Blood lipids influence DNA methylation in circulating cells

K.F. Dekkers; M. van Iterson; R.C. Slieker; M.H. Moed; M.J. Bonder; M. van Galen; H. Mei; D.V. Zhernakova; L.H. Van den Berg; J. Deelen; J. van Dongen; D. van Heemst; A. Hofman; J.J. Hottenga; C.J.H. van der Kallen; C.G. Schalkwijk; C.D.A. Stehouwer; E.F. Tigchelaar; A.G. Uitterlinden; G. Willemsen; A. Zhernakova; L. Franke; P.A.C. 't Hoen; R. Jansen; J. van Meurs; D.I. Boomsma; C.M. van Duijn; M.M.J. van Greevenbroek; J.H. Veldink; C. Wijmenga; E.W. van Zwet; P.E. Slagboom; J.W. Jukema; B.T. Heijmans

doi:10.1186/s13059-016-1000-6

Blood lipids influence DNA methylation in circulating cells

K.F. Dekkers, M. van Iterson, R.C. Slieker, M.H. Moed, M.J. Bonder, M. van Galen, H. Mei, D.V. Zhernakova, L.H. Van den Berg, J. Deelen, J. van Dongen, D. van Heemst, A. Hofman, J.J. Hottenga, C.J.H. van der Kallen, C.G. Schalkwijk, C.D.A. Stehouwer, E.F. Tigchelaar, A.G. Uitterlinden, G. WillemsenA. Zhernakova, L. Franke, P.A.C. 't Hoen, R. Jansen, J. van Meurs, D.I. Boomsma, C.M. van Duijn, M.M.J. van Greevenbroek, J.H. Veldink, C. Wijmenga, E.W. van Zwet, P.E. Slagboom, J.W. Jukema, B.T. Heijmans

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

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
Pages (from-to)	1-12
Journal	Genome Biology
Volume	17
Issue number	138
DOIs	https://doi.org/10.1186/s13059-016-1000-6
Publication status	Published - 2016

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10.1186/s13059-016-1000-6

Additional file 13: of Blood lipids influence DNA methylation in circulating cells
Dekkers, K. (Contributor), Iterson, M. V. (Contributor), Slieker, R. (Contributor), Moed, M. (Contributor), Bonder, M. (Contributor), Galen, M. V. (Contributor), Mei, H. (Contributor), Zhernakova, D. (Contributor), Berg, L. V. D. (Contributor), Deelen, J. (Contributor), Dongen, J. V. (Contributor), Heemst, D. V. (Contributor), Hofman, A. (Contributor), Hottenga, J. J. (Contributor), Kallen, C. V. D. (Contributor), Schalkwijk, C. (Contributor), Stehouwer, C. (Contributor), Tigchelaar, E. (Contributor), Uitterlinden, A. (Contributor), Willemsen, A. (Contributor), Zhernakova, A. (Contributor), Franke, L. (Contributor), Hoen, P. (Contributor), Jansen, R. (Contributor), Meurs, J. V. (Contributor), Boomsma, D. (Contributor), Duijn, C. V. (Contributor), Greevenbroek, M. V. (Contributor), Veldink, J. (Contributor), Wijmenga, C. (Contributor), Zwet, E. V. (Contributor), Slagboom, P. (Contributor), Jukema, J. (Contributor) & Heijmans, B. (Contributor), Unknown Publisher, 27 Jun 2016
DOI: 10.6084/m9.figshare.c.3596987_d4.v1, https://springernature.figshare.com/articles/dataset/Additional_file_13_of_Blood_lipids_influence_DNA_methylation_in_circulating_cells/4320569/1
Dataset
Additional file 6: of Blood lipids influence DNA methylation in circulating cells
Dekkers, K. (Contributor), Iterson, M. V. (Contributor), Slieker, R. (Contributor), Moed, M. (Contributor), Bonder, M. (Contributor), Galen, M. V. (Contributor), Mei, H. (Contributor), Zhernakova, D. (Contributor), Berg, L. V. D. (Contributor), Deelen, J. (Contributor), Dongen, J. V. (Contributor), Heemst, D. V. (Contributor), Hofman, A. (Contributor), Hottenga, J. J. (Contributor), Kallen, C. V. D. (Contributor), Schalkwijk, C. (Contributor), Stehouwer, C. (Contributor), Tigchelaar, E. (Contributor), Uitterlinden, A. (Contributor), Willemsen, A. (Contributor), Zhernakova, A. (Contributor), Franke, L. (Contributor), Hoen, P. (Contributor), Jansen, R. (Contributor), Meurs, J. V. (Contributor), Boomsma, D. (Contributor), Duijn, C. V. (Contributor), Greevenbroek, M. V. (Contributor), Veldink, J. (Contributor), Wijmenga, C. (Contributor), Zwet, E. V. (Contributor), Slagboom, P. (Contributor), Jukema, J. (Contributor) & Heijmans, B. (Contributor), Unknown Publisher, 27 Jun 2016
DOI: 10.6084/m9.figshare.c.3596987_d3.v1, https://springernature.figshare.com/articles/dataset/Additional_file_6_of_Blood_lipids_influence_DNA_methylation_in_circulating_cells/4320551/1
Dataset
Additional file 8: of Blood lipids influence DNA methylation in circulating cells
Dekkers, K. (Contributor), Iterson, M. V. (Contributor), Slieker, R. (Contributor), Moed, M. (Contributor), Bonder, M. (Contributor), Galen, M. V. (Contributor), Mei, H. (Contributor), Zhernakova, D. (Contributor), Berg, L. V. D. (Contributor), Deelen, J. (Contributor), Dongen, J. V. (Contributor), Heemst, D. V. (Contributor), Hofman, A. (Contributor), Hottenga, J. J. (Contributor), Kallen, C. V. D. (Contributor), Schalkwijk, C. (Contributor), Stehouwer, C. (Contributor), Tigchelaar, E. (Contributor), Uitterlinden, A. (Contributor), Willemsen, A. (Contributor), Zhernakova, A. (Contributor), Franke, L. (Contributor), Hoen, P. (Contributor), Jansen, R. (Contributor), Meurs, J. V. (Contributor), Boomsma, D. (Contributor), Duijn, C. V. (Contributor), Greevenbroek, M. V. (Contributor), Veldink, J. (Contributor), Wijmenga, C. (Contributor), Zwet, E. V. (Contributor), Slagboom, P. (Contributor), Jukema, J. (Contributor) & Heijmans, B. (Contributor), Unknown Publisher, 27 Jun 2016
DOI: 10.6084/m9.figshare.c.3596987_d9.v1, https://springernature.figshare.com/articles/dataset/Additional_file_8_of_Blood_lipids_influence_DNA_methylation_in_circulating_cells/4320662/1
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., ... Heijmans, B. T. (2016). Blood lipids influence DNA methylation in circulating cells. Genome Biology, 17(138), 1-12. https://doi.org/10.1186/s13059-016-1000-6

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. ; Willemsen, G. ; Zhernakova, A. ; Franke, L. ; 't Hoen, P.A.C. ; Jansen, R. ; van Meurs, J. ; Boomsma, D.I. ; van Duijn, C.M. ; van Greevenbroek, M.M.J. ; Veldink, J.H. ; Wijmenga, C. ; van Zwet, E.W. ; Slagboom, P.E. ; Jukema, J.W. ; Heijmans, B.T. / Blood lipids influence DNA methylation in circulating cells. In: Genome Biology. 2016 ; Vol. 17, No. 138. pp. 1-12.

@article{c3f9e8992e3b4226a8ce2f9952c9c0d9,

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.",

author = "K.F. Dekkers and {van Iterson}, M. and R.C. Slieker and M.H. Moed and M.J. Bonder and {van Galen}, M. and H. Mei and D.V. Zhernakova and {Van den Berg}, L.H. and J. Deelen and {van Dongen}, J. and {van Heemst}, D. and A. Hofman and J.J. Hottenga and {van der Kallen}, C.J.H. and C.G. Schalkwijk and C.D.A. Stehouwer and E.F. Tigchelaar and A.G. Uitterlinden and G. Willemsen and A. Zhernakova and L. Franke and {'t Hoen}, P.A.C. and R. Jansen and {van Meurs}, J. and D.I. Boomsma and {van Duijn}, C.M. and {van Greevenbroek}, M.M.J. and J.H. Veldink and C. Wijmenga and {van Zwet}, E.W. and P.E. Slagboom and J.W. Jukema and B.T. Heijmans",

year = "2016",

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

language = "English",

volume = "17",

pages = "1--12",

journal = "Genome Biology",

issn = "1465-6906",

publisher = "Springer Verlag",

number = "138",

}

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 2016, 'Blood lipids influence DNA methylation in circulating cells', Genome Biology, vol. 17, no. 138, pp. 1-12. https://doi.org/10.1186/s13059-016-1000-6

Blood lipids influence DNA methylation in circulating cells. / 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.; Willemsen, G.; Zhernakova, A.; Franke, L.; 't Hoen, P.A.C.; Jansen, R.; van Meurs, J.; Boomsma, D.I.; van Duijn, C.M.; van Greevenbroek, M.M.J.; Veldink, J.H.; Wijmenga, C.; van Zwet, E.W.; Slagboom, P.E.; Jukema, J.W.; Heijmans, B.T.

In: Genome Biology, Vol. 17, No. 138, 2016, p. 1-12.

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

TY - JOUR

T1 - Blood lipids influence DNA methylation in circulating cells

AU - Dekkers, K.F.

AU - van Iterson, M.

AU - Slieker, R.C.

AU - Moed, M.H.

AU - Bonder, M.J.

AU - van Galen, M.

AU - Mei, H.

AU - Zhernakova, D.V.

AU - Van den Berg, L.H.

AU - Deelen, J.

AU - van Dongen, J.

AU - van Heemst, D.

AU - Hofman, A.

AU - Hottenga, J.J.

AU - van der Kallen, C.J.H.

AU - Schalkwijk, C.G.

AU - Stehouwer, C.D.A.

AU - Tigchelaar, E.F.

AU - Uitterlinden, A.G.

AU - Willemsen, G.

AU - Zhernakova, A.

AU - Franke, L.

AU - 't Hoen, P.A.C.

AU - Jansen, R.

AU - van Meurs, J.

AU - Boomsma, D.I.

AU - van Duijn, C.M.

AU - van Greevenbroek, M.M.J.

AU - Veldink, J.H.

AU - Wijmenga, C.

AU - van Zwet, E.W.

AU - Slagboom, P.E.

AU - Jukema, J.W.

AU - Heijmans, B.T.

PY - 2016

Y1 - 2016

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.

U2 - 10.1186/s13059-016-1000-6

DO - 10.1186/s13059-016-1000-6

M3 - Article

VL - 17

SP - 1

EP - 12

JO - Genome Biology

JF - Genome Biology

SN - 1465-6906

IS - 138

ER -

Blood lipids influence DNA methylation in circulating cells

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

Additional file 6: of Blood lipids influence DNA methylation in circulating cells

Additional file 8: of Blood lipids influence DNA methylation in circulating cells

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