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.
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
U2 - 10.1186/s13059-016-1000-6
DO - 10.1186/s13059-016-1000-6
M3 - Article
C2 - 27350042
SN - 1474-760X
VL - 17
JO - Genome Biology (Online)
JF - Genome Biology (Online)
M1 - 135
ER -