TY - JOUR
T1 - Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes
AU - CHARGE Consortium Epigenetics group and BIOS Consortium
AU - Mandaviya, Pooja R
AU - Joehanes, Roby
AU - Aïssi, Dylan
AU - Kühnel, Brigitte
AU - Marioni, Riccardo E
AU - Truong, Vinh
AU - Stolk, Lisette
AU - Beekman, Marian
AU - Bonder, Marc Jan
AU - Franke, Lude
AU - Gieger, Christian
AU - Huan, Tianxiao
AU - Ikram, M Arfan
AU - Kunze, Sonja
AU - Liang, Liming
AU - Lindemans, Jan
AU - Liu, Chunyu
AU - McRae, Allan F
AU - Mendelson, Michael M
AU - Müller-Nurasyid, Martina
AU - Peters, Annette
AU - Slagboom, P Eline
AU - Starr, John M
AU - Trégouët, David-Alexandre
AU - Uitterlinden, André G
AU - van Greevenbroek, Marleen M J
AU - van Heemst, Diana
AU - van Iterson, Maarten
AU - Wells, Philip S
AU - Yao, Chen
AU - Deary, Ian J
AU - Gagnon, France
AU - Heijmans, Bastiaan T
AU - Levy, Daniel
AU - Morange, Pierre-Emmanuel
AU - Waldenberger, Melanie
AU - Heil, Sandra G
AU - van Meurs, Joyce B J
PY - 2017/10/30
Y1 - 2017/10/30
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pone.0182472
DO - 10.1371/journal.pone.0182472
M3 - Article
C2 - 29084233
SN - 1932-6203
VL - 12
SP - 1
EP - 19
JO - PLoS ONE
JF - PLoS ONE
IS - 10
M1 - e0182472
ER -