Scientific Publications Database

Article Title: Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes
Authors: Mandaviya, Pooja R.; Joehanes, Roby; Aissi, Dylan; Kuehnel, 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.; Muller-Nurasyid, Martina; Peters, Annette; Slagboom, P. Eline; Starr, John M.; Tregouet, David -Alexandre; Uitterlinden, Andre G.; van Greevenbroek, Marleen M. J.; van Heemst, Diana; van Iterson, Maarten; Wells, Philip S.; Yao, Chen; Deary, Ian J.; Gagnon, France; Heijmans, Bastiaan T.; Levy, Daniel; Morange, Pierre-Emmanuel; Waldenberger, Melanie; Heil, Sandra G.; van Meurs, Joyce B. J.
Journal: PLOS ONE Volume 12 Issue 10
Date of Publication:2017
Abstract:
BackgroundDNA 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.MethodsMethylation 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.ResultsMeta-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.ConclusionsOur 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.