title: Epigenome-wide association study (EWAS) on lipids: the Rotterdam Study.
abstract: DNA methylation is a key epigenetic mechanism that is suggested to be associated with blood lipid levels. We aimed to identify CpG sites at which DNA methylation levels are associated with blood levels of triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total cholesterol in 725 participants of the Rotterdam Study, a population-based cohort study. Subsequently, we sought replication in a non-overlapping set of 760 participants.
  
  
  
  Genome-wide methylation levels were measured in whole blood using the Illumina Methylation 450 array. Associations between lipid levels and DNA methylation beta values were examined using linear mixed-effect models. All models were adjusted for sex, age, smoking, white blood cell proportions, array number, and position on array. A Bonferroni-correctedpvalue lower than 1.08 × 10-7was considered statistically significant. Five CpG sites annotated to genes includingDHCR24,CPT1A,ABCG1, andSREBF1were identified and replicated. Four CpG sites were associated with triglycerides, including CpG sites annotated toCPT1A(cg00574958 and cg17058475),ABCG1(cg06500161), andSREBF1(cg11024682). Two CpG sites were associated with HDL-C, includingABCG1(cg06500161) andDHCR24(cg17901584). No significant associations were observed with LDL-C or total cholesterol.
  
  
  
  We report an association of HDL-C levels with methylation of a CpG site nearDHCR24, a protein-coding gene involved in cholesterol biosynthesis, which has previously been reported to be associated with other metabolic traits. Furthermore, we confirmed previously reported associations of methylation of CpG sites withinCPT1A,ABCG1, andSREBF1and lipids. These results provide insight in the mechanisms that are involved in lipid metabolism.
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, Office NA2906, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Kim V E
authors.initials: KVE
authors.lastname: Braun
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, Office NA2906, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Klodian
authors.initials: K
authors.lastname: Dhana
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, Office NA2906, PO Box 2040, 3000 CA Rotterdam, The Netherlands.|Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: de Vries
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, Office NA2906, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Trudy
authors.initials: T
authors.lastname: Voortman
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.|The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands.
authors.forename: Joyce B J
authors.initials: JBJ
authors.lastname: van Meurs
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, Office NA2906, PO Box 2040, 3000 CA Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.|The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, Office NA2906, PO Box 2040, 3000 CA Rotterdam, The Netherlands.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA USA.|Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA USA.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Hu
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, Office NA2906, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, Office NA2906, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000235:genetics; D000368:Aged; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics
chemical_list: C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D008055:Lipids; D009419:Nerve Tissue Proteins; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase
keywords: Cohort; DNA methylation; EWAS; HDL-C; LDL-C; Lipids; Total cholesterol; Triglycerides