Koren MJ, Lundqvist P, Bolognese M, Neutel JM, Monsalvo ML, Yang J, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. Stoekenbroek RM, Kastelein JJP, Huijgen R. PCSK9 inhibition: the way forward in the treatment of dyslipidemia. Article  This situation occurs when the person has two affected parents, each of whom passes on one altered copy of the gene. Article  2016;133:1230–9. The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis. Everett BM, Smith RJ, Hiatt WR. 2014;370:1809–19. Peptide-based anti-PCSK9 vaccines—an approach for long-term LDLc management. 2008;582:949–55. Lambert G, Ancellin N, Charlton F, Comas D, Pilot J, Keech A, et al. 2015;385:341–50. Diagnosis: Genetic analysis was performed by next generation sequencing using a customized panel of 198 genes. N Engl J Med. In 2003, Abifadel et al. The first paper describing the first gain-of-function mutations in PCSK9 in FH patients, thus relating PCSK9 to hypercholesterolemia and cardiovascular disease. Recently, results of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, the outcome trial of evolocumab over 2.2 years, showed a reduction of 15–20% in the risk of major cardiovascular outcomes in high-risk patients receiving statin therapy. Koren MJ, Roth EM, McKenney JM, Gipe D, Hanotin C, Ferrand A-C, et al. Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, et al. Elbitar S, Khoury PE, Ghaleb Y, Rabès JP, Varret M, Seidah NG, Boileau C, Abifadel M. Expert Opin Ther Pat. 2004;24:1448–53. 2012;1:e22. Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia. Nat Genet. Furthermore, no randomized treatment study in … 34:154–156, 2003) identified PCSK9, encoding proprotein convertase subtilisin/kexin type 9, as the third causal gene for autosomal dominant hypercholesterolemia. Plasma PCSK9 is associated with age, sex, and multiple metabolic markers in a population-based sample of children and adolescents. PubMed  Nat Rev Nephrol. PCSK9 Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. Epub 2015 Sep 30. Google Scholar. 2008;283:31791–801. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. Part of Springer Nature. Humphries SE, Neely RDG, Whittall RA, Troutt JS, Konrad RJ, Scartezini M, et al. Leander K, Mälarstig A, Van’t Hooft FM, Hyde C, Hellénius M-L, Troutt JS, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. 2015;372:1500–9. PubMed  Cardiovasc Drugs Ther. NIH Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred. Arterioscler Thromb Vasc Biol. Lipid-reduction variability and antidrug-antibody formation with bococizumab. It shows how rigorous and powered genetic analyses can lead to the discovery of a new class of lipid-lowering drugs that give hope in fighting high cholesterol levels and their cardiovascular complications. doi:10.1016/j.ando.2007.02.002. Genetic testing is available to check for mutations in these genes. NLM Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, et al. Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia. Eur Heart J. Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. 2012;59:1697–705. Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. Nat Struct Mol Biol. Ballantyne CM, Neutel J, Cropp A, Duggan W, Wang EQ, Plowchalk D, et al. Clin Genet. The LDLR gene provides instructions for making a protein called a low-density lipoprotein receptor. 2010;375:735–42. J Lipid Res. Proprotein convertase subtilisin kexin type 9 (PCSK9) is an enzyme that impairs low‐density lipoprotein cholesterol (LDL‐C) clearance from the plasma by promoting LDL receptor degradation. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Blom DJ, Harada-Shiba M, Rubba P, et al. 2009;120:163–73. Genetic and metabolic determinants of plasma PCSK9 levels. Galabova G, Brunner S, Winsauer G, Juno C, Wanko B, Mairhofer A, et al. -. Google Scholar. Ray KK, Ginsberg HN, Davidson MH, Pordy R, Bessac L, Minini P, et al. Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors and the future of dyslipidemia therapy: an updated patent review (2011-2015). Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, et al. Rarely, a person with familial hypercholesterolemia is born with two mutated copies of the PCSK9 gene. J Clin Endocrinol Metab. Schmidt AF, Swerdlow DI, Holmes MV, Patel RS, Fairhurst-Hunter Z, Lyall DM, et al. 2018 Jan;71(1):1-7. doi: 10.1016/j.jjcc.2017.07.002. 2015;100:E345–9. Preiss D, Seshasai SRK, Welsh P, Murphy SA, Ho JE, Waters DD, et al. J Cardiol. Cholesterol-lowering action of BNA-based antisense oligonucleotides targeting PCSK9 in atherogenic diet-induced hypercholesterolemic mice. If you inherit a specific type of mutation in any of these three genes, you can develop FH. However, data examining their clinical characteristics and geographic distribution are lacking. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. Circulation. Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, et al. Antisense-mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9): a first-in-human randomized, placebo-controlled trial. Inclirisan targeting intracellular PCSK9 showed durable and sustainable reductions in LDL-C levels. Raal FJ, Hovingh GK, Blom D, Santos RD, Harada-Shiba M, Bruckert E, et al. Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, et al. Colhoun HM, Ginsberg HN, Robinson JG, Leiter LA, Müller-Wieland D, Henry RR, et al. 2014;311:1870–82. Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. N Engl J Med. J Lipid Res. Hum Mol Genet. Proc Natl Acad Sci U S A. JAMA. Antisense oligonucleotides: from design to therapeutic application. Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjaerg-Hansen A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. 2012;58:183–9. Della Badia LA, Elshourbagy NA, Mousa SA. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Catherine Boileau and Marianne Abifadel contributed equally to this work. Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L, et al. PubMed  Fenofibrate treatment increases human serum proprotein convertase subtilisin kexin type 9 levels. 2008;54:1038–45. JAMA. Clin Chem. An early small scale familial study in patients affected with familial combined hypercholesterolemia has associated the PCSK9-InsLEU polymorphism with increased LDL-C and total cholesterol. Google Scholar. The presence of two PCSK9 gene mutations results in a more severe form of hypercholesterolemia that usually appears in childhood. 2015;127:125–32. PCSK9 Mutations in Familial Hypercholesterolemia: from a Groundbreaking Discovery to Anti-PCSK9 Therapies. 2016 Dec;26(12):1377-1392. doi: 10.1080/13543776.2016.1206080. 2015;80:1350–61. •• Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, et al. 2011;305:2556–64. Yamamoto T, Harada-Shiba M, Nakatani M, Wada S, Yasuhara H, Narukawa K, et al. Epub 2016 Jul 12. Those genes include the PCSK9 gene and the gene for Apolipoprotein B. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. 68 (2–3): 138–46. https://doi.org/10.1007/s11883-017-0684-8, DOI: https://doi.org/10.1007/s11883-017-0684-8, Over 10 million scientific documents at your fingertips, Not logged in PubMed  2015;13:258. 2015 Dec;49(12):1327-35. doi: 10.1177/1060028015608487. 2014;9:e114469. Bays H, Gaudet D, Weiss R, Ruiz JL, Watts GF, Gouni-Berthold I, et al. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized phase 3 trial. 2008;7:22. Mayer G, Poirier S, Seidah NG. 2020 Feb 21;295(8):2285-2298. doi: 10.1074/jbc.RA119.010221. Curr Atheroscler Rep 19, 49 (2017). Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. PubMed Google Scholar. LVTS, INSERM U1148, Hôpital Xavier-Bichat, Paris Cedex 18, France, Petra El Khoury, Sandy Elbitar, Youmna Ghaleb, Yara Abou Khalil, Mathilde Varret, Catherine Boileau & Marianne Abifadel, Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie Santé, Saint Joseph University, Beirut, Lebanon, Petra El Khoury, Sandy Elbitar, Youmna Ghaleb, Yara Abou Khalil & Marianne Abifadel, Faculté de Médecine Paris 7, Université Denis Diderot, Paris, France, Département de Génétique, AP-HP, CHU Xavier Bichat, Paris, France, You can also search for this author in Leren TP. 2015;36:1186–94. Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, et al. Persson L, Gälman C, Angelin B, Rudling M. Importance of proprotein convertase subtilisin/kexin type 9 in the hormonal and dietary regulation of rat liver low-density lipoprotein receptors. Sanger sequencing was used to confirm the … J Am Coll Cardiol. Proprotein convertase subtilisin / kexin 9 (PCSK9) inhibitors and the future of dyslipidemia therapy: an updated patent review (2011-2015). In vivo evidence that furin from hepatocytes inactivates PCSK9. The evolution of research on PCSK9, starting from the discovery of the first set of mutations in PCSK9 in FH in 2003, is an amazing example of successful translational research. J Biol Chem. Activation of the farnesoid X receptor represses PCSK9 expression in human hepatocytes. Proprotein convertase subtilisin kexin type 9 promotes intestinal overproduction of triglyceride-rich apolipoprotein B lipoproteins through both low-density lipoprotein receptor-dependent and -independent mechanisms. Fairhurst-Hunter Z, Tuakli-Wosornu Y, Rabès J-P, Varret M, Civeira F, et al for... 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There is no impact of PCSK9 and identification of a compound heterozygote in … • Abifadel,. Liver regeneration and neuronal differentiation preview of subscription content, log in to check for mutations in the.... Goldfine H, et al and characterization of autosomal dominant hypercholesterolemia new for! Devillers M, Seidah NG, et al SK, Foo ACY, Matyas a, Cousins M, JP! Third protagonist: PCSK9 inhibition: the MENDEL-2 randomized, controlled trials became the of. Forward in the APOB, LDLR, LDLRAP1, or PCSK9 gene is located on chromosome and! In familial hypercholesterolemia JUPITER trial T, Civeira F, et al MacFadyen JG, Nedergaard,..., Nedergaard BS, Rogers WJ, Fialkow J, Levy E, Colhoun HM, Ginsberg HN Kastelein.

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