title: Blood lipids influence DNA methylation in circulating cells.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, Leiden, The Netherlands.
authors.forename: Koen F
authors.initials: KF
authors.lastname: Dekkers
authors.affiliation: Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, Leiden, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: van Iterson
authors.affiliation: Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, Leiden, The Netherlands.
authors.forename: Roderick C
authors.initials: RC
authors.lastname: Slieker
authors.affiliation: Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, Leiden, The Netherlands.
authors.forename: Matthijs H
authors.initials: MH
authors.lastname: Moed
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Broerstraat 5, Groningen, The Netherlands.
authors.forename: Marc Jan
authors.initials: MJ
authors.lastname: Bonder
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, Leiden, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: van Galen
authors.affiliation: Sequence Analysis Support Core, Leiden University Medical Center, Einthovenweg 20, Leiden, The Netherlands.
authors.forename: Hailiang
authors.initials: H
authors.lastname: Mei
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Broerstraat 5, Groningen, The Netherlands.
authors.forename: Daria V
authors.initials: DV
authors.lastname: Zhernakova
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.affiliation: Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, Leiden, The Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: Deelen
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.
authors.forename: Jenny
authors.initials: J
authors.lastname: van Dongen
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, Einthovenweg 20, Leiden, The Netherlands.
authors.forename: Diana
authors.initials: D
authors.lastname: van Heemst
authors.affiliation: Department of Genetic Epidemiology, ErasmusMC, 's-Gravendijkwal 230, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.
authors.forename: Jouke J
authors.initials: JJ
authors.lastname: Hottenga
authors.affiliation: Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, P. Debyelaan 25, Maastricht, The Netherlands.
authors.forename: Carla J H
authors.initials: CJ
authors.lastname: van der Kallen
authors.affiliation: Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, P. Debyelaan 25, Maastricht, The Netherlands.
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.affiliation: Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, P. Debyelaan 25, Maastricht, The Netherlands.
authors.forename: Coen D A
authors.initials: CD
authors.lastname: Stehouwer
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Broerstraat 5, Groningen, The Netherlands.
authors.forename: Ettje F
authors.initials: EF
authors.lastname: Tigchelaar
authors.affiliation: Department of Internal Medicine, ErasmusMC, 's-Gravendijkwal 230, Rotterdam, The Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Broerstraat 5, Groningen, The Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Broerstraat 5, Groningen, The Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, Leiden, The Netherlands.
authors.forename: Peter A C
authors.initials: PA
authors.lastname: 't Hoen
authors.affiliation: Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Jansen
authors.affiliation: Department of Internal Medicine, ErasmusMC, 's-Gravendijkwal 230, Rotterdam, The Netherlands.
authors.forename: Joyce
authors.initials: J
authors.lastname: van Meurs
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Department of Genetic Epidemiology, ErasmusMC, 's-Gravendijkwal 230, Rotterdam, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, P. Debyelaan 25, Maastricht, The Netherlands.
authors.forename: Marleen M J
authors.initials: MM
authors.lastname: van Greevenbroek
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Broerstraat 5, Groningen, The Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Einthovenweg 20, Leiden, The Netherlands.
authors.forename: Erik W
authors.initials: EW
authors.lastname: van Zwet
authors.affiliation: Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, Leiden, The Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Einthovenweg 20, Leiden, The Netherlands.
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.affiliation: Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, Leiden, The Netherlands. bas.heijmans@lumc.nl.
authors.forename: Bastiaan T
authors.initials: BT
authors.lastname: Heijmans
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000097:blood / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002334:Carnitine O-Palmitoyltransferase / Q000097:blood / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000097:blood / Q000235:genetics; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000097:blood / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000097:blood / Q000235:genetics; D014280:Triglycerides / Q000097:blood / Q000235:genetics
chemical_list: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008055:Lipids; D009419:Nerve Tissue Proteins; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase
keywords: DNA methylation; Gene expression; Lipids; Mendelian randomization