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P.R. Mandaviya (Pooja), R. Joehanes (Roby), Aïssi, D. (Dylan), B. Kuhnel (Brigitte), R.E. Marioni (Riccardo), V. Truong (Vinh), L. Stolk (Lisette), M. Beekman (Marian), M.J. Bonder (Marc), L. Franke (Lude), et al. C. Gieger (Christian), Huan, T. (Tianxiao), M.K. Ikram (Kamran), Kunze, S. (Sonja), Liang, L. (Liming), J. Lindemans (Jan), Liu, C. (Chunyu), McRae, A.F. (Allan F.), Mendelson, M.M. (Michael M.), Müller-Nurasyid, M. (Martina), A. Peters (Annette), P.E. Slagboom (Eline), J.M. Starr (John), D.-A. Tregouet (David-Alexandre), A.G. Uitterlinden (André), M.M. van Greevenbroek, D. van Heemst (Diana), M. van Iterson (Maarten), Wells, P.S. (Philip S.), Yao, C. (Chen), I.J. Deary (Ian), F. Gagnon (France), Heijmans, B.T. (Bastiaan T.), Levy, D. (Daniel), P.-E. Morange (P.), Waldenberger, M. (Melanie), S.G. Heil (Sandra) and J.B.J. van Meurs (Joyce)

2017-10-01

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

Publication

Publication

PLoS ONE , Volume 12 - Issue 10

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.

Additional Metadata
Persistent URL doi.org/10.1371/journal.pone.0182472, hdl.handle.net/1765/102755
Journal PLoS ONE
Grant This work was funded by the European Commission 7th Framework Programme; grant id fp7/603288 - Systems Biology to Identify Molecular Targets for Vascular Disease Treatment (SYSVASC)
Organisation Erasmus MC: University Medical Center Rotterdam
Citation
Mandaviya, P., Joehanes, R., Aïssi, D. (Dylan), Kuhnel, B., Marioni, R., Truong, V., … van Meurs, J. (2017). Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes. PLoS ONE, 12(10). doi:10.1371/journal.pone.0182472
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