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

Nash, Alexander J, Mandaviya, Pooja R, Dib, Marie-Joe, Uitterlinden, André G., van Meurs, Joyce, Heil, Sandra G, Andrew, Toby and Ahmadi, Kourosh R (2018) Interaction between plasma homocysteine and the MTHFR c.677C>T polymorphism is associated with site-specific changes in DNA methylation in humans The FASEB Journal.

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Abstract

One-carbon metabolism provides a direct link between dietary folate/vitamin B12 exposure, the activity of the enzyme methylenetetrahydrofolate reductase (MTHFR) and epigenetic regulation of the genome via DNA methylation. Previously, Friso et al. (2002) showed that the common c.677C>T polymorphism in MTHFR influences global DNA methylation status through a direct interaction with folate status and (indirectly) with homocysteine (tHcy) levels. To build on this and other more recent observations that have further highlighted associations between MTHFR c.677C>T, tHcy and aberrations in DNA methylation, we investigated whether 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 Caucasian females and 335 males from the TwinsUK (n=610) and Rotterdam study (n=670). We carried out methylome-wide association analyses in each cohort to model the interaction between levels of tHcy and c.677C>T genotypes on DNA methylation beta values. Our meta-analysis identified a total of 13 probes significantly associated with [rs1801133 x tHcy] levels (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 TNFRSF8 gene/locus on this chromosome. This is the first study to provide a direct link between perturbations in one-carbon metabolism, through an interaction of tHcy and the activity of MTHFR enzyme on epigenetic regulation of the genome via DNA methylation.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Nash, Alexander J
Mandaviya, Pooja R
Dib, Marie-Joem.dib@surrey.ac.uk
Uitterlinden, André G.
van Meurs, Joyce
Heil, Sandra G
Andrew, Toby
Ahmadi, Kourosh Rk.ahmadi@surrey.ac.uk
Date : 6 August 2018
DOI : 10.1096/fj.201800400R
Copyright Disclaimer : Copyright 2018 FASEB
Related URLs :
Depositing User : Clive Harris
Date Deposited : 12 Jul 2018 09:45
Last Modified : 07 Nov 2018 16:04
URI: http://epubs.surrey.ac.uk/id/eprint/848698

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