Genetic Regulation of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Plasma Levels
Another Piece of the Puzzle
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See Article by Pott et al
LDL-C (low-density lipoprotein cholesterol) is a major and well-recognized risk factor for atherosclerosis and cardiovascular disease (CVD). PCSK9 (proprotein convertase subtilisin/kexin type 9) was discovered by Dr Nabil Seidah in 2003,1 and since then, extensive research on this protein led to the development of a novel class of LDL-C lowering medication, namely the PCSK9 inhibitors. Secreted by the liver in the circulation, PCSK9 binds to the LDLR (LDL receptor) at the cell surface of the hepatocytes and promotes its lysosomal degradation, which results in the increase in circulating LDL-C. Several gain-of-function mutations in the PCSK9 gene have been shown to cause familial hypercholesterolemia, whereas some loss-of-function variants such as rs11591147 (R46L) have been associated with lower LDL-C levels as well as lower CVD risk in candidate gene studies.2 Therefore, PCSK9 is a major regulator of LDL-C metabolism. However, whether PCSK9 represents a predictor of CVD risk independently of its effect on LDL-C remains controversial. In a recent prospective study, circulating PCSK9 have been associated with incident CVD, even after adjustment for traditional risk …