Blood lipids influence DNA methylation in circulating cells

Koen F. Dekkers; Maarten van Iterson; Roderick C. Slieker; Matthijs H. Moed; Marc Jan Bonder; Michiel van Galen; Hailiang Mei; Daria V. Zhernakova; Leonard H. van den Berg; Joris Deelen; Jenny van Dongen; Diana van Heemst; Albert Hofman; Jouke J. Hottenga; Carla J. H. van der Kallen; Casper G. Schalkwijk; Coen D. A. Stehouwer; Ettje F. Tigchelaar; Andre G. Uitterlinden; Gonneke Willemsen; Alexandra Zhernakova; Lude Franke; Peter A. C. 't Hoen; Rick Jansen; Joyce van Meurs; Dorret I. Boomsma; Cornelia M. van Duijn; Marleen M. J. van Greevenbroek; Jan H. Veldink; Cisca Wijmenga; Erik W. van Zwet; P. Eline Slagboom; J. Wouter Jukema; Bastiaan T. Heijmans; BIOS Consortium

doi:10.1186/s13059-016-1000-6

Blood lipids influence DNA methylation in circulating cells

Koen F. Dekkers, Maarten van Iterson, Roderick C. Slieker, Matthijs H. Moed, Marc Jan Bonder, Michiel van Galen, Hailiang Mei, Daria V. Zhernakova, Leonard H. van den Berg, Joris Deelen, Jenny van Dongen, Diana van Heemst, Albert Hofman, Jouke J. Hottenga, Carla J. H. van der Kallen, Casper G. Schalkwijk, Coen D. A. Stehouwer, Ettje F. Tigchelaar, Andre G. Uitterlinden, Gonneke WillemsenAlexandra Zhernakova, Lude Franke, Peter A. C. 't Hoen, Rick Jansen, Joyce van Meurs, Dorret I. Boomsma, Cornelia M. van Duijn, Marleen M. J. van Greevenbroek, Jan H. Veldink, Cisca Wijmenga, Erik W. van Zwet, P. Eline Slagboom, J. Wouter Jukema, Bastiaan T. Heijmans^*, BIOS Consortium

^*Corresponding author for this work

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

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Abstract

Background: Cells can be primed by external stimuli to obtain a long-term epigenetic memory. We hypothesize that long-term exposure to elevated blood lipids can prime circulating immune cells through changes in DNA methylation, a process that may contribute to the development of atherosclerosis. To interrogate the causal relationship between triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels and genome-wide DNA methylation while excluding confounding and pleiotropy, we perform a stepwise Mendelian randomization analysis in whole blood of 3296 individuals.

Results: This analysis shows that differential methylation is the consequence of inter-individual variation in blood lipid levels and not vice versa. Specifically, we observe an effect of triglycerides on DNA methylation at three CpGs, of LDL cholesterol at one CpG, and of HDL cholesterol at two CpGs using multivariable Mendelian randomization. Using RNA-seq data available for a large subset of individuals (N = 2044), DNA methylation of these six CpGs is associated with the expression of CPT1A and SREBF1 (for triglycerides), DHCR24 (for LDL cholesterol) and ABCG1 (for HDL cholesterol), which are all key regulators of lipid metabolism.

Conclusions: Our analysis suggests a role for epigenetic priming in end-product feedback control of lipid metabolism and highlights Mendelian randomization as an effective tool to infer causal relationships in integrative genomics data.

Original language	English
Article number	138
Number of pages	12
Journal	Genome Biology
Volume	17
DOIs	https://doi.org/10.1186/s13059-016-1000-6
Publication status	Published - 27-Jun-2016

Keywords

DNA methylation
Lipids
Mendelian randomization
Gene expression
EPIGENOME-WIDE ASSOCIATION
MENDELIAN RANDOMIZATION
CPT1A LOCUS
CHOLESTEROL
PLASMA
ATHEROSCLEROSIS
NORMALIZATION
EPIDEMIOLOGY
MICROARRAY
POPULATION

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Additional file 12: of Blood lipids influence DNA methylation in circulating cells
van Duijn, C. M. (Contributor), van Heemst, D. (Contributor), Wijmenga, C. (Contributor), Boomsma, D. I. (Contributor), van Meurs, J. (Contributor), Moed, M. H. (Contributor), Deelen, J. (Contributor), Hofman, A. (Contributor), Slieker, R. C. (Contributor), van Iterson, M. (Contributor), Heijmans, B. T. (Contributor), Willemsen, G. (Contributor), van Dongen, J. (Contributor), Jukema, J. W. (Contributor), Stehouwer, C. D. A. (Contributor), Slagboom, P. E. (Contributor), Zhernakova, S. (Contributor), van Greevenbroek, M. M. J. (Contributor), 't Hoen, P. A. C. (Contributor), Hottenga, J. J. (Contributor), Tigchelaar - Feenstra, E. (Contributor), van Galen, M. (Contributor), Uitterlinden, A. G. (Contributor), Zhernakova, D. (Contributor), Franke, L. (Contributor), van Zwet, E. W. (Contributor), van der Kallen, C. J. H. (Contributor), Jansen, R. (Contributor), van den Berg, L. H. (Contributor), Mei, H. (Contributor), Veldink, J. H. (Contributor), Dekkers, K. F. (Contributor), Schalkwijk, C. G. (Contributor) & Bonder, M. J. (Contributor), University of Groningen, 14-Dec-2016
DOI: 10.6084/m9.figshare.c.3596987_d7.v1, https://doi.org/10.6084%2Fm9.figshare.c.3596987_d7.v1
Dataset
Additional file 7: of Blood lipids influence DNA methylation in circulating cells
van Greevenbroek, M. M. J. (Contributor), Boomsma, D. I. (Contributor), Heijmans, B. T. (Contributor), van den Berg, L. H. (Contributor), van Iterson, M. (Contributor), Willemsen, G. (Contributor), Wijmenga, C. (Contributor), van Duijn, C. M. (Contributor), Slagboom, P. E. (Contributor), 't Hoen, P. A. C. (Contributor), Franke, L. (Contributor), Hottenga, J. J. (Contributor), Tigchelaar - Feenstra, E. (Contributor), Deelen, J. (Contributor), Zhernakova, S. (Contributor), Zhernakova, D. (Contributor), van Galen, M. (Contributor), Bonder, M. J. (Contributor), van der Kallen, C. J. H. (Contributor), Slieker, R. C. (Contributor), Jukema, J. W. (Contributor), van Dongen, J. (Contributor), van Zwet, E. W. (Contributor), Schalkwijk, C. G. (Contributor), Uitterlinden, A. G. (Contributor), Jansen, R. (Contributor), Stehouwer, C. D. A. (Contributor), Mei, H. (Contributor), Moed, M. H. (Contributor), Veldink, J. H. (Contributor), van Meurs, J. (Contributor), Dekkers, K. F. (Contributor), Hofman, A. (Contributor) & van Heemst, D. (Contributor), University of Groningen, 14-Dec-2016
DOI: 10.6084/m9.figshare.c.3596987_d1.v1, https://doi.org/10.6084%2Fm9.figshare.c.3596987_d1.v1
Dataset
Additional file 13: of Blood lipids influence DNA methylation in circulating cells
Schalkwijk, C. G. (Contributor), Deelen, J. (Contributor), Zhernakova, S. (Contributor), Mei, H. (Contributor), Hofman, A. (Contributor), van den Berg, L. H. (Contributor), Stehouwer, C. D. A. (Contributor), van Greevenbroek, M. M. J. (Contributor), Zhernakova, D. (Contributor), van Zwet, E. W. (Contributor), Wijmenga, C. (Contributor), van Iterson, M. (Contributor), Tigchelaar - Feenstra, E. (Contributor), Slagboom, P. E. (Contributor), van Galen, M. (Contributor), Boomsma, D. I. (Contributor), Hottenga, J. J. (Contributor), 't Hoen, P. A. C. (Contributor), van der Kallen, C. J. H. (Contributor), van Meurs, J. (Contributor), Veldink, J. H. (Contributor), van Dongen, J. (Contributor), van Duijn, C. M. (Contributor), Jansen, R. (Contributor), Dekkers, K. F. (Contributor), Slieker, R. C. (Contributor), Moed, M. H. (Contributor), Jukema, J. W. (Contributor), Heijmans, B. T. (Contributor), Bonder, M. J. (Contributor), van Heemst, D. (Contributor), Franke, L. (Contributor), Willemsen, G. (Contributor) & Uitterlinden, A. G. (Contributor), University of Groningen, 14-Dec-2016
DOI: 10.6084/m9.figshare.c.3596987_d4.v1, https://doi.org/10.6084%2Fm9.figshare.c.3596987_d4.v1
Dataset

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Dekkers, K. F., van Iterson, M., Slieker, R. C., Moed, M. H., Bonder, M. J., van Galen, M., Mei, H., Zhernakova, D. V., van den Berg, L. H., Deelen, J., van Dongen, J., van Heemst, D., Hofman, A., Hottenga, J. J., van der Kallen, C. J. H., Schalkwijk, C. G., Stehouwer, C. D. A., Tigchelaar, E. F., Uitterlinden, A. G., ... BIOS Consortium (2016). Blood lipids influence DNA methylation in circulating cells. Genome Biology, 17, Article 138. https://doi.org/10.1186/s13059-016-1000-6

@article{07f51c32ca724eb5b419d7085b8ef3d8,

title = "Blood lipids influence DNA methylation in circulating cells",

abstract = "Background: Cells can be primed by external stimuli to obtain a long-term epigenetic memory. We hypothesize that long-term exposure to elevated blood lipids can prime circulating immune cells through changes in DNA methylation, a process that may contribute to the development of atherosclerosis. To interrogate the causal relationship between triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels and genome-wide DNA methylation while excluding confounding and pleiotropy, we perform a stepwise Mendelian randomization analysis in whole blood of 3296 individuals.Results: This analysis shows that differential methylation is the consequence of inter-individual variation in blood lipid levels and not vice versa. Specifically, we observe an effect of triglycerides on DNA methylation at three CpGs, of LDL cholesterol at one CpG, and of HDL cholesterol at two CpGs using multivariable Mendelian randomization. Using RNA-seq data available for a large subset of individuals (N = 2044), DNA methylation of these six CpGs is associated with the expression of CPT1A and SREBF1 (for triglycerides), DHCR24 (for LDL cholesterol) and ABCG1 (for HDL cholesterol), which are all key regulators of lipid metabolism.Conclusions: Our analysis suggests a role for epigenetic priming in end-product feedback control of lipid metabolism and highlights Mendelian randomization as an effective tool to infer causal relationships in integrative genomics data.",

keywords = "DNA methylation, Lipids, Mendelian randomization, Gene expression, EPIGENOME-WIDE ASSOCIATION, MENDELIAN RANDOMIZATION, CPT1A LOCUS, CHOLESTEROL, PLASMA, ATHEROSCLEROSIS, NORMALIZATION, EPIDEMIOLOGY, MICROARRAY, POPULATION",

author = "Dekkers, {Koen F.} and {van Iterson}, Maarten and Slieker, {Roderick C.} and Moed, {Matthijs H.} and Bonder, {Marc Jan} and {van Galen}, Michiel and Hailiang Mei and Zhernakova, {Daria V.} and {van den Berg}, {Leonard H.} and Joris Deelen and {van Dongen}, Jenny and {van Heemst}, Diana and Albert Hofman and Hottenga, {Jouke J.} and {van der Kallen}, {Carla J. H.} and Schalkwijk, {Casper G.} and Stehouwer, {Coen D. A.} and Tigchelaar, {Ettje F.} and Uitterlinden, {Andre G.} and Gonneke Willemsen and Alexandra Zhernakova and Lude Franke and {'t Hoen}, {Peter A. C.} and Rick Jansen and {van Meurs}, Joyce and Boomsma, {Dorret I.} and {van Duijn}, {Cornelia M.} and {van Greevenbroek}, {Marleen M. J.} and Veldink, {Jan H.} and Cisca Wijmenga and {van Zwet}, {Erik W.} and Slagboom, {P. Eline} and Jukema, {J. Wouter} and Heijmans, {Bastiaan T.} and {BIOS Consortium}",

year = "2016",

month = jun,

day = "27",

doi = "10.1186/s13059-016-1000-6",

language = "English",

volume = "17",

journal = "Genome Biology",

issn = "1465-6906",

publisher = "BMC",

}

Dekkers, KF, van Iterson, M, Slieker, RC, Moed, MH, Bonder, MJ, van Galen, M, Mei, H, Zhernakova, DV, van den Berg, LH, Deelen, J, van Dongen, J, van Heemst, D, Hofman, A, Hottenga, JJ, van der Kallen, CJH, Schalkwijk, CG, Stehouwer, CDA, Tigchelaar, EF, Uitterlinden, AG, Willemsen, G, Zhernakova, A , Franke, L, 't Hoen, PAC, Jansen, R, van Meurs, J, Boomsma, DI, van Duijn, CM, van Greevenbroek, MMJ, Veldink, JH, Wijmenga, C, van Zwet, EW, Slagboom, PE, Jukema, JW, Heijmans, BT & BIOS Consortium 2016, 'Blood lipids influence DNA methylation in circulating cells', Genome Biology, vol. 17, 138. https://doi.org/10.1186/s13059-016-1000-6

TY - JOUR

T1 - Blood lipids influence DNA methylation in circulating cells

AU - Dekkers, Koen F.

AU - van Iterson, Maarten

AU - Slieker, Roderick C.

AU - Moed, Matthijs H.

AU - Bonder, Marc Jan

AU - van Galen, Michiel

AU - Mei, Hailiang

AU - Zhernakova, Daria V.

AU - van den Berg, Leonard H.

AU - Deelen, Joris

AU - van Dongen, Jenny

AU - van Heemst, Diana

AU - Hofman, Albert

AU - Hottenga, Jouke J.

AU - van der Kallen, Carla J. H.

AU - Schalkwijk, Casper G.

AU - Stehouwer, Coen D. A.

AU - Tigchelaar, Ettje F.

AU - Uitterlinden, Andre G.

AU - Willemsen, Gonneke

AU - Zhernakova, Alexandra

AU - Franke, Lude

AU - 't Hoen, Peter A. C.

AU - Jansen, Rick

AU - van Meurs, Joyce

AU - Boomsma, Dorret I.

AU - van Duijn, Cornelia M.

AU - van Greevenbroek, Marleen M. J.

AU - Veldink, Jan H.

AU - Wijmenga, Cisca

AU - van Zwet, Erik W.

AU - Slagboom, P. Eline

AU - Jukema, J. Wouter

AU - Heijmans, Bastiaan T.

AU - BIOS Consortium

PY - 2016/6/27

Y1 - 2016/6/27

N2 - Background: Cells can be primed by external stimuli to obtain a long-term epigenetic memory. We hypothesize that long-term exposure to elevated blood lipids can prime circulating immune cells through changes in DNA methylation, a process that may contribute to the development of atherosclerosis. To interrogate the causal relationship between triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels and genome-wide DNA methylation while excluding confounding and pleiotropy, we perform a stepwise Mendelian randomization analysis in whole blood of 3296 individuals.Results: This analysis shows that differential methylation is the consequence of inter-individual variation in blood lipid levels and not vice versa. Specifically, we observe an effect of triglycerides on DNA methylation at three CpGs, of LDL cholesterol at one CpG, and of HDL cholesterol at two CpGs using multivariable Mendelian randomization. Using RNA-seq data available for a large subset of individuals (N = 2044), DNA methylation of these six CpGs is associated with the expression of CPT1A and SREBF1 (for triglycerides), DHCR24 (for LDL cholesterol) and ABCG1 (for HDL cholesterol), which are all key regulators of lipid metabolism.Conclusions: Our analysis suggests a role for epigenetic priming in end-product feedback control of lipid metabolism and highlights Mendelian randomization as an effective tool to infer causal relationships in integrative genomics data.

AB - Background: Cells can be primed by external stimuli to obtain a long-term epigenetic memory. We hypothesize that long-term exposure to elevated blood lipids can prime circulating immune cells through changes in DNA methylation, a process that may contribute to the development of atherosclerosis. To interrogate the causal relationship between triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels and genome-wide DNA methylation while excluding confounding and pleiotropy, we perform a stepwise Mendelian randomization analysis in whole blood of 3296 individuals.Results: This analysis shows that differential methylation is the consequence of inter-individual variation in blood lipid levels and not vice versa. Specifically, we observe an effect of triglycerides on DNA methylation at three CpGs, of LDL cholesterol at one CpG, and of HDL cholesterol at two CpGs using multivariable Mendelian randomization. Using RNA-seq data available for a large subset of individuals (N = 2044), DNA methylation of these six CpGs is associated with the expression of CPT1A and SREBF1 (for triglycerides), DHCR24 (for LDL cholesterol) and ABCG1 (for HDL cholesterol), which are all key regulators of lipid metabolism.Conclusions: Our analysis suggests a role for epigenetic priming in end-product feedback control of lipid metabolism and highlights Mendelian randomization as an effective tool to infer causal relationships in integrative genomics data.

KW - DNA methylation

KW - Lipids

KW - Mendelian randomization

KW - Gene expression

KW - EPIGENOME-WIDE ASSOCIATION

KW - MENDELIAN RANDOMIZATION

KW - CPT1A LOCUS

KW - CHOLESTEROL

KW - PLASMA

KW - ATHEROSCLEROSIS

KW - NORMALIZATION

KW - EPIDEMIOLOGY

KW - MICROARRAY

KW - POPULATION

U2 - 10.1186/s13059-016-1000-6

DO - 10.1186/s13059-016-1000-6

M3 - Article

C2 - 27350042

SN - 1465-6906

VL - 17

JO - Genome Biology

JF - Genome Biology

M1 - 138

ER -

Blood lipids influence DNA methylation in circulating cells

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Additional file 12: of Blood lipids influence DNA methylation in circulating cells

Additional file 7: of Blood lipids influence DNA methylation in circulating cells

Additional file 13: of Blood lipids influence DNA methylation in circulating cells

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