Epigenome-wide association study of fasting blood lipids in the Genetics of Lipid-lowering Drugs and Diet Network study

Marguerite R Irvin; Degui Zhi; Roby Joehanes; Michael Mendelson; Stella Aslibekyan; Steven A Claas; Krista S Thibeault; Nikita Patel; Kenneth Day; Lindsay Waite Jones; Liming Liang; Brian H Chen; Chen Yao; Hemant K Tiwari; Jose M Ordovas; Daniel Levy; Devin Absher; Donna K Arnett

doi:10.1161/CIRCULATIONAHA.114.009158

Epigenome-wide association study of fasting blood lipids in the Genetics of Lipid-lowering Drugs and Diet Network study

Circulation. 2014 Aug 12;130(7):565-72. doi: 10.1161/CIRCULATIONAHA.114.009158. Epub 2014 Jun 11.

Authors

Marguerite R Irvin¹, Degui Zhi², Roby Joehanes², Michael Mendelson², Stella Aslibekyan², Steven A Claas², Krista S Thibeault², Nikita Patel², Kenneth Day², Lindsay Waite Jones², Liming Liang², Brian H Chen², Chen Yao², Hemant K Tiwari², Jose M Ordovas², Daniel Levy², Devin Absher², Donna K Arnett²

Affiliations

¹ 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.
² 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.).

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.

Methods and 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.

Keywords: cholesterol; fatty acids; genetics, medical; lipids; lipoproteins.

Publication types

Multicenter Study
Research Support, N.I.H., Extramural

MeSH terms

Adult
Anticholesteremic Agents / pharmacology
Anticholesteremic Agents / therapeutic use
Carnitine O-Palmitoyltransferase / blood
Carnitine O-Palmitoyltransferase / genetics*
Cohort Studies
Epigenomics / methods*
Fasting* / blood
Female
Genome-Wide Association Study / methods*
Humans
Lipoproteins, VLDL / blood
Lipoproteins, VLDL / genetics*
Male
Middle Aged
Triglycerides / blood
Triglycerides / genetics*

Substances

Anticholesteremic Agents
Lipoproteins, VLDL
Triglycerides
CPT1A protein, human
Carnitine O-Palmitoyltransferase

Abstract

Publication types

MeSH terms

Substances

Grants and funding