TY - JOUR
T1 - Interaction between plasma homocysteine and the MTHFR c.677C > T polymorphism is associated with site-specific changes in DNA methylation in humans
AU - Nash, Alexander J
AU - Mandaviya, Pooja R
AU - Dib, Marie-Joe
AU - Uitterlinden, André G
AU - van Meurs, Joyce
AU - Heil, Sandra G
AU - Andrew, Toby
AU - Ahmadi, Kourosh R
N1 - Funding Information:
For the TwinsUK study, the authors thank all the participants well as the staff. The TwinsUK National Institute for Health Research Biomedical Research Centre BioResource is funded by the Wellcome Trust, the European Community’s Seventh Framework Programme (Grant FP7/2007–2013), and the National Institute for Health Research (NIHR) BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ National Health Service (NHS) Foundation Trust and King’s College London. For the Rotterdam study, the authors thank Michael Verbiest, Mila Jhamai, Sarah Higgins, and Marijn Verkerk [Erasmus University Medical Center (Erasmus MC)] for their help in creating the methylation database. The authors are grateful to the study participants, the staff from the Rotterdam study, and the participating general practitioners and pharmacists. The generation and management of the Illumina 450,000 methylation array data [epigenome-wide association study (EWAS) data] for the Rotterdam study were executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC. The EWAS data were funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by The Netherlands Organization for Scientific Research (NWO; Project 184021007), and made available as a Rainbow Project [RP3; Biobank-Based Integrative Omics Study (BIOS)] of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). The Rotterdam study is funded by Erasmus MC and Erasmus University Organization for Health Research and Development (ZonMw), the Research Institute of Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB.
PY - 2019/1
Y1 - 2019/1
N2 - One-carbon metabolism provides a direct link among dietary folate/vitamin B-12 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 values. Our meta-analysis identified 13 probes significantly associated with rs1801133 x 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.
AB - One-carbon metabolism provides a direct link among dietary folate/vitamin B-12 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 values. Our meta-analysis identified 13 probes significantly associated with rs1801133 x 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.
KW - 1-carbon metabolism
KW - DEMENTIA
KW - DETERMINANTS
KW - EXPRESSION
KW - FOLATE INTAKE
KW - HYPERHOMOCYSTEINEMIA
KW - HYPOMETHYLATION
KW - METABOLISM
KW - METHYLENETETRAHYDROFOLATE-REDUCTASE
KW - NEPHROPATHY
KW - RISK-FACTOR
KW - epigenetics
KW - methylenetetrahydrofolate reductase
KW - methylome-wide association study
KW - vascular disease
U2 - 10.1096/fj.201800400r
DO - 10.1096/fj.201800400r
M3 - Article
C2 - 30080444
SN - 0892-6638
VL - 33
SP - 833
EP - 843
JO - Faseb Journal
JF - Faseb Journal
IS - 1
ER -