Atherosclerosis is a precipitating event in the development of cardiovascular disease (CVD). The progression of the disease is prevalent in developed countries and there are currently limited options for prevention and treatment interventions. Recent studies report that liver transcriptome and gut microbiota contributes to the pathogenesis of CVD, including metabolic syndrome. While host genetic variants are known factors that affect atherosclerosis development, liver transcriptome, and gut microbiota composition, the mechanisms underlying genetic variations are not yet clear. Here, we interrogated atherosclerosis regulatory networks in hyperlipidemic Diversity Outbred (DO) mice to reveal key insights into control of atherosclerosis using system genetic approaches of cardiometabolic traits, liver transcriptome, and microbiome. Global hepatic gene expression analysis showed that both atherogenic diet and host genetics have profound effects on the liver transcriptome in eight DO founder strains. These also include identifying sex-specific cardiometabolic traits, liver genetic pathways and networks, and abundance of fecal microbial taxa associated with atherosclerotic traits, defining the functionality of genes associated with the atherosclerotic traits and gut microbiota, and finding signatures of functional gene variants predicted to modulate those traits in the hyperlipidemic DO mice. Collectively, this study provides a rich resource for investigating the pathogenesis of atherosclerosis and suggests an opportunity to discover therapeutics and biomarkers in the setting of hyperlipidemia
