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

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 and on behalf of The CHARGE Consortium Epigenetics group and BIOS Consortium

PLOS ONE, 2017, vol. 12, issue 10, 1-19

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.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0182472

DOI: 10.1371/journal.pone.0182472

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