Artificial Neural Networks Link One-Carbon Metabolism to Gene-Promoter Methylation in Alzheimer’s Disease

Grossi, Enzo; Stoccoro, Andrea; Tannorella, Pierpaola; Migliore, Lucia; Coppedè, Fabio

doi:10.3233/jad-160210

Cited by 43 publications

(31 citation statements)

References 23 publications

(39 reference statements)

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“…Plasma Hcy, serum folate, and vitamin B12 levels were available from 158 individuals, and their average values are shown in Table 1. The promoter methylation levels of the DNMT1 gene ranged from 0% to 15% in the study population ( Figure 2), with an average value of 2.2% (Table 1), which is in agreement with previous investigations in other cohorts [14,20,21]. The genotype distribution of the investigated polymorphisms is shown in Table 2.…”

Section: Distribution Of the Investigated Variables In The Study Popusupporting

confidence: 89%

“…Little is still known concerning genetic, dietary, or environmental factors linked to changes in DNMT1 methylation levels. In this regard, a previous investigation in peripheral blood DNA samples of Alzheimer's disease (AD) individuals suggested that the promoter methylation levels of several genes, including DNMT1, could be linked to circulating markers of folate metabolism, and particularly to plasma homocysteine (Hcy) levels [14].…”

Section: Introductionmentioning

confidence: 99%

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Plasma Homocysteine and Polymorphisms of Genes Involved in Folate Metabolism Correlate with DNMT1 Gene Methylation Levels

et al. 2019

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DNA methyltransferase 1 (DNMT1) is responsible for the maintenance of DNA methylation patterns during cell division. Several human diseases are characterized by impaired DNMT1 gene methylation, but less is known about the factors that regulate DNMT1 promoter methylation levels. Dietary folates and related B-vitamins are essential micronutrients for DNA methylation processes, and we performed the present study to investigate the contribution of circulating folate, vitamin B12, homocysteine, and common polymorphisms in folate pathway genes to the DNMT1 gene methylation levels. We investigated DNMT1 gene methylation levels in peripheral blood DNA samples from 215 healthy individuals. All the DNA samples were genotyped 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 insertion/deletion (indel) (rs34489327), DNMT3A -448A > G (rs1550117), and DNMT3B -149C > T (rs2424913) polymorphisms. Circulating homocysteine, folate, and vitamin B12 levels were available from 158 of the recruited individuals. We observed an inverse correlation between plasma homocysteine and DNMT1 methylation levels. Furthermore, both MTR rs1805087 and TYMS rs34743033 polymorphisms showed a statistically significant effect on DNMT1 methylation levels. The present study revealed several correlations between the folate metabolic pathway and DNMT1 promoter methylation that could be of relevance for those disorders characterized by altered DNA methylation.

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Section: Distribution Of the Investigated Variables In The Study Popusupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Plasma Homocysteine and Polymorphisms of Genes Involved in Folate Metabolism Correlate with DNMT1 Gene Methylation Levels

et al. 2019

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“…However, as far as MTHFR promoter methylation in the blood is concerned, it should be noted that rather than being a specific marker of a given disease, it could represent a more general biomarker of increased genomic instability. For example, some studies suggest a correlation between hyperhomocysteinemia and MTHFR promoter methylation [26]; others have linked MTHFR promoter methylation in blood cells with markers of chromosome damage, such as an increased frequency of micronuclei [27] or alterations of LINE-1 methylation and stability [15], and there is also indication that MTHFR promoter methylation in blood DNA might reflect dietary B-group vitamin deficiency [18,30] or environmental exposure to cancerous agents, such as those deriving from tobacco smoking [15]. Collectively, those studies suggest that increased MTHFR promoter methylation in blood cells might be a more general marker of impaired one-carbon metabolism and genome instability, rather than a specific disease biomarker.…”

Section: Discussionmentioning

confidence: 99%

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

Lopomo

Ricciardi

Maestri

et al. 2016

IJMS

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Thymomas are uncommon neoplasms that arise from epithelial cells of the thymus and are often associated with myasthenia gravis (MG), an autoimmune disease characterized by autoantibodies directed to different targets at the neuromuscular junction. Little is known, however, concerning epigenetic changes occurring in thymomas from MG individuals. To further address this issue, we analyzed DNA methylation levels of genes involved in one-carbon metabolism (MTHFR) and DNA methylation (DNMT1, DNMT3A, and DNMT3B) in blood, tumor tissue, and healthy thymic epithelial cells from MG patients that underwent a surgical resection of a thymic neoplasm. For the analyses we applied the methylation-sensitive high-resolution melting technique. Both MTHFR and DNMT3A promoters showed significantly higher methylation in tumor tissue with respect to blood, and MTHFR also showed significantly higher methylation levels in tumor tissue respect to healthy adjacent thymic epithelial cells. Both DNMT1 and DNMT3B promoter regions were mostly hypomethylated in all the investigated tissues. The present study suggests that MTHFR methylation is increased in thymomas obtained from MG patients; furthermore, some degrees of methylation of the DNMT3A gene were observed in thymic tissue with respect to blood.

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“…Grossi et al [17] used artificial neural network analysis to illustrate how low cobalamin; low folate and high Hcy are linked to AD. Low PSEN1 methylation was linked to low folate levels and low promoter methylation of BACE1 and DNMT genes.…”

Section: Gene Regulation Is Achieved By 5mc Silencing Gene Expressionmentioning

confidence: 99%

Epigenetic Factors in Late-Onset Alzheimer’s Disease: <em>MTHFR</em> and<em> CTH </em>Gene Polymorphisms, Metabolic Trans-sulfuration and Methylation Pathways, and B Vitamins

Román¹,

Mancera-Páez²,

Bernal³

2018

Preprint

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DNA methylation and other epigenetic factors are important in the pathogenesis of late-onset Alzheimer’s disease (LOAD).  Methylenetetrahydrofolate reductase (MTHFR) gene mutations occur in most elderly patients with memory loss.  MTHFR is critical for production of S-adenosyl-L-methionine (SAM), the principal methyl donor.  A common mutation (1364T/T) of the cystathionine-γ-lyase (CTH) gene affects the enzyme that converts cystathionine to cysteine in the trans-sulfuration pathway causing plasma elevation of total homocysteine (tHcy) or hyperhomocysteinemia – a strong and independent risk factor for cognitive loss and AD. Other causes of hyperhomocysteinemia include aging, nutritional factors, and deficiencies of B vitamins. We emphasize the importance of supplementing vitamin B12 (methylcobalamin), vitamin B9 (folic acid), vitamin B6 (pyridoxine), and SAM to patients in early stages of LOAD.

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Artificial Neural Networks Link One-Carbon Metabolism to Gene-Promoter Methylation in Alzheimer’s Disease

Abstract: The present pilot study suggests that promoter methylation levels of the studied genes are linked to circulating levels of folates, hcy, and vitamin B12.

Cited by 43 publications

References 23 publications

Plasma Homocysteine and Polymorphisms of Genes Involved in Folate Metabolism Correlate with DNMT1 Gene Methylation Levels

Plasma Homocysteine and Polymorphisms of Genes Involved in Folate Metabolism Correlate with DNMT1 Gene Methylation Levels

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

Epigenetic Factors in Late-Onset Alzheimer’s Disease: <em>MTHFR</em> and<em> CTH </em>Gene Polymorphisms, Metabolic Trans-sulfuration and Methylation Pathways, and B Vitamins

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Artificial Neural Networks Link One-Carbon Metabolism to Gene-Promoter Methylation in Alzheimer’s Disease

Abstract: The present pilot study suggests that promoter methylation levels of the studied genes are linked to circulating levels of folates, hcy, and vitamin B12.

Cited by 43 publications

References 23 publications

Plasma Homocysteine and Polymorphisms of Genes Involved in Folate Metabolism Correlate with DNMT1 Gene Methylation Levels

Plasma Homocysteine and Polymorphisms of Genes Involved in Folate Metabolism Correlate with DNMT1 Gene Methylation Levels

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

Epigenetic Factors in Late-Onset Alzheimer&rsquo;s Disease: <em>MTHFR</em> and<em> CTH </em>Gene Polymorphisms, Metabolic Trans-sulfuration and Methylation Pathways, and B Vitamins

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Product

Resources

About

Epigenetic Factors in Late-Onset Alzheimer’s Disease: <em>MTHFR</em> and<em> CTH </em>Gene Polymorphisms, Metabolic Trans-sulfuration and Methylation Pathways, and B Vitamins