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.

Background-Although US cholesterol concentrations have dropped, Ϸ50% of adults have total cholesterol concentrations Ն5.18 mmol/L, putting them at "borderline-high risk" for heart disease. Whether the decline has continued into the 21st century is unknown. We assessed 20-year trends in cholesterol, hypercholesterolemia, lipid-lowering drug use, and cholesterol awareness, treatment, and control from Minnesota Heart Survey (MHS) data. Methods and Results-Five independent, cross-sectional, population-based surveys of 2500 to 5000 adults were conducted in the Minneapolis-St.