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. Methods and Results To identify whether differential methylation of cytosine-guanine dinucleotides (CpGs) correlated with lipid phenotypes, we isolated DNA from CD4+ T-cells and quantified proportion of sample methylation at over 450,000 CpGs using the Illumina Infinium HumanMethylation450 Beadchip in 991 participants of the Genetics of Lipid Lowering Drugs and Diet Network. We modeled percent methylation at individual CpGs as a function of fasting very low density lipoprotein cholesterol (VLDL-C) and triglycerides (TG) using mixed linear regression adjusted for age, gender, study site, cell purity, and family structure. Four CpGs (cg00574958, cg17058475, cg01082498, cg09737197) in intron 1 of carnitine palmitoyltransferase 1A (CPT1A) were strongly associated with VLDL-C (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 qPCR 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 VLDL-C and TG. Identifying novel epigenetic contributions to lipid traits may inform future efforts to identify new treatment targets and/or biomarkers of disease risk.

Mechanisms and treatment of ischaemic stroke—insights from genetic associations

“…Array-based methods can analyse patterns of DNA methylation in large populations, akin to GWASs at the DNA level. With small patient cohorts, this approach has demonstrated differential methylation in stroke-relevant risk factors such as BMI, 75 lipid levels 76 and smoking status. 77 In view of the probable importance of gene-environment interactions in cardiovascular disease and stroke, this approach may be particularly interesting in stroke.…”

Epigenetic Mechanisms Underlying the Pathogenesis of Neurogenetic Diseases

“…The authors replicated this finding in 2 separate cohorts and correlated the body mass indexassociated epigenetic information with genomic and transcriptomic data. Another analysis utilized leukocytes and identified differentially methylated sites in intron 1 of CPT1A that correlated strongly with levels of very low-density lipoprotein cholesterol and triglycerides [101]. The authors replicated this observation in a Framingham study cohort.…”

An Epigenome-Wide Association Study of Inflammatory Response to Fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network

“…The protocol was approved by the Institutional Review Boards of University of Minnesota, University of Utah, Tufts University/New England Medical Center, and the University of Alabama at Birmingham. More details about the GOLDN study have been published in earlier reports [17][18][25][26][27]. Baseline and postfenofibrate intervention data were available for 750 participants with DNA methylation measurements.…”

“…Random subsets of 10,000 CpGs per run were run after normalization, in which each array of 12 samples were used as batch. Correction for differing probe chemistry was performed on Illumina Infinium HumanMethylation450 Bead chip, normalizing the probes separately from the Infinium I and II [26][27]29,31].…”