Summary Heart disease is the number one killer of men and women in the United States. Although the incidence of cardiovascular disease deaths has declined, it still accounts for ~1 out of every 3 deaths. Coronary artery disease (CAD) due to atherosclerosis was responsible for most of these deaths. Despite increased knowledge about CAD risk factors and the availably of drugs to treat them, the CAD problem has not been solved. Large human genome wide association studies have identified many common genetic variants associated with CAD, but only a small fraction of the heritable risk has been discovered. This proposal aims to perform mouse genetic and genomic studies to identify atherosclerosis modifier genes and genetic modifiers of macrophage foam cell lipid droplet metabolism and inflammation, yielding insights into the mechanisms that regulate these pathways. The first aim of the proposed studies involves identifying the responsible genes and genetic variation that give rise to in vitro macrophage phenotypes using sophisticated genetic and gene editing approaches. The second aim of the proposed studies is to identify the mouse atherosclerosis modifier gene in a genetic locus identified on chromosome 2. This aim will use sophisticated gene editing as well as a newer mouse model of atherosclerosis induced by treatment with an antisense oligonucleotide targeting the low density lipoprotein receptor. These findings may lead to novel drug targets and therapies to prevent or treat CAD. The relevance of the proposed studies is that they address a significant health concern, coronary artery disease, and will yield insight into the mechanisms that modify atherosclerosis susceptibility. The discovery of novel pathways and proteins that regulate atherosclerosis and foam cell cholesterol metabolism and inflammation offers hope for new modes of risk assessment, prevention, and therapy.