Atherosclerosis, the buildup of plaque in artery walls, is a complex disease driven by an interaction between environmental factors and genetics. Numerous genes influence a person's risk by regulating lipid metabolism, inflammation, and vascular cell function. Genetic variations in genes that control cholesterol and lipid levels in the blood are the most well-established genetic contributors to atherosclerosis. Apolipoprotein E provides instructions for a protein that helps carry cholesterol and fats in the bloodstream, of which three major variants exist. The APOE allele is associated with higher total and LDL cholesterol levels and an increased risk of atherosclerosis. Mutations in the Low-Density Lipoprotein Receptor cause Familial Hypercholesterolemia (FH), a monogenic disorder leading to dangerously high LDL-C (bad cholesterol) levels from birth. LDLR is critical for clearing LDL from the blood. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) encodes a protein that regulates the number of LDL receptors on the liver surface. Gain-of-function mutations in PCSK9 increase LDL-C levels, dramatically raising atherosclerosis risk. Loss-of-function mutations in PCSK9 decrease LDL-C, offering significant protection against the disease. This discovery led to the development of powerful PCSK9 inhibitor drugs. Apolipoprotein B (APOB) is the main structural component of LDL cholesterol. Mutations in the APOB gene can impair LDL's ability to bind to the LDLR, a condition known as familial defective apolipoprotein B-100, which elevates LDL-C. Atherosclerosis is fundamentally a chronic inflammatory condition, and several genes linked to the immune response and vascular wall integrity play a role. Inflammatory Cytokines Genes, such as Interleukin-6 (IL6), Tumor Necrosis Factor alpha (TNFalpha), and various chemokines (e.g., CXCL2, CXCR4) have variants that can increase chronic inflammation, accelerating the formation and progression of atherosclerotic plaques. Vascular Genes (e.g., SVEP1) have been recently identified as potentially influencing plaque development independent of cholesterol by promoting the proliferation of vascular smooth muscle cells in the artery wall.