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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.

SUBMITTER: Dekkers KF

PROVIDER: S-EPMC4922056 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Blood lipids influence DNA methylation in circulating cells.

Dekkers Koen F KF van Iterson Maarten M Slieker Roderick C RC Moed Matthijs H MH Bonder Marc Jan MJ van Galen Michiel M Mei Hailiang H Zhernakova Daria V DV van den Berg Leonard H LH Deelen Joris J van Dongen Jenny J van Heemst Diana D Hofman Albert A Hottenga Jouke J JJ van der Kallen Carla J H CJ Schalkwijk Casper G CG Stehouwer Coen D A CD Tigchelaar Ettje F EF Uitterlinden André G AG Willemsen Gonneke G Zhernakova Alexandra A Franke Lude L 't Hoen Peter A C PA Jansen Rick R van Meurs Joyce J Boomsma Dorret I DI van Duijn Cornelia M CM van Greevenbroek Marleen M J MM Veldink Jan H JH Wijmenga Cisca C van Zwet Erik W EW Slagboom P Eline PE Jukema J Wouter JW Heijmans Bastiaan T BT

Genome biology 20160627 1

<h4>Background</h4>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 ...[more]

PMID: 27350042

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Project description:An emerging body of evidence indicates that early-life arsenic (As) exposure may influence the trajectory of health outcomes later in life. However, the mechanisms underlying these observations are unknown.The objective of this study was to investigate the influence of prenatal As exposure on global methylation of cord blood DNA in a study of mother/newborn pairs in Matlab, Bangladesh.Maternal and cord blood DNA were available from a convenience sample of 101 mother/newborn pairs. Measures of As exposure included maternal urinary As (uAs), maternal blood As (mbAs) and cord blood As (cbAs). Several measures of global DNA methylation were assessed, including the [3H]-methyl-incorporation assay and three Pyrosequencing assays: Alu, LINE-1 and LUMA.In the total sample, increasing quartiles of maternal uAs were associated with an increase in covariate-adjusted means of newborn global DNA methylation as measured by the [3H]-methyl-incorporation assay (quartile 1 (Q1) and Q2 vs. Q4; p?=?0.06 and 0.04, respectively). Sex-specific linear regression analyses, while not reaching significance level of 0.05, indicated that the associations between As exposures and Alu, LINE-1 and LUMA were positive among male newborns (N?=?58) but negative among female newborns (N?=?43); tests for sex differences were borderline significant for the association of cbAs and mbAs with Alu (p?=?0.05 and 0.09, respectively) and for the association between maternal uAs and LINE-1 (p?=?0.07). Sex-specific correlations between maternal urinary creatinine and newborn methyl-incorporation, Alu and LINE-1 were also evident (p<0.05).These results suggest that prenatal As exposure is associated with global DNA methylation in cord blood DNA, possibly in a sex-specific manner. Arsenic-induced epigenetic modifications in utero may potentially influence disease outcomes later in life. Additional studies are needed to confirm these findings and to examine the persistence of DNA methylation marks over time.

Dataset Information

Blood lipids influence DNA methylation in circulating cells.

Publications

Blood lipids influence DNA methylation in circulating cells.

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