Abstract

Intro: Exposure to atherogenic lipoproteins is a central determinant of atherosclerotic cardiovascular disease (ASCVD) events. Shared and unique biological pathways influence lipoprotein particle content (non-HDL-C, LDL-C) and number (apoB, LDL-P), but significant unexplained variance in blood lipoprotein levels remains. Understanding the associations between lipoprotein particle number, content, and repeated DNA methylation (DNAm) measures may provide novel insights into lipoprotein level determinants. Methods: We included 2962 participants from the Coronary Artery Risk Development in Young Adults study that had DNAm, LDL-C, non-HDL-C, apoB, and LDL-P measurements at exam years 15, 20, 25, and 30. Non-HDL-C and LDL-C were determined using standard laboratory technique. LDL particle number (LDL-P) and apoB were measured using NMR. DNAm was assessed using the Illumina Epic Array. We used separate mixed linear models adjusted for age, sex, race, and technical variables to quantify associations between DNAm sites and non-HDL-C, LDL-C, LDL-P, and apoB. We performed pathway analysis of DNAm located in gene promoter regions. We estimated % variance in lipid levels explained by associated DNAm sites using ANOVA. Results: There were 127, 182, 40, and 110 DNAm sites that were uniquely associated with LDL-C, non-HDL-C, LDL-P, and apoB, respectively. There were 114 DNAm sites associated with 3 or more of these atherogenic lipid measures. Of note, 6 DNAm sites were in the promoter of LDLR. Shared pathways included cholesterol and fatty acid metabolism, steroid and alcohol biosynthesis, as well as cellular protein transport (Table).Unique pathways generally included cholesterol synthesis for LDL-C, and energy metabolism, inflammation, and calcium transport for apoB and LDL-P. In total, identified CpGs in circulating blood leukocytes explained 14%, 24%, 16%, and 17% variance in LDL-C, non-HDL-C, LDL-P, and apoB, respectively. Conclusions: Assessment of longitudinal epigenetic patterns in peripheral leukocytes suggest unique and shared pathways mediate a large % variance in atherogenic lipids. Further exploration of the function of these DNAm sites may enhance mechanistic insight into the determinants of atherogenic lipid exposure.