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. 2016 Jun 27;17(1):138.
doi: 10.1186/s13059-016-1000-6.

Blood lipids influence DNA methylation in circulating cells

Koen F Dekkers  1 , Maarten van Iterson  1 , Roderick C Slieker  1 , Matthijs H Moed  1 , Marc Jan Bonder  2 , Michiel van Galen  3 , Hailiang Mei  4 , Daria V Zhernakova  2 , Leonard H van den Berg  5 , Joris Deelen  1 , Jenny van Dongen  6 , Diana van Heemst  7 , Albert Hofman  8 , Jouke J Hottenga  6 , Carla J H van der Kallen  9 , Casper G Schalkwijk  9 , Coen D A Stehouwer  9 , Ettje F Tigchelaar  2 , André G Uitterlinden  10 , Gonneke Willemsen  6 , Alexandra Zhernakova  2 , Lude Franke  2 , Peter A C 't Hoen  3 , Rick Jansen  11 , Joyce van Meurs  10 , Dorret I Boomsma  6 , Cornelia M van Duijn  8 , Marleen M J van Greevenbroek  9 , Jan H Veldink  5 , Cisca Wijmenga  2 ; BIOS Consortium; Erik W van Zwet  12 , P Eline Slagboom  1 , J Wouter Jukema  13 , Bastiaan T Heijmans  14
Affiliations

Blood lipids influence DNA methylation in circulating cells

Koen F Dekkers et al. Genome Biol. .

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; Gene expression; Lipids; Mendelian randomization.

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Figures

Fig. 1
Fig. 1
Illustration of the stepwise Mendelian randomization approach. a In a conventional EWAS, associations observed are potentially confounded (C) and the direction of the association between lipids (L) and DNA methylation (M) cannot be inferred. b Using Mendelian randomization, polygenic scores (P) are used to obtain an unconfounded proxy for lipid levels and, since M cannot influence P, an effect of L on M can be inferred. c An additional analysis is required to exclude a direct effect of P on M (i.e., cis-methylation quantitative trait loci (QTL) effect of polygenic score SNPs) not mediated through L. d Reverse causation, i.e., an effect of M on L, is excluded by evaluating the association of local genetic variation (S) affecting M (cis-methylation QTL) on lipid levels. e Pleiotropic effects are excluded using a multivariate model that incorporates all lipids and their polygenic scores
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