The altered LDLR pathway clearance of plasma LDL-C may be one of the main causes of hypercholesterolemia that may also occur for mutations of LDLR and APO-B100; also, PCSK9 gain-of-function mutations may be associated with hypercholesterolemia whereas loss-of-function mutations are responsible for lowered plasma LDL-C levels, thus decreasing CV risk. This evidence concerns the gene PCSK9 and familial hypercholesterolemia.