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Mandaviya, Pooja R.; Jöhanes, Roby; Aissi, Dylan; Kühnel, Brigitte; Marioni, Riccardo E.; Truong, Vinh; Stolk, Lisette; Beekman, Marian; Bonder, Marc Jan; Franke, Lude; Gieger, Christian; Huan, Tianxiao; Ikram, M. Arfan; Kunze, Sonja; Liang, Liming; Lindemann, Jan; Liu, Chunyu; McRae, Allan F.; Mendelson, Michael M.; Müller-Nurasyid, Martina; Peters, Annette; Slagboom, P. Eline; Starr, John M.; Trégouët, David-Alexandre ORCID logoORCID: https://orcid.org/0000-0001-9084-7800; Uitterlinden, Andre G.; Greevenbroek, Marleen M. J. van ORCID logoORCID: https://orcid.org/0000-0002-2989-1631; Heemst, Diana van; Iterson, Maarten van; Wells, Philip S.; Yao, Chen; Deary, Ian J.; Gagnon, France; Heijmans, Bastiaan T.; Levy, Daniel; Morange, Pierre-Emmanuel; Waldenberger, Melanie; Heil, Sandra G. and Meurs, Joyce B. J. van (2017): Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes.
In: PLOS One 12(10), e0182472 [PDF, 1MB]

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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.

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