title: Epigenome-wide association study of fasting blood lipids in the Genetics of Lipid-lowering Drugs and Diet Network study.
abstract: BACKGROUND
  Genetic research regarding blood lipids has largely focused on DNA sequence variation; few studies have explored epigenetic effects. Genome-wide surveys of DNA methylation may uncover epigenetic factors influencing lipid metabolism.
  
  
  RESULTS
  To identify whether differential methylation of cytosine-(phosphate)-guanine dinucleotides (CpGs) correlated with lipid phenotypes, we isolated DNA from CD4+ T cells and quantified the proportion of sample methylation at >450 000 CpGs by using the Illumina Infinium HumanMethylation450 Beadchip in 991 participants of the Genetics of Lipid Lowering Drugs and Diet Network. We modeled the percentage of methylation at individual CpGs as a function of fasting very-low-density lipoprotein cholesterol and triglycerides (TGs) by using mixed linear regression adjusted for age, sex, study site, cell purity, and family structure. Four CpGs (cg00574958, cg17058475, cg01082498, and cg09737197) in intron 1 of carnitine palmitoyltransferase 1A (CPT1A) were strongly associated with very-low low-density lipoprotein cholesterol (P=1.8×10(-21) to 1.6×10(-8)) and TG (P=1.6×10(-26) to 1.5×10(-9)). Array findings were validated by bisulfite sequencing. We performed quantitative polymerase chain reaction experiments demonstrating that methylation of the top CpG (cg00574958) was correlated with CPT1A expression. The association of cg00574958 with TG and CPT1A expression were replicated in the Framingham Heart Study (P=4.1×10(-14) and 3.1×10(-13), respectively). DNA methylation at CPT1A cg00574958 explained 11.6% and 5.5% of the variation in TG in the discovery and replication cohorts, respectively.
  
  
  CONCLUSIONS
  This genome-wide epigenomic study identified CPT1A methylation as strongly and robustly associated with fasting very-low low-density lipoprotein cholesterol and TG. Identifying novel epigenetic contributions to lipid traits may inform future efforts to identify new treatment targets and biomarkers of disease risk.
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.). irvinr@uab.edu.
authors.forename: Marguerite R
authors.initials: MR
authors.lastname: Irvin
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Degui
authors.initials: D
authors.lastname: Zhi
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Roby
authors.initials: R
authors.lastname: Joehanes
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Michael
authors.initials: M
authors.lastname: Mendelson
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Stella
authors.initials: S
authors.lastname: Aslibekyan
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Steven A
authors.initials: SA
authors.lastname: Claas
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Krista S
authors.initials: KS
authors.lastname: Thibeault
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Nikita
authors.initials: N
authors.lastname: Patel
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Kenneth
authors.initials: K
authors.lastname: Day
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Lindsay Waite
authors.initials: LW
authors.lastname: Jones
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Liming
authors.initials: L
authors.lastname: Liang
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Brian H
authors.initials: BH
authors.lastname: Chen
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Chen
authors.initials: C
authors.lastname: Yao
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Tiwari
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovas
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Devin
authors.initials: D
authors.lastname: Absher
authors.affiliation: From the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL (M.R.I., S.A., S.A.C., D.K.A.); Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL (D.Z., H.K.T.); Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Framingham Heart Study, Framingham, MA (R.J., M.M., L.L., B.H.C., C.Y., D.L.); Department of Cardiology, Boston Children's Hospital, Boston, MA (M.M.); Hudson Alpha Institute for Biotechnology, Huntsville, AL (K.S.T, N.P., K.D., L.W.J., D.A.); Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, MA (L.L.); and Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA (J.M.O.).
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
mesh_terms: D000328:Adult; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002334:Carnitine O-Palmitoyltransferase / Q000097:blood / Q000235:genetics*; D015331:Cohort Studies; D057890:Epigenomics / Q000379:methods*; D005215:Fasting / Q000097:blood; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008079:Lipoproteins, VLDL / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D014280:Triglycerides / Q000097:blood / Q000235:genetics*
chemical_list: D000924:Anticholesteremic Agents; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase
keywords: cholesterol; fatty acids; genetics, medical; lipids; lipoproteins