Dataset Information

Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes.

ABSTRACT: Background: DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation.

Methods: Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation.

Results: Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5.

Conclusions: Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.

SUBMITTER: Mandaviya PR

PROVIDER: S-EPMC5662081 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes.

Mandaviya Pooja R PR Joehanes Roby R Aïssi Dylan D Kühnel Brigitte B Marioni Riccardo E RE Truong Vinh V Stolk Lisette L Beekman Marian M Bonder Marc Jan MJ Franke Lude L Gieger Christian C Huan Tianxiao T Ikram M Arfan MA Kunze Sonja S Liang Liming L Lindemans Jan J Liu Chunyu C McRae Allan F AF Mendelson Michael M MM Müller-Nurasyid Martina M Peters Annette A Slagboom P Eline PE Starr John M JM Trégouët David-Alexandre DA Uitterlinden André G AG van Greevenbroek Marleen M J MMJ van Heemst Diana D van Iterson Maarten M Wells Philip S PS Yao Chen C Deary Ian J IJ Gagnon France F Heijmans Bastiaan T BT Levy Daniel D Morange Pierre-Emmanuel PE Waldenberger Melanie M Heil Sandra G SG van Meurs Joyce B J JBJ

PloS one 20171030 10

<h4>Background</h4>DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation.<h4>Methods</h4>Methylation levels were assessed using Illumina 450k arrays on 9,894 ...[more]

PMID: 29084233

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Project description:ObjectiveSeizures are a common clinical presentation in patients with glioma and substantially impact patients' quality of life. Hyperhomocysteinemia is defined as abnormally high serum levels of homocysteine (Hcy) and is reportedly linked to susceptibility to various nervous system diseases. However, it remains unclear whether and how hyperhomocysteinemia and its associated genetic polymorphisms promote seizures in glioma patients.MethodsWe retrospectively reviewed all medical data from 127 patients with malignant gliomas, who underwent initial tumor resection by our team between July 2019 and June 2021 and had preoperative measurements of serum Hcy levels. According to whether they had at least one seizure before surgery, they were divided into the seizure and nonseizure groups. We also detected polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and measured intratumoral Hcy levels in these patients.ResultsHyperhomocysteinemia was a susceptibility factor for preoperative seizures in glioma patients according to both univariate analyses (P < 0.001) and multivariate logistic regression analyses (OR 1.239, 95% CI 1.062-1.445, P = 0.007). Patients with the MTHFR C677T variant exhibited elevated serum Hcy levels (P = 0.027) and an increased prevalence of preoperative seizures (P = 0.019). Intratumoral Hcy levels were positively correlated with serum Hcy levels (R = 0.231, P = 0.046) and were elevated in patients with hyperhomocysteinemia (P = 0.031), the MTHFR C677T variant (P = 0.002) and preoperative seizures (P = 0.003). High intratumoral Hcy levels, rather than hyperhomocysteinemia or the MTHFR C677T variant, emerged as an independent risk factor for preoperative seizures (OR 1.303, 95% CI 1.015-1.673, P = 0.038). Furthermore, the effects of hyperhomocysteinemia on epileptic susceptibility were reduced to nonsignificance when intratumoral Hcy was controlled to the same level between groups.SignificanceGlioma patients with hyperhomocysteinemia and the MTHFR C677T variant were susceptible to preoperative seizures, suggesting their potential as biomarkers for the management of seizures in glioma patients. The elevation of intratumoral Hcy is a possible mechanism underlying this susceptibility.

Dataset Information

Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes.

Publications

Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes.

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