PCSK9 locus influence circulating PCSK9 levels

PCSK9 is a circulating protein, synthesized predominantly in the liver, involved in the regulation of the plasma low-density lipoprotein (LDL)–cholesterol concentration and associated with susceptibility to coronary heart disease (CHD). Proprotein convertase subtilisin/kexin type 9 (PCSK9) shortens the half-life of the LDL-receptor (LDLR), a process independent of its catalytic activity. Human studies demonstrated that dominant gain-of-function mutations of PCSK9 cause familial hypercholesterolemia and CHD, whereas loss-of-function mutations are associated with hypocholesterolemia and protection from CHD. Studies in experimental animals corroborated these observations. Overexpression of PCSK9 in mice greatly reduced hepatic LDLR expression and was associated with increased plasma LDL concentration, whereas PCSK9 deficiency resulted in a significantly increased hepatic LDLR number. Parabiosis experiments in mice confirmed that circulating PCSK9 is involved in the degradation of hepatic LDLR. Overall, these results are compatible with the notion that circulating PCSK9 regulates plasma LDL concentration through regulation of the LDLR density on the plasma membrane. PCSK9 is therefore considered a promising target to treat hypercholesterolemia and prevent CHD. Circulating PCSK9 levels have been measured in healthy, middle-aged individuals of European descent, in children and adolescents, and in Chinese and ethnically diverse cohorts. The general findings of these studies are that the circulating PCSK9 levels vary over a wide range among apparently healthy subjects and correlate with the plasma LDL concentration. The nature of the remarkable interindividual variation in circulating PCSK9 level is not known, but it is generally assumed that genetic factors contribute to this variability. However, only 1 high-impact genetic variant associated with circulating PCSK9 levels has thus far been identified in whites, the low-frequency PCSK9-R46L variant. The minor allele of this polymorphism has a frequency of 1% to 2% in European populations, indicating that it explains only a minor fraction of the variation in circulating PCSK9 level in healthy common and low-Frequency Genetic Variants in the PCSK9 locus influence circulating PCSK9 levels