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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 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.

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