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Mandaviya, P.R.* ; Joehanes, R.* ; Aïssi, D.* ; Kühnel, B. ; Marioni, R.E.* ; Truong, V.* ; Stolk, L.* ; Beekman, M.* ; Bonder, M.J.* ; Franke, L.* ; Gieger, C. ; Huan, T.* ; Ikram, M.A.* ; Kunze, S. ; Liang, L.* ; Lindemans, J.* ; Liu, C.* ; McRae, A.F.* ; Mendelson, M.M.* ; Müller-Nurasyid, M. ; Peters, A. ; Slagboom, P.E.* ; Starr, J.M.* ; Trégouët, D.A.* ; Uitterlinden, A.G.* ; Van Greevenbroek, M.M.J.* ; van Heemst, D.* ; van Iterson, M.* ; Wells, P.S.* ; Yao, C.* ; Deary, I.J.* ; Gagnon, F.* ; Heijmans, B.T.* ; Levy, D.* ; Morange, P.E.* ; Waldenberger, M. ; Heil, S.G.* ; van Meurs, J.B.J.*

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

PLoS ONE 12:e0182472 (2017)
Publ. Version/Full Text Research data DOI
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Genome-wide Association; Mendelian Randomization; Folate Status; Instrumental Variables; Gene-expression; Cancer; Metaanalysis; Variants; Region; Risk
ISSN (print) / ISBN 1932-6203
Journal PLoS ONE
Quellenangaben Volume: 12, Issue: 10, Pages: , Article Number: e0182472 Supplement: ,
Publisher Public Library of Science (PLoS)
Publishing Place Lawrence, Kan.
Reviewing status Peer reviewed