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

Pooja R. Mandaviya, Roby Joehanes, Dylan Aissi, Brigitte Kuehnel, 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 Lindemann, Chunyu Liu, Allan F. McRae, Michael M. Mendelson, Martina Muller-NurasyidAnnette Peters, P. Eline Slagboom, John M. Starr, David -Alexandre Tregouet, Andre 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*, Charge Consortium Epigenetics Grp

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 homocysteineassociated 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.

Original languageEnglish
Article numbere0182472
Number of pages19
JournalPLoS ONE
Volume12
Issue number10
DOIs
Publication statusPublished - 30-Oct-2017

Keywords

  • GENOME-WIDE ASSOCIATION
  • MENDELIAN RANDOMIZATION
  • FOLATE STATUS
  • INSTRUMENTAL VARIABLES
  • GENE-EXPRESSION
  • CANCER
  • METAANALYSIS
  • VARIANTS
  • REGION
  • RISK

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