Interaction between plasma homocysteine and the MTHFR C.677C > T polymorphism is associated with site‐specific changes in DNA methylation in humans

Abstract

One-carbon metabolism provides a direct link among dietary folate/vitamin B exposure, the activity of the enzyme methylenetetrahydrofolate reductase (MTHFR), and epigenetic regulation of the genome via DNA methylation. Previously, it has been shown that the common c.677C > T polymorphism in MTHFR influences global DNA methylation status through a direct interaction with folate status and (indirectly) with total homocysteine (tHcy) levels. To build on that and other more-recent observations that have further highlighted associations among MTHFR c.677C > T, tHcy, and aberrations in DNA methylation, we investigated whether the interaction between mildly elevated plasma tHcy and the c.677C > T polymorphism is associated with site-specific changes in DNA methylation in humans. We used data on plasma tHcy levels, c.677C > T polymorphism, and site-specific DNA methylation levels for a total of 915 white women and 335 men from the TwinsUK registry ( n = 610) and the Rotterdam study ( n = 670). We performed methylome-wide association analyses in each cohort to model the interaction between levels of tHcy and c.677C > T genotypes on DNA methylation β values. Our meta-analysis identified 13 probes significantly associated with rs1801133 × tHcy levels [false-discovery rate (FDR) < 0.05]. The most significant associations were with a cluster of probes at the AGTRAP-MTHFR-NPPA/B gene locus on chromosome 1 (FDR = 1.3E-04), with additional probes on chromosomes 2, 3, 4, 7, 12, 16, and 19. Our top 2 hits on chromosome 1 were functionally associated with variability in expression of the TNF receptor superfamily member 8 ( TNFRSF8) gene/locus on that chromosome. This is the first study, to our knowledge, to provide a direct link between perturbations in 1-carbon metabolism, through an interaction of tHcy and the activity of MTHFR enzyme on epigenetic regulation of the genome via DNA methylation.-Nash, A. J., Mandaviya, P. R., Dib, M.-J., Uitterlinden, A. G., van Meurs, J., Heil, S. G., Andrew, T., Ahmadi, K. R. Interaction between plasma homocysteine and the MTHFR c.677C>T polymorphism is associated with site-specific changes in DNA methylation in humans.

Life-threatening course in coronavirus disease 2019 (COVID-19): Is there a link to methylenetetrahydrofolic acid reductase (MTHFR) polymorphism and hyperhomocysteinemia?

“…In an interesting case report, the therapeutic supplementation of glutathione lead to rapid symptom improvement of two cases of Covid-19 all of which points to the well-known role of glutathione as an important part of the anti-oxidative defense system in viral illness [18] . Interestingly, methylome-wide association analyses identified 13 probes significantly associated with the interaction of mild H-Hcy and C677T polymorphism [19] . The most significant associations were observed with a cluster of probes at the angiotensin II receptor associate protein-methylenetetrahydrofolate reductase-natriuretic peptide A/B (AGTRAP-MTHFR-NPPA/B) gene cluster on chromosome 1 [19] .…”

Association between the methylenetetrahydrofolate reductase (MTHFR) gene 677C>T and 1298A>C polymorphisms and the risk of diabetic nephropathy; a meta-analysis

“…Further, a direct link between perturbations in 1-carbon metabolism, through an interaction of total homocysteine and the activity of MTHFR enzyme on epigenetic regulation of the genome via DNA methylation (52).…”

Nutritional Epigenomics and Age-Related Disease

“…Perturbations in 1-carbon metabolism may occur through low intake of nutrients involved in 1-carbon metabolism ( 7 ), malabsorption of nutrients via disease or cellular conditions, interactions in regulatory enzymes in 1-carbon metabolism pathways as well as common polymorphisms within genes that code for enzymes important for the normal functioning of 1-carbon metabolism ( 2 , 39 ). Apart from significant disruption to 1-carbon metabolism, these perturbations may have functional implications on downstream biological processes including DNA methylation and synthesis.…”

“…Folate and related B-vitamins, essential cofactors in 1-carbon metabolism, the main metabolic pathway for generating methyl groups for DNA methylation ( 6 ), are emerging as factors that can modify epigenetic age. Perturbations to DNA methylation owing to imbalances in the supply of B-vitamins, or to polymorphisms or interactions between the various regulating enzymes, could lead to aberrant DNA methylation and subsequently influence epigenetic age and disease susceptibility ( 7 ).…”