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

Pooja R. Mandaviya; Roby Joehanes; Dylan Aissi; Brigitte Kuehnel; Riccardo E. Marioni; Vinh Truong; Lisette Stolk; Marian Beekman; Marc Jan Bonder; Lude Franke; Christian Gieger; Tianxiao Huan; M. Arfan Ikram; Sonja Kunze; Liming Liang; Jan Lindemann; Chunyu Liu; Allan F. McRae; Michael M. Mendelson; Martina Muller-Nurasyid; Annette Peters; P. Eline Slagboom; John M. Starr; David -Alexandre Tregouet; Andre G. Uitterlinden; Marleen M. J. van Greevenbroek; Diana van Heemst; Maarten van Iterson; Philip S. Wells; Chen Yao; Ian J. Deary; France Gagnon; Bastiaan T. Heijmans; Daniel Levy; Pierre-Emmanuel Morange; Melanie Waldenberger; Sandra G. Heil; Joyce B. J. van Meurs; Charge Consortium Epigenetics Grp

doi:10.1371/journal.pone.0182472

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

Pooja R. Mandaviya, Roby Joehanes, Dylan Aissi, Brigitte Kuehnel, Riccardo E. Marioni, Vinh Truong, Lisette Stolk, Marian Beekman, Marc Jan Bonder, Lude Franke, Christian Gieger, Tianxiao Huan, M. Arfan Ikram, Sonja Kunze, Liming Liang, Jan Lindemann, Chunyu Liu, Allan F. McRae, Michael M. Mendelson, Martina Muller-NurasyidAnnette Peters, P. Eline Slagboom, John M. Starr, David -Alexandre Tregouet, Andre G. Uitterlinden, Marleen M. J. van Greevenbroek, Diana van Heemst, Maarten van Iterson, Philip S. Wells, Chen Yao, Ian J. Deary, France Gagnon, Bastiaan T. Heijmans, Daniel Levy, Pierre-Emmanuel Morange, Melanie Waldenberger, Sandra G. Heil, Joyce B. J. van Meurs^*, Charge Consortium Epigenetics Grp

^*Corresponding author for this work

Interne Geneeskunde

Research output: Contribution to journal › Article › Academic › peer-review

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 homocysteineassociated 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.

Original language	English
Article number	0182472
Number of pages	19
Journal	PLOS ONE
Volume	12
Issue number	10
DOIs	https://doi.org/10.1371/journal.pone.0182472
Publication status	Published - 30 Oct 2017

Keywords

GENOME-WIDE ASSOCIATION
MENDELIAN RANDOMIZATION
FOLATE STATUS
INSTRUMENTAL VARIABLES
GENE-EXPRESSION
CANCER
METAANALYSIS
VARIANTS
REGION
RISK

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Cite this

Mandaviya, P. R., Joehanes, R., Aissi, D., Kuehnel, B., Marioni, R. E., Truong, V., Stolk, L., Beekman, M., Bonder, M. J., Franke, L., Gieger, C., Huan, T., Ikram, M. A., Kunze, S., Liang, L., Lindemann, J., Liu, C., McRae, A. F., Mendelson, M. M., ... Charge Consortium Epigenetics Grp (2017). Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes. PLOS ONE, 12(10), Article 0182472. https://doi.org/10.1371/journal.pone.0182472

@article{7b93060fb38e49eb92ae0dc92543248b,

title = "Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes",

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.",

keywords = "GENOME-WIDE ASSOCIATION, MENDELIAN RANDOMIZATION, FOLATE STATUS, INSTRUMENTAL VARIABLES, GENE-EXPRESSION, CANCER, METAANALYSIS, VARIANTS, REGION, RISK",

author = "Mandaviya, {Pooja R.} and Roby Joehanes and Dylan Aissi and Brigitte Kuehnel and Marioni, {Riccardo E.} and Vinh Truong and Lisette Stolk and Marian Beekman and Bonder, {Marc Jan} and Lude Franke and Christian Gieger and Tianxiao Huan and Ikram, {M. Arfan} and Sonja Kunze and Liming Liang and Jan Lindemann and Chunyu Liu and McRae, {Allan F.} and Mendelson, {Michael M.} and Martina Muller-Nurasyid and Annette Peters and Slagboom, {P. Eline} and Starr, {John M.} and Tregouet, {David -Alexandre} and Uitterlinden, {Andre G.} and {van Greevenbroek}, {Marleen M. J.} and {van Heemst}, Diana and {van Iterson}, Maarten and Wells, {Philip S.} and Chen Yao and Deary, {Ian J.} and France Gagnon and Heijmans, {Bastiaan T.} and Daniel Levy and Pierre-Emmanuel Morange and Melanie Waldenberger and Heil, {Sandra G.} and {van Meurs}, {Joyce B. J.} and {Charge Consortium Epigenetics Grp}",

year = "2017",

month = oct,

day = "30",

doi = "10.1371/journal.pone.0182472",

language = "English",

volume = "12",

journal = "PLOS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "10",

}

Mandaviya, PR, Joehanes, R, Aissi, D, Kuehnel, B, Marioni, RE, Truong, V, Stolk, L, Beekman, M, Bonder, MJ, Franke, L, Gieger, C, Huan, T, Ikram, MA, Kunze, S, Liang, L, Lindemann, J, Liu, C, McRae, AF, Mendelson, MM, Muller-Nurasyid, M, Peters, A, Slagboom, PE, Starr, JM, Tregouet, D-A, Uitterlinden, AG, van Greevenbroek, MMJ, van Heemst, D, van Iterson, M, Wells, PS, Yao, C, Deary, IJ, Gagnon, F, Heijmans, BT, Levy, D, Morange, P-E, Waldenberger, M, Heil, SG, van Meurs, JBJ & Charge Consortium Epigenetics Grp 2017, 'Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes', PLOS ONE, vol. 12, no. 10, 0182472. https://doi.org/10.1371/journal.pone.0182472

TY - JOUR

T1 - Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes

AU - Mandaviya, Pooja R.

AU - Joehanes, Roby

AU - Aissi, Dylan

AU - Kuehnel, 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 - Lindemann, Jan

AU - Liu, Chunyu

AU - McRae, Allan F.

AU - Mendelson, Michael M.

AU - Muller-Nurasyid, Martina

AU - Peters, Annette

AU - Slagboom, P. Eline

AU - Starr, John M.

AU - Tregouet, David -Alexandre

AU - Uitterlinden, Andre 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.

AU - Charge Consortium Epigenetics Grp

PY - 2017/10/30

Y1 - 2017/10/30

N2 - 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.

AB - 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.

KW - GENOME-WIDE ASSOCIATION

KW - MENDELIAN RANDOMIZATION

KW - FOLATE STATUS

KW - INSTRUMENTAL VARIABLES

KW - GENE-EXPRESSION

KW - CANCER

KW - METAANALYSIS

KW - VARIANTS

KW - REGION

KW - RISK

U2 - 10.1371/journal.pone.0182472

DO - 10.1371/journal.pone.0182472

M3 - Article

SN - 1932-6203

VL - 12

JO - PLOS ONE

JF - PLOS ONE

IS - 10

M1 - 0182472

ER -