Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels

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.

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

“…The genotype distribution of the investigated polymorphisms is shown in Table 2. Genotype frequencies are in agreement with those previously observed in healthy Caucasians [19,22], and conformed to Hardy-Weinberg equilibrium (HWE) expectations (p > 0.05). Figure 3 shows the correlation between DNMT1 promoter methylation and circulating folate, Hcy, and vitamin B12 levels.…”

“…We collected blood samples from 215 healthy individuals, investigated DNMT1 methylation levels in the extracted DNA, and searched for correlation between DNMT1 promoter methylation levels and circulating folate, Hcy, or vitamin B12 levels. In addition, the major polymorphisms on folate-pathway genes, such as methylenetetrahydrofolate reductase (MTHFR) 677C > T (rs1801133) and 1298A > C (rs1801131), methionine synthase (MTR) 2756A > G (rs1805087), methionine synthase reductase (MTRR) 66A > G (rs1801394), thymidilate synthase (TYMS) 28-bp tandem repeat (rs34743033) and 1494 insertion/deletion (indel) (rs34489327), and reduced folate carrier (SLC19A1 or RFC1) 80A > G (rs1051266), as well as both DNMT3A -448A > G (rs1550117) and DNMT3B -149C > T (rs2424913) polymorphisms, are often linked to changes in DNA methylation levels [15][16][17][18][19]. Therefore, we also investigated the contribution of these major polymorphisms of genes involved in the folate pathway to DNMT1 promoter methylation levels.…”

Association of MTHFR C677T polymorphism with severity and localization of chronic atrophic gastritis patients without Helicobacter pylori infection : a case control study

“…Epigenetic changes such as DNA methylation have a role in cancer development and progression [5] 5,10-Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme in folate metabolism and is involved in DNA, RNA, and protein methylation [6]. The polymorphism C677T in the MTHFR gene has been shown to be associated with various tumors, as this change in sequence reduces the activity of this enzyme [6,7]. Indeed, individuals with the TT and CT genotypes have mildly higher homocysteine levels than CC homozygotes [8].…”

“…As MTHFR is the key gene and metabolite in the one-carbon metabolism pathway that allows for the metabolism of homocysteine and the provision of methyl groups [20,21], the MTHFR C677T polymorphism may be considered as a reliable factor for predicting the prognosis of gastric precancerous lesions [22,23]. The reduced activity of the MTHFR enzyme resulting from TT mutation has been associated with alterations in methylation patterns and potentially aberrant DNA synthesis, repair, and chromosomal damage [6]. This study evaluated the degree of atrophy and IM in different biopsies to examine whether the TT genotype confers an increased risk for developing moderate-to-severe lesions (moderate-to-severe atrophy or IM in any one biopsy) in patients without Helicobacter pylori infection.…”

Association of MTHFR C677T polymorphism with severity and localization of chronic atrophic gastritis patients without Helicobacter pylori infection: a case control study

“…Epigenetic changes like DNA methylation play an important part in cancer development [5]. 5,10-Methylenetetrahydrofolate reductase (MTHFR) has a role in folate metabolism and is associated with DNA, RNA, and protein methylation [6]. MTHFR C677T polymorphism is associated with various tumors, as this change in sequence reduces the activity of this enzyme [6,7].…”