Little is known about the epigenetic bases of atherosclerotic cardiovascular disease (CVD) risk. Our recent large cross-sectional study revealed many monocyte transcriptome and epigenome signatures associated with subclinical atherosclerosis. Some of these genomic features appeared to partially mediate the relationship between traditional CVD risk factors (e.g. age, obesity, and smoking) and measures of atherosclerosis. The transcriptome signatures included an H3K9me2 demethylase transcription coactivator, ARID5B, which is known to promote adipogenesis and smooth muscle development. Methylation of ARID5B enhancer was inversely associated with both ARID5B expression and atherosclerosis. Our experimental in vitro study further showed that ARID5B promotes expression of genes involved in atherosclerosis-related pro-inflammatory and lipid metabolism pathways after lipopolysaccharide (LPS) stimulation. These results support a pivotal epigenetic checkpoint for controlling immunometabolic homeostasis and promoting chronic inflammatory reactions, which may contribute to atherosclerosis. These data set a compelling stage for prospective studies of the candidate genomic features and mechanistic dissection of the role of ARID5B in atherogenesis. The goals of our proposed study are to identify atherosclerosis associated ?promising? genomic features that are predictive of atherogenesis and its progression, to characterize their associations with plaque vulnerability, to determine their genetic and non-genetic predictors, and to elucidate their mechanistic linkage to atherogenesis. We will study 1,892 randomly selected subjects from four Multi-Ethnic Study of Atherosclerosis (MESA) field centers that have planned genomic, DNA methylomic, and transcriptomic data from purified CD14+ monocytes, as well as concurrent assessment of CVD risk factors and ultrasonographic carotid plaque burden from MESA Exam 5. We will repeat ultrasound imaging to quantify and characterize carotid plaques, and re-evaluate DNA methylomic and transcriptomic profiles of monocytes at MESA Exam 6, and we will perform in vivo and in vitro functional studies to achieve the following specific aims: Aim 1. To validate predictive effects of atherosclerosis-associated genomic features identified at Exam 5 on initiation and progression of atherosclerosis in a prospective study with 6-years of follow-up. Aim 2. To characterize the associations of the ?promising? genomic features with carotid plaque vulnerability. Aim 3. To identify potential temporal and causal relationships between known genetic and non-genetic CVD risk factors, the ?promising? genomic features, and plaque burden. Aim 4. To determine the functional consequences of alterations of most the ?promising? genomic features. If successful, the identified ?promising? genomic features will provide mechanistic insights into the etiology of atherosclerosis and potential targets for therapeutic intervention.