1. Blood lipids influence DNA methylation in circulating cells
- Author
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Dekkers, K.F., Iterson, M. van, Slieker, R.C., Moed, M.H., Bonder, M.J., Galen, M. van, Mei, H.L., Zhernakova, D.V., Berg, L.H. van den, Deelen, J., Dongen, J. van, Heemst, D. van, Hofman, A., Hottenga, J.J., Kallen, C.J.H. van der, Schalkwijk, C.G., Stehouwer, C.D.A., Tigchelaar, E.F., Uitterlinden, A.G., Willemsen, G., Zhernakova, A., Franke, L., Hoen, P.A.C. 't, Jansen, R., Meurs, J. van, Boomsma, D.I., Duijn, C.M. van, Greevenbroek, M.M.J. van, Veldink, J.H., Wijmenga, C., Zwet, E.W. van, Slagboom, P.E., Jukema, J.W., Heijmans, B.T., BIOS Consortium, Amsterdam Neuroscience - Complex Trait Genetics, Biological Psychology, RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, Interne Geneeskunde, MUMC+: HVC Pieken Maastricht Studie (9), MUMC+: MA Interne Geneeskunde (3), Epidemiology, Internal Medicine, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), Epidemiology and Data Science, Laboratory Medicine, and Psychiatry
- Subjects
0301 basic medicine ,Netherlands Twin Register (NTR) ,Blood lipids ,030204 cardiovascular system & hematology ,Biology ,Bioinformatics ,Epigenesis, Genetic ,NORMALIZATION ,lipids ,Random Allocation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,MICROARRAY ,Mendelian randomization ,Journal Article ,Humans ,EPIDEMIOLOGY ,Epigenetics ,CPT1A LOCUS ,POPULATION ,EPIGENOME-WIDE ASSOCIATION ,Molecular Epidemiology ,DNA methylation ,PLASMA ,Cholesterol ,Research ,CHOLESTEROL ,Mendelian Randomization Analysis ,Lipid metabolism ,3. Good health ,Phenotype ,030104 developmental biology ,chemistry ,ATHEROSCLEROSIS ,lipids (amino acids, peptides, and proteins) ,Gene expression ,Lipoprotein - 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. Electronic supplementary material The online version of this article (doi:10.1186/s13059-016-1000-6) contains supplementary material, which is available to authorized users.
- Published
- 2016