DNA methylation is an epigenetic phenomenon that affects the regulation of gene expression and genome integrity. Folate, providing methyl groups for DNA methylation, plays a key role in the maintenance of genomic stability. Accordingly, folate-mediated one-carbon metabolism is linked to DNA methylation status but it is also influenced by genetic polymorphisms. Methylenetetrahydrofolate reductase (MTHFR), which is involved in the supply of the methylation group, is an enzyme necessary for the folate metabolic pathway and is considered to result in hypermethylation of genomic DNA. Particularly, the MTHFR C677T polymorphism results in an alanine (C)-to-valine (T) substitution and makes the enzyme less active. This literature review focuses on the recent evidence-based reports on the relationship between MTHFR C677T polymorphism, folate metabolism and global DNA methylation in various physiological or pathological conditions. Medline database was searched to select articles, published before January 2015, investigating the link between MTHFR C677T polymorphism and global DNA methylation. Information about Author's last name, year of publication, country where the study was performed, experimental methods and outcome were collected in a standard format. The number of searched articles was limited (24) and selected studies were highly heterogeneous regarding to study design, sample source, experimental methods and outcome. Overall, no significant relationship between MTHFR C677T polymorphism and DNA methylation was reported, although only one study showed a significant difference in methyl group acceptance capacity between carriers of the MTHFR677T/T genotype and carriers of the wild-type MTHFR677C/C genotype. The enhanced methyl group acceptance capacity in MTHFR677T/T carriers indicated genomic hypomethylation status compared to carriers of MTHFR677C/C genotype. In addition, a further study revealed that reduction in DNA methylation levels was significantly associated with the T allele only in those subjects with low plasma folate concentrations. Evidence from this review, conducted on a small number of subjects, did not support the hypothesis that decreased global DNA methylation status is directly associated with MTHFR C677T polymorphism. However, if associated with low plasma folate, the MTHFR 677TT homozygous mutant genotype appears to be crucial in determining the lowest DNA methylation levels. Thus, only the interaction between MTHFR polymorphisms and folate deficiency may play a potential role in the complex mechanism of global DNA hypomethylation.
|Title of host publication||Methylenetetrahydrofolate Reductase (MTHFR) in Health and Disease|
|Publisher||Nova Science Publishers, Inc.|
|Number of pages||11|
|Publication status||Published - 1 Jul 2015|