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

Alexander J Nash, Pooja R Mandaviya, Marie-Joe Dib, André G Uitterlinden, Joyce van Meurs, Sandra G Heil, Toby Andrew, Kourosh R Ahmadi

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

One-carbon metabolism provides a direct link among dietary folate/vitamin B12 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.

Original languageEnglish
Pages (from-to)833-843
Number of pages11
JournalFaseb Journal
Volume33
Issue number1
DOIs
Publication statusPublished - Jan 2019

Keywords

  • 1-carbon metabolism
  • DEMENTIA
  • DETERMINANTS
  • EXPRESSION
  • FOLATE INTAKE
  • HYPERHOMOCYSTEINEMIA
  • HYPOMETHYLATION
  • METABOLISM
  • METHYLENETETRAHYDROFOLATE-REDUCTASE
  • NEPHROPATHY
  • RISK-FACTOR
  • epigenetics
  • methylenetetrahydrofolate reductase
  • methylome-wide association study
  • vascular disease

Cite this

Nash, Alexander J ; Mandaviya, Pooja R ; Dib, Marie-Joe ; Uitterlinden, André G ; van Meurs, Joyce ; Heil, Sandra G ; Andrew, Toby ; Ahmadi, Kourosh R. / Interaction between plasma homocysteine and the MTHFR c.677C > T polymorphism is associated with site-specific changes in DNA methylation in humans. In: Faseb Journal. 2019 ; Vol. 33, No. 1. pp. 833-843.
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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; Ahmadi, Kourosh R.

In: Faseb Journal, Vol. 33, No. 1, 01.2019, p. 833-843.

Research output: Contribution to journalArticleAcademicpeer-review

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

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AB - One-carbon metabolism provides a direct link among dietary folate/vitamin B12 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.

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

VL - 33

SP - 833

EP - 843

JO - Faseb Journal

JF - Faseb Journal

SN - 0892-6638

IS - 1

ER -