism ◽

The One ◽

And Oxidative Stress

Maternal nutrition is an important determinant of one-carbon metabolism and defects in the one-carbon metabolism may lead to poor obstetric outcomes. This study was designed to test the hypothesis that altered intake/metabolism of micronutrients (folic acid and vitamin B12) and docosahexaenoic acid (DHA) contributes to increased homocysteine and oxidative stress leading to altered levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in women delivering preterm. We have earlier reported increased vitamin B12, homocysteine, and oxidative stress along with reduced placental DHA in women delivering preterm. In this study, we further examine the placental levels of MMP2, MMP3, TIMP1, and TIMP2 in 75 women delivering at term and 73 women delivering preterm. Placental levels of MMPs and TIMPs were determined by ELISA. Placental MMP2 and MMP3 levels were higher (P<0.01) in women delivering preterm as compared with term. There was no difference in the placental TIMP1 and TIMP2 levels in women delivering preterm and at term. Further placental MMP2 and MMP3 levels were higher (P<0.01) in women with preterm labor as compared with those in labor at term, suggesting that MMPs may favor degradation of extracellular matrix in the placenta during preterm labor. Our study for the first time suggests a crucial role of micronutrients and MMPs in preterm birth. Future studies need to examine if epigenetic modifications through the one-carbon cycle contribute to increased levels of MMPs leading to preterm deliveries.

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Maternal intake of one-carbon metabolism-related B vitamins and anorectal malformations in the Japan Environment and Children’s Study

British Journal Of Nutrition ◽

10.1017/s0007114520001816 ◽

2020 ◽

Vol 124 (8) ◽

pp. 865-873

Author(s):

Takehiro Michikawa ◽

Hiroshi Nitta ◽

Makiko Sekiyama ◽

Tatsuo Kuroda ◽

Shoji F. Nakayama ◽

...

Keyword(s):

Early Pregnancy ◽

Carbon Metabolism ◽

Anorectal Malformations ◽

B Vitamins ◽

Vitamin B ◽

Inverse Association ◽

Live Births ◽

Vitamin Intake ◽

One Carbon Metabolism ◽

B Vitamin

AbstractThe occurrence of anorectal malformations (ARM) is thought to be reduced with sufficient folate intake. However, there is no apparent evidence. We focused on enzyme cofactors for one-carbon metabolism, including folate (vitamin B9), vitamin B6 and vitamin B12, and explored the association between maternal combined intake of these B vitamins and the risk of ARM. Using baseline data from a Japanese nationwide birth cohort study between 2011 and 2014, we analysed data of 89 235 women (mean age at delivery = 31·2 years) who delivered singleton live births without chromosomal anomalies. Information on dietary intake was obtained via a FFQ focused on early pregnancy and used to estimate B vitamin intake. We also collected information on the frequency of folic acid supplement use. ARM occurrence was ascertained from medical records. We identified forty-three cases of ARM diagnosed up to the first month after birth (4·8 per 10 000 live births). In terms of individual intake of the respective B vitamins, high vitamin B6 intake was non-significantly associated with reduced odds of ARM. Compared with women in the low combined B vitamin intake group, the OR of having an infant with ARM was 0·4 (95 % CI 0·2, 1·0) in the high intake group (folate ≥400 μg/d, and upper half of vitamin B6 and/or vitamin B12). In conclusion, our cohort analysis suggested an inverse association between the combined intake of one-carbon metabolism-related B vitamins in early pregnancy and ARM occurrence.

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