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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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)
Mandaviya, P.R, Joehanes, R, Aïssi, D. (Dylan), Kuhnel, B, Marioni, R.E, Truong, V, … van Meurs, J.B.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