Abstract
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.
Highlights
The folate and methionine cycles are the “core” part of the one-carbon metabolism, a set of interconnected pathways that supply methyl groups for the synthesis of nucleic acids, amino acids, and S-adenosylmethionine (SAM), the main intracellular methylating agent [1]
Little is still known concerning the contribution of common polymorphisms in one-carbon metabolism genes to Methylenetetrahydrofolate reductase (MTHFR) methylation levels. To further address this issue, in the present study we investigated a cohort of 206 healthy individuals searching for correlation between common polymorphisms in the main genes of one-carbon metabolism and the methylation levels of the MTHFR gene
We investigated a CpG island located in the 5 untranslated region (5 UTR) of the MTHFR gene, whose methylation levels are inversely correlated with gene expression levels [24,34]
Summary
The folate and methionine cycles are the “core” part of the one-carbon metabolism, a set of interconnected pathways that supply methyl groups for the synthesis of nucleic acids, amino acids, and S-adenosylmethionine (SAM), the main intracellular methylating agent [1]. Methylenetetrahydrofolate reductase (MTHFR) is a pivotal enzyme in one-carbon metabolism and catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-methylTHF), the main form of circulating folate and the methyl donor for homocysteine (hcy) remethylation to methionine in the reaction catalyzed by methionine synthase (MTR) that transfers the methyl group from 5-methylTHF to hcy, forming tetrahydrofolate (THF) and methionine. Een circulating folate levels and the methylation statuIsnocrfesaesvinegralevgiedneensce[26s–u2g8g],esatnsdacnomasmsoocniaptioolnymboertpwheiesnmsciorfcugleantiensg infvoloaltveedleivnelosnea-ncdarbtohne mmeettahbyolalitsimon, instcalutudsinogfMseTvHeFraRl6g7e7nCe>sT[a2n6d–2182]9, 8aAn>dCc, oMmTmRo2n756pAol>yGm(orrsp18h0is5m08s7)o, fmgeethnieosniinnevsoylvnethdasine one-carbon metabolism, including MTHFR 677C>T and 1298A>C, MTR 2756A>G (rs1805087), methionine synthase reductase (MTRR) 66A>G (rs1801394), thymidilate synthase (TYMS) 28-bp. Little is still known concerning the contribution of common polymorphisms in one-carbon metabolism genes to MTHFR methylation levels.
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