Atherosclerotic cardiovascular disease is the leading cause of death for both men and women among all racial and ethnic backgrounds in Western populations, accounting for nearly 1 million deaths in the United States annually. The development of atherosclerosis involves initial injury to the endothelial cell lining, followed by accumulation of macrophages, adherence of LDL, and accumulation of cholesterol. Apolipoprotein E (apoE) plays a major role in the metabolisms of cholesterol and triglyceride by serving as a ligand for receptors that clear remnants of chylomicrons and very low density lipoprotein (VLDL) from plasma. The link between APOE, serum cholesterol levels, and the development of atherosclerosis has been well established in humans. Numerous animal models have been used to study the pathogenesis and potential treatment of the lesions of atherosclerosis. Mice are highly resistant to atherosclerosis and the vascular lesions differ in location and histology when compared to humans. Rats and dogs are not good models for atherosclerosis because they do not develop spontaneous lesions and require heavy modifications of diet to develop vascular lesions. Rabbits are highly responsive to cholesterol manipulation, but the lesions they develop are much more fatty and macrophage-rich than the human and their plasma cholesterol levels are extraordinarily high. Pigs, however, are very good models when fed high cholesterol diets because they reach plasma cholesterol levels and atherosclerotic lesions similar to humans. In addition, pig models of the disease initially revealed that monocyte infiltration was one of the primary cellular events in the atherogenic process. Therefore, we are investigating the potential of the pig as a model for atherosclerosis by utilizing sequence information to compare human APOE to pig APOE. We are comparing the coding region SNPs in exon 4 of human APOE to pig APOE, which account for the phenotypic differences. We are also comparing SNP frequencies of APOE in twelve animals from eight different pig breeds. Ultimately, we aim to develop a pig model of atherosclerosis that will be used for therapeutic intervention and prevention. We will accomplish this by making a point mutation in the pig at the location of the SNP that accounts for the high cholesterol phenotype in humans as well as create an apoE-knockout pig.