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. <i>MTHFR</i> hypermethylation, resulting in reduced gene expression, can contribute to several human disorders, but little is still known about the factors that regulate <i>MTHFR</i> methylation levels. We performed the present study to investigate if common polymorphisms in one-carbon metabolism genes contribute to <i>MTHFR</i> methylation levels. <i>MTHFR</i> methylation was assessed in peripheral blood DNA samples from 206 healthy subjects with methylation-sensitive high-resolution melting (MS-HRM); genotyping was performed for <i>MTHFR</i> 677C>T (rs1801133) and 1298A>C (rs1801131), <i>MTRR</i> 66A>G (rs1801394), <i>MTR</i> 2756A>G (rs1805087), <i>SLC19A1</i> (<i>RFC1</i>) 80G>A (rs1051266), <i>TYMS</i> 28-bp tandem repeats (rs34743033) and 1494 6-bp ins/del (rs34489327), <i>DNMT3A</i> -448A>G (rs1550117), and <i>DNMT3B</i> -149C>T (rs2424913) polymorphisms. We observed a statistically significant effect of the <i>DNMT3B</i> -149C>T polymorphism on mean <i>MTHFR</i> 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 <i>DNMT3B</i> and <i>MTHFR</i> 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.