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

Pooja R Mandaviya; Roby Joehanes; Dylan Aïssi; Brigitte Kühnel; 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 Lindemans; Chunyu Liu; Allan F McRae; Michael M Mendelson; Martina Müller-Nurasyid; Annette Peters; P Eline Slagboom; John M Starr; David-Alexandre Trégouët; André 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 group and BIOS Consortium

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 Aïssi, Brigitte Kühnel, 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 Lindemans, Chunyu Liu, Allan F McRae, Michael M Mendelson, Martina Müller-NurasyidAnnette Peters, P Eline Slagboom, John M Starr, David-Alexandre Trégouët, André 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 group and BIOS Consortium

Research output: Contribution to journal › Article › 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 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.

Original language	English
Article number	e0182472
Pages (from-to)	1-19
Journal	PLoS ONE
Volume	12
Issue number	10
DOIs	https://doi.org/10.1371/journal.pone.0182472
Publication status	Published - 30 Oct 2017

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Mandaviya, P. R., Joehanes, R., Aïssi, D., Kühnel, 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., Lindemans, J., Liu, C., McRae, A. F., Mendelson, M. M., ... CHARGE Consortium Epigenetics group and BIOS Consortium (2017). Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes. PLoS ONE, 12(10), 1-19. [e0182472]. https://doi.org/10.1371/journal.pone.0182472

Mandaviya, Pooja R ; Joehanes, Roby ; Aïssi, Dylan ; Kühnel, 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 ; Lindemans, Jan ; Liu, Chunyu ; McRae, Allan F ; Mendelson, Michael M ; Müller-Nurasyid, Martina ; Peters, Annette ; Slagboom, P Eline ; Starr, John M ; Trégouët, David-Alexandre ; Uitterlinden, André 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 ; CHARGE Consortium Epigenetics group and BIOS Consortium. / Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes. In: PLoS ONE. 2017 ; Vol. 12, No. 10. pp. 1-19.

@article{1517bef9b0144addad7966766fe3268e,

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

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.",

author = "Mandaviya, {Pooja R} and Roby Joehanes and Dylan A{\"i}ssi and Brigitte K{\"u}hnel 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 Lindemans and Chunyu Liu and McRae, {Allan F} and Mendelson, {Michael M} and Martina M{\"u}ller-Nurasyid and Annette Peters and Slagboom, {P Eline} and Starr, {John M} and David-Alexandre Tr{\'e}gou{\"e}t and Uitterlinden, {Andr{\'e} 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 group and BIOS Consortium}",

year = "2017",

month = oct,

day = "30",

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

language = "English",

volume = "12",

pages = "1--19",

journal = "PLoS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "10",

}

Mandaviya, PR, Joehanes, R, Aïssi, D, Kühnel, B, Marioni, RE, Truong, V, Stolk, L, Beekman, M, Bonder, MJ, Franke, L, Gieger, C, Huan, T, Ikram, MA, Kunze, S, Liang, L, Lindemans, J, Liu, C, McRae, AF, Mendelson, MM, Müller-Nurasyid, M, Peters, A, Slagboom, PE, Starr, JM, Trégouët, 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 group and BIOS Consortium 2017, 'Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes', PLoS ONE, vol. 12, no. 10, e0182472, pp. 1-19. https://doi.org/10.1371/journal.pone.0182472

Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes. / Mandaviya, Pooja R; Joehanes, Roby; Aïssi, Dylan; Kühnel, 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; Lindemans, Jan; Liu, Chunyu; McRae, Allan F; Mendelson, Michael M; Müller-Nurasyid, Martina; Peters, Annette; Slagboom, P Eline; Starr, John M; Trégouët, David-Alexandre; Uitterlinden, André 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; CHARGE Consortium Epigenetics group and BIOS Consortium.

In: PLoS ONE, Vol. 12, No. 10, e0182472, 30.10.2017, p. 1-19.

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

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 - 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

AU - CHARGE Consortium Epigenetics group and BIOS Consortium

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

VL - 12

SP - 1

EP - 19

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 10

M1 - e0182472

ER -