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

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From: PLoS ONE(Vol. 12, Issue 10)
Publisher: Public Library of Science
Document Type: Report
Length: 8,796 words
Lexile Measure: 1460L

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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.

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Gale Document Number: GALE|A512307166