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Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes

Author

Listed:
  • Pooja R Mandaviya
  • Roby Joehanes
  • Dylan Aïssi
  • Brigitte Kühnel
  • Riccardo E Marioni
  • Vinh Truong
  • Lisette Stolk
  • Marian Beekman
  • Marc Jan Bonder
  • Lude Franke
  • Christian Gieger
  • Tianxiao Huan
  • M Arfan Ikram
  • Sonja Kunze
  • Liming Liang
  • Jan Lindemans
  • Chunyu Liu
  • Allan F McRae
  • Michael M Mendelson
  • Martina Müller-Nurasyid
  • Annette Peters
  • P Eline Slagboom
  • John M Starr
  • David-Alexandre Trégouët
  • André G Uitterlinden
  • Marleen M J van Greevenbroek
  • Diana van Heemst
  • Maarten van Iterson
  • Philip S Wells
  • Chen Yao
  • Ian J Deary
  • France Gagnon
  • Bastiaan T Heijmans
  • Daniel Levy
  • Pierre-Emmanuel Morange
  • Melanie Waldenberger
  • Sandra G Heil
  • Joyce B J van Meurs
  • on behalf of The CHARGE Consortium Epigenetics group and BIOS Consortium

Abstract

Background: DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation. Methods: Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation. Results: Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5. Conclusions: Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.

Suggested Citation

  • Pooja R Mandaviya & Roby Joehanes & Dylan Aïssi & Brigitte Kühnel & Riccardo E Marioni & Vinh Truong & Lisette Stolk & Marian Beekman & Marc Jan Bonder & Lude Franke & Christian Gieger & Tianxiao Huan, 2017. "Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes," PLOS ONE, Public Library of Science, vol. 12(10), pages 1-19, October.
    • Handle: RePEc:plo:pone00:0182472
    DOI: 10.1371/journal.pone.0182472
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