The influence of PCSK9 polymorphisms on serum low-density lipoprotein cholesterol and risk of atherosclerosis.
Pro-protein-convertase-subtilisin-kexin-9 (PCSK9) enhances the degradation of the low-density lipoprotein receptor (LDLR) that plays a major role in cholesterol homeostasis. Recent advances have revealed a large number of genetic variants of PCSK9 that may modulate plasma cholesterol levels either positively or negatively, therefore influencing the risk of atherosclerosis. Recognition of these mutants may have clinical implication in assessing severity of disease, prognosis, or response to drug therapy. PCSK9's expression, secretion, and plasma levels maybe modulated by the proprotein convertase furin, by natural inhibitors (annexin-A2), or influenced by lipid-altering agents such as statins, fibrates, ezetimibe, and berberine. It is now a prime target for therapy, prompting the development of various approaches to reduce its LDLR degrading activity, including antibody neutralization, anti-sense oligonucleotides such as phosphorothioates, locked nucleic acids, and RNA interference, and eventually small molecule inhibitors. Which one will be clinically applicable will depend on long-term effects, cost, and ease of administration.
Davignon
Jean
J
Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal (IRCM), 110 Pine Avenue West, Montreal, QC, H2W 1R7, Canada. davignj@ircm.qc.ca
Dubuc
Geneviève
G
Seidah
Nabil G
NG
D050197:Atherosclerosis / Q000097:blood / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood*; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D006801:Humans; D011110:Polymorphism, Genetic; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012313:RNA / Q000235:genetics*; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000097:blood / Q000235:genetics*
D008078:Cholesterol, LDL; D012313:RNA; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases