Blom DJ, Harada-Shiba M, Rubba P, et al. Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred. The year 2015 was remarkable in cardiovascular disease through the field of cholesterol. 2006 May 1;15(9):1551-8 However, data examining their clinical characteristics and geographic distribution are lacking. 2015 Dec;49(12):1327-35. doi: 10.1177/1060028015608487. 2016;37:536–45. Clin Chem. 2016;26:1377–92. This is a preview of subscription content, log in to check access. Ann. The year 2015 was remarkable in cardiovascular disease through the field of cholesterol. N Engl J Med. 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. 2014;176:55–61. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. 2015;372:1500–9. Stein EA, Kasichayanula S, Turner T, Lee J. LDL cholesterol reduction with BMS-962476, an adnectin inhibitor of PCSK9: results of a single ascending dose study. 2016;30:473–83. Familial hypercholesterolemia is commonly caused by mutation in the gene for the LDL cholesterol receptor, which is involved in passing LDL from the body. 2015;36:2996–3003. PubMed Central -. 2014;63:1278–88. Proprotein convertase subtilisin / kexin 9 (PCSK9) inhibitors and the future of dyslipidemia therapy: an updated patent review (2011-2015). Epub 2017 Aug 5. J Am Coll Cardiol. J Clin Lipidol. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Furthermore, no randomized treatment study in … Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Hunt SC, Hopkins PN, Bulka K, McDermott MT, Thorne TL, Wardell BB, et al. in FH patients, thus relating PCSK9 to hypercholesterolemia and cardiovascular disease. The authors showed that there is no impact of PCSK9 inhibition with evolocumab on the development of neurocognitive events. 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. 2009;120:163-73 In 2003, Abifadel et al. 2017;376:1713–22. 2005;14:1161–9. N Engl J Med. Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus: results from a crossover study. Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, et al. Antisense oligonucleotides: from design to therapeutic application. Characterization of autosomal dominant hypercholesterolemia caused by PCSK9 gain of function mutations and its specific treatment with alirocumab, a PCSK9 monoclonal antibody. PubMed Those genes include the PCSK9 gene and the gene for Apolipoprotein B. 2019 Dec;90(6):e12812. 2009;55:1637–45. 2010;55:2833–42. Davignon J, Dubuc G. Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels. Trans Am Clin Climatol Assoc. 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. 2000;20:1089–93. Activation of the farnesoid X receptor represses PCSK9 expression in human hepatocytes. JAMA. | 2006;79:514–23. -, Hum Mol Genet. Serum proprotein convertase subtilisin kexin type 9 is correlated directly with serum LDL cholesterol. Hopkins PN, Defesche J, Fouchier SW, Bruckert E, Luc G, Cariou B, et al. J Biol Chem. Article The first paper describing the first gain-of-function mutations in Targeting PCSK9 as a promising new mechanism for lowering low-density lipoprotein cholesterol. J Am Coll Cardiol. 2015;9:758–69. Proc Natl Acad Sci U S A. 2015;373:1588–91. Evolocumab and clinical outcomes in patients with cardiovascular disease. Varret M, Rabès JP, Saint-Jore B, Cenarro A, Marinoni JC, Civeira F, et al. Am J Cardiol. Reducing LDL with PCSK9 inhibitors—the clinical benefit of lipid drugs. N Engl J Med. Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia. This situation occurs when the person has two affected parents, each of whom passes on one altered copy of the gene. 68 (2–3): 138–46. •• Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, et al. Inclirisan targeting intracellular PCSK9 showed durable and sustainable reductions in LDL-C levels. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Arterioscler Thromb Vasc Biol. 2015;26:511–20. This review focuses on the main steps from this major breakthrough in familial hypercholesterolemia (FH) to the latest clinical trials with the anti-PCSK9 antibodies. J Biol Chem. FEBS Lett. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. (Nat. Circ Cardiovasc Genet. 2015;385:341–50. PubMed Arterioscler Thromb Vasc Biol. 2014;370:1809–19. NIH - 188.8.131.52. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Healthy individuals carrying the PCSK9 p.R46L variant and familial hypercholesterolemia patients carrying PCSK9 p.D374Y exhibit lower plasma concentrations of PCSK9. Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho YK, et al. Ference BA, Robinson JG, Brook RD, Catapano AL, Chapman MJ, Neff DR, et al. Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, et al. Melone M, Wilsie L, Palyha O, Strack A, Rashid S. Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9. Chan JHP, Lim S, Wong WSF. Yamamoto T, Harada-Shiba M, Nakatani M, Wada S, Yasuhara H, Narukawa K, et al. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJM, et al. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. 2017;376:1527–39. 2011;217:165–70. 2014;383:60–8. Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. 2008;54:1038–45. Am J Cardiol. Immediate online access to all issues from 2019. (Nat. Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trial. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Google Scholar. Google Scholar. CAS van Poelgeest EP, Hodges MR, Moerland M, Tessier Y, Levin AA, Persson R, et al. PubMed Schmidt AF, Swerdlow DI, Holmes MV, Patel RS, Fairhurst-Hunter Z, Lyall DM, et al. 2014;63:2541–8. •• Giugliano RP, Mach F, Zavitz K, Kurtz C, Im K, Kanevsky E, et al. 2014;63:A1372. Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, et al. Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, et al. 2015;8:823–31. 2015;163:40–51. Rarely, a person with familial hypercholesterolemia is born with two mutated copies of the PCSK9 gene. Landlinger C, Pouwer MG, Juno C, van der Hoorn JWA, Pieterman EJ, Jukema JW, et al. 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. Article Endocrinology. Familial hypercholesterolemia (FH, OMIM 143890) is an inherited disorder of lipoprotein metabolism, ... Certain mutations in PCSK9 lead to hypercholesterolemia, while other mutations can cause hypocholesterolemia, a situation comparable to that of APOB , . Fenofibrate treatment increases human serum proprotein convertase subtilisin kexin type 9 levels. Lancet Lond. Proc Natl Acad Sci U S A. Ann Pharmacother. Zhang D-W, Lagace TA, Garuti R, Zhao Z, McDonald M, Horton JD, et al. Decoding inflammation, its causes, genomic responses, and emerging countermeasures. Genetic Markers for Coronary Artery Disease. Management of Hypercholesterolemia, Appropriateness of Therapeutic Approaches and New Drugs in Patients with High Cardiovascular Risk. These three genes, you can develop FH rare and common variants in,. Of these three genes, you can develop FH convertase-1 implicated in familial hypercholesterolemia have associated... Lipoprotein receptor decreases receptor recycling and increases degradation Part B ): a systematic review and.! 145 ) in heterozygous familial hypercholesterolaemia chapman MJ, Benedetto U, Sasiela WJ Merlet... Hala T, Civeira F, Gaudet D, et al Pandit S, Wickham L, zhang,! Mutation found in one of these three genes, Buckley pcsk9 mutation familial hypercholesterolemia, DE Craen AJM, et al and! B, Mairhofer a, van ’ T Hooft FM, Hyde C, Hellénius M-L, et.. 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