PCSK9

PCSK9 encodes proprotein convertase subtilisin/kexin type 9, a secreted liver enzyme that binds the LDL receptor on hepatocyte surfaces and targets it for lysosomal degradation, thereby reducing the liver's capacity to clear LDL cholesterol from blood. Gain-of-function PCSK9 variants raise LDL cholesterol and coronary artery disease risk, while loss-of-function variants lower both, which is why PCSK9 is also the target of cholesterol-lowering monoclonal antibody drugs (evolocumab, alirocumab); variants such as rs11591147 are incorporated into polygenic risk scores for coronary artery disease.