PCSK9 inhibition in LDL cholesterol reduction: Genetics and therapeutic implications of very low plasma lipoprotein levels

Pharmacology and Therapeutics

Volumn 145, Issue , 2015, Pages 58-66

  Marais, A David ^a   Kim, Jae B ^b   Wasserman, Scott M ^b   Lambert, Gilles ^c,d  

^a UNIVERSITY OF CAPE TOWN   (South Africa)

^b AMGEN INC   (United States)

^c UNIVERSITÉ DE NANTES   (France)

^d HÔTEL DIEU   (France)

Author keywords

Low density lipoprotein cholesterol; Low density lipoprotein receptor Genetics; Proprotein convertase subtilisin kexin type 9

Indexed keywords

ALIROCUMAB; ATORVASTATIN; BOCOCIZUMAB; EVOLOCUMAB; EZETIMIBE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LOW DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN RECEPTOR; PLACEBO; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9; SERINE PROTEINASE; UNCLASSIFIED DRUG; LIPOPROTEIN; PCSK9 PROTEIN, HUMAN;

ARTICLE; BRAIN HEMORRHAGE; CONTROLLED STUDY; DRUG EFFICACY; DRUG HYPERSENSITIVITY; DRUG SAFETY; DYSLIPIDEMIA; ENZYME INHIBITION; GAIN OF FUNCTION MUTATION; GENE EXPRESSION; GENETICS; HUMAN; HYPERCHOLESTEROLEMIA; HYPOLIPEMIA; LIPOPROTEIN BLOOD LEVEL; LOSS OF FUNCTION MUTATION; MOUSE; NONHUMAN; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PHASE 3 CLINICAL TRIAL; PHENOTYPE; PLASMA CLEARANCE; PROTEIN FUNCTION; ANIMAL; ANTAGONISTS AND INHIBITORS; BLOOD; DYSLIPIDEMIAS; METABOLISM;

ANIMALS; DYSLIPIDEMIAS; HUMANS; LIPOPROTEINS; PROPROTEIN CONVERTASES; RECEPTORS, LDL; SERINE ENDOPEPTIDASES;

EID: 84918820589     PISSN: 01637258     EISSN: 1879016X     Source Type: Journal    
DOI: 10.1016/j.pharmthera.2014.07.004     Document Type: Review

References (106)

1. M. Abifadel, J.P. Rabes, M. Devillers, A. Munnich, D. Erlich, and C. Junien Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease Hum Mutat 30 2009 520 529
2. M. Abifadel, M. Varret, J.P. Rabes, D. Allard, K. Ouguerram, and M. Devillers Mutations in PCSK9 cause autosomal dominant hypercholesterolemia Nat Genet 34 2003 154 156
3. R.H. Al-Mashhadi, C.B. Sorensen, P.M. Kragh, C. Christoffersen, M.B. Mortensen, and L.P. Tolbod Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant Sci Transl Med 5 2013 (166ra161)
4. P. Amarenco, J. Bogousslavsky, A. Callahan III, L.B. Goldstein, M. Hennerici, and A.E. Rudolph High-dose atorvastatin after stroke or transient ischemic attack N Engl J Med 355 2006 549 559
5. K.M. Anderson, W.P. Castelli, and D. Levy Cholesterol and mortality. 30 years of follow-up from the Framingham study JAMA 257 1987 2176 2180
6. G. Assmann, H. Schulte, and P. Cullen New and classical risk factors - the Munster heart study (PROCAM) Eur J Med Res 2 1997 237 242
7. C. Baigent, L. Blackwell, J. Emberson, L.E. Holland, C. Reith, and N. Bhala Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials Lancet 376 2010 1670 1681
8. C. Baigent, A. Keech, P.M. Kearney, L. Blackwell, G. Buck, and C. Pollicino Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins Lancet 366 2005 1267 1278
9. C. Baigent, M.J. Landray, C. Reith, J. Emberson, D.C. Wheeler, and C. Tomson The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial Lancet 377 2011 2181 2192
10. S. Benjannet, D. Rhainds, R. Essalmani, J. Mayne, L. Wickham, and W. Jin NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol J Biol Chem 279 2004 48865 48875
11. M. Benn, B.G. Nordestgaard, P. Grande, P. Schnohr, and A. Tybjaerg-Hansen PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses J Am Coll Cardiol 55 2010 2833 2842
12. K.E. Berge, L. Ose, and T.P. Leren Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy Arterioscler Thromb Vasc Biol 26 2006 1094 1100
13. L.R. Brunham, J.K. Kruit, T.D. Pape, J.M. Timmins, A.Q. Reuwer, and Z. Vasanji Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment Nat Med 13 2007 340 347
14. J.R. Burnett, J. Shan, B.A. Miskie, A.J. Whitfield, J. Yuan, and K. Tran A novel nontruncating APOB gene mutation, R463W, causes familial hypobetalipoproteinemia J Biol Chem 278 2003 13442 13452
15. J. Cameron, O.L. Holla, J.K. Laerdahl, M.A. Kulseth, K.E. Berge, and T.P. Leren Mutation S462P in the PCSK9 gene reduces secretion of mutant PCSK9 without affecting the autocatalytic cleavage Atherosclerosis 203 2009 161 165
16. J. Cameron, O.L. Holla, J.K. Laerdahl, M.A. Kulseth, T. Ranheim, and T. Rognes Characterization of novel mutations in the catalytic domain of the PCSK9 gene J Intern Med 263 2008 420 431
17. J. Cameron, O.L. Holla, T. Ranheim, M.A. Kulseth, K.E. Berge, and T.P. Leren Effect of mutations in the PCSK9 gene on the cell surface LDL receptors Hum Mol Genet 15 2006 1551 1558
18. M. Canuel, X. Sun, M.C. Asselin, E. Paramithiotis, A. Prat, and N.G. Seidah Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1) PLoS One 8 2013 e64145
19. B. Cariou, K. Ouguerram, Y. Zair, R. Guerois, C. Langhi, and S. Kourimate PCSK9 dominant negative mutant results in increased LDL catabolic rate and familial hypobetalipoproteinemia Arterioscler Thromb Vasc Biol 29 2009 2191 2197
20. C. Cholesterol Treatment Trialists, J.R. Emberson, P.M. Kearney, L. Blackwell, C. Newman, and C. Reith Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy PLoS One 7 2012 e29849
21. J.C. Cohen, E. Boerwinkle, T.H. Mosley Jr., and H.H. Hobbs Sequence variations in PCSK9, low LDL, and protection against coronary heart disease N Engl J Med 354 2006 1264 1272
22. J. Cohen, A. Pertsemlidis, I.K. Kotowski, R. Graham, C.K. Garcia, and H.H. Hobbs Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9 Nat Genet 37 2005 161 165
23. A.H. Dannoura, N. Berriot-Varoqueaux, P. Amati, V. Abadie, N. Verthier, and J. Schmitz Anderson's disease: exclusion of apolipoprotein and intracellular lipid transport genes Arterioscler Thromb Vasc Biol 19 1999 2494 2508
24. M.H. Davidson, K.C. Maki, T.A. Pearson, R.C. Pasternak, P.C. Deedwania, and J.M. McKenney Results of the National Cholesterol Education (NCEP) Program Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II survey and implications for treatment under the recent NCEP Writing Group recommendations Am J Cardiol 96 2005 556 563
25. M. Denis, J. Marcinkiewicz, A. Zaid, D. Gauthier, S. Poirier, and C. Lazure Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice Circulation 125 2012 894 901
26. T. Dewpura, A. Raymond, J. Hamelin, N.G. Seidah, M. Mbikay, and M. Chretien PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans FEBS J 275 2008 3480 3493
27. G. Dubuc, A. Chamberland, H. Wassef, J. Davignon, N.G. Seidah, and L. Bernier Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia Arterioscler Thromb Vasc Biol 24 2004 1454 1459
28. European Association for Cardiovascular Prevention & Rehabilitation, Z. Reiner, A.L. Catapano, G. De Backer, I. Graham, and M.R. Taskinen ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) Eur Heart J 32 2011 1769 1818
29. T. Fasano, A.B. Cefalu, E. Di Leo, D. Noto, D. Pollaccia, and L. Bocchi A novel loss of function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol Arterioscler Thromb Vasc Biol 27 2007 677 681
30. T.S. Fisher, P. Lo Surdo, S. Pandit, M. Mattu, J.C. Santoro, and D. Wisniewski Effects of pH and low density lipoprotein (LDL) on PCSK9-dependent LDL receptor regulation J Biol Chem 282 2007 20502 20512
31. K. Fitzgerald, M. Frank-Kamenetsky, S. Shulga-Morskaya, A. Liebow, B.R. Bettencourt, and J.E. Sutherland 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 Lancet 383 2014 60 68
32. K. Garber Biologics inch toward cholesterol-lowering market Nat Biotechnol 30 2012 302 304
33. A. Georges, J. Bonneau, D. Bonnefont-Rousselot, J. Champigneulle, J.P. Rabes, and M. Abifadel Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease) Orphanet J Rare Dis 6 2011 1
34. R.P. Giugliano, N.R. Desai, P. Kohli, W.J. Rogers, R. Somaratne, and F. Huang Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study Lancet 380 2012 2007 2017
35. J.L. Goldstein, and M.S. Brown The LDL receptor Arterioscler Thromb Vasc Biol 29 2009 431 438
36. B. Gumbiner, C. Udata, T. Joh, H. Liang, H. Wan, and D. Shelton The effects of multiple dose administration of RN316 (PF-04950615), a humanized IgG2a monoclonal antibody binding proprotein convertase subtilisin kexin type 9, in hypercholesterolemic subjects [abstract 13524] 2012 Presented at: American Heart Association Scientific Sessions 2012, Nov 3-7, 2012a Los Angeles, CA
37. B. Gumbiner, C. Udata, T. Joh, H. Liang, H. Wan, and D. Shelton The effects of single dose administration of RN316 (PF-04950615), a humanized IgG2a monoclonal antibody binding proprotein convertase subtilisin kexin type 9, in hypercholesterolemic subjects treated with and without atorvastatin [abstract 13322] 2012 Presented at: American Heart Association Scientific Sessions 2012, Nov 3-7, 2012b Los Angeles, CA
38. D.M. Hallman, S.R. Srinivasan, W. Chen, E. Boerwinkle, and G.S. Berenson Relation of PCSK9 mutations to serum low-density lipoprotein cholesterol in childhood and adulthood (from The Bogalusa Heart Study) Am J Cardiol 100 2007 69 72
39. A.J. Hooper, A.D. Marais, D.M. Tanyanyiwa, and J.R. Burnett The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population Atherosclerosis 193 2007 445 448
40. C.C. Huang, M. Fornage, D.M. Lloyd-Jones, G.S. Wei, E. Boerwinkle, and K. Liu Longitudinal association of PCSK9 sequence variations with low-density lipoprotein cholesterol levels: the Coronary Artery Risk Development in Young Adults Study Circ Cardiovasc Genet 2 2009 354 361
41. B.N. Huisa, A.B. Stemer, and J.A. Zivin Atorvastatin in stroke: a review of SPARCL and subgroup analysis Vasc Health Risk Manag 6 2010 229
42. S.E. Humphries, R.D. Neely, R.A. Whittall, J.S. Troutt, R.J. Konrad, and M. Scartezini Healthy individuals carrying the PCSK9 p.R46L variant and familial hypercholesterolemia patients carrying PCSK9 p.D374Y exhibit lower plasma concentrations of PCSK9 Clin Chem 55 2009 2153 2161
43. D. Jacobs, H. Blackburn, M. Higgins, D. Reed, H. Iso, and G. McMillan Report of the conference on Low blood cholesterol: mortality associations Circulation 86 1992 1046 1060
44. M.C. Jonas, C. Costantini, and L. Puglielli PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1 EMBO Rep 9 2008 916 922
45. B. Jones, E.L. Jones, S.A. Bonney, H.N. Patel, A.R. Mensenkamp, and S. Eichenbaum-Voline Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders Nat Genet 34 2003 29 31
46. P.H. Jones, R. Nair, and K.M. Thakker Prevalence of dyslipidemia and lipid goal attainment in statin-treated subjects from 3 data sources: a retrospective analysis J Am Heart Assoc 1 2012 e001800
47. S. Kathiresan, and Myocardial Infarction Genetics Consortium A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction N Engl J Med 358 2008 2299 2300
48. M.J. Koren, R.P. Giugliano, F.J. Raal, D. Sullivan, M. Bolognese, and G. Langslet Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the open-label study of long-term evaluation against LDL-C (OSLER) randomized trial Circulation 129 2014 234 243
49. M.J. Koren, R. Scott, J.B. Kim, B. Knusel, T. Liu, and L. Lei Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study Lancet 380 2012 1995 2006
50. T. Kosenko, M. Golder, G. Leblond, W. Weng, and T.A. Lagace Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation J Biol Chem 288 2013 8279 8288
51. G. Kostrzewa, G. Broda, P. Kurjata, W. Piotrowski, and R. Ploski Effect of protein convertase subtilisin/kexin type 9 (PCSK9) 46L gene polymorphism on LDL cholesterol concentration in a Polish adult population Mol Genet Metab 94 2008 259 262
52. I.K. Kotowski, A. Pertsemlidis, A. Luke, R.S. Cooper, G.L. Vega, and J.C. Cohen A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol Am J Hum Genet 78 2006 410 422
53. K. Kysenius, P. Muggalla, K. Matlik, U. Arumae, and H.J. Huttunen PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling Cell Mol Life Sci 69 2012 1903 1916
54. P. Labonte, S. Begley, C. Guevin, M.C. Asselin, N. Nassoury, and G. Mayer PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression Hepatology 50 2009 17 24
55. S.G. Lakoski, T.A. Lagace, J.C. Cohen, J.D. Horton, and H.H. Hobbs Genetic and metabolic determinants of plasma PCSK9 levels J Clin Endocrinol Metabol 94 2009 2537 2543
56. G. Lambert, N. Ancellin, F. Charlton, D. Comas, J. Pilot, and A. Keech Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment Clin Chem 54 2008 1038 1045
57. G. Lambert, F. Petrides, M. Chatelais, D.J. Blom, B. Choque, and F. Tabet Elevated plasma PCSK9 level is equally detrimental for patients with nonfamilial hypercholesterolemia and heterozygous familial hypercholesterolemia, irrespective of low-density lipoprotein receptor defects J Am Coll Cardiol 63 2014 2365 2373
58. G. Lambert, B. Sjouke, B. Choque, J.J. Kastelein, and G.K. Hovingh The PCSK9 decade: thematic review series: new lipid and lipoprotein targets for the treatment of cardiometabolic diseases J Lipid Res 53 2012 2515 2524
59. M.R. Law, and S.G. Thompson Low serum cholesterol and the risk of cancer: an analysis of the published prospective studies Cancer Causes Control 2 1991 253 261
60. C. Le May, J.M. Berger, A. Lespine, B. Pillot, X. Prieur, and E. Letessier Transintestinal cholesterol excretion is an active metabolic process modulated by PCSK9 and statin involving ABCB1 Arterioscler Thromb Vasc Biol 33 2013 1484 1493
61. C. Le May, S. Kourimate, C. Langhi, M. Chetiveaux, A. Jarry, and C. Comera Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia Arterioscler Thromb Vasc Biol 29 2009 684 690
62. T.P. Leren Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia Clin Genet 65 2004 419 422
63. J.K. Liao, and U. Laufs Pleiotropic effects of statins Annu Rev Pharmacol Toxicol 45 2005 89 118
64. A.D. Marais Familial hypercholesterolaemia Clin Biochem Rev 25 2004 49 68
65. J. Mayne, T. Dewpura, A. Raymond, L. Bernier, M. Cousins, and T.C. Ooi Novel loss-of-function PCSK9 variant is associated with low plasma LDL cholesterol in a French-Canadian family and with impaired processing and secretion in cell culture Clin Chem 57 2011 1415 1423
66. J. Mayne, T. Dewpura, A. Raymond, M. Cousins, A. Chaplin, and K.A. Lahey Plasma PCSK9 levels are significantly modified by statins and fibrates in humans Lipids Health Dis 7 2008 22
67. J.M. McKenney, M.J. Koren, D.J. Kereiakes, C. Hanotin, A.C. Ferrand, and E.A. Stein Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy J Am Coll Cardiol 59 2012 2344 2353
68. A. Menotti, M. Lanti, D. Kromhout, H. Blackburn, D. Jacobs, and A. Nissinen Homogeneity in the relationship of serum cholesterol to coronary deaths across different cultures: 40-year follow-up of the Seven Countries Study Eur J Cardiovasc Prev Rehabil 15 2008 719 725
69. Y. Miyake, R. Kimura, Y. Kokubo, A. Okayama, H. Tomoike, and T. Yamamura Genetic variants in PCSK9 in the Japanese population: rare genetic variants in PCSK9 might collectively contribute to plasma LDL cholesterol levels in the general population Atherosclerosis 196 2008 29 36
70. R.P. Naoumova, I. Tosi, D. Patel, C. Neuwirth, S.D. Horswell, and A.D. Marais Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response Arterioscler Thromb Vasc Biol 25 2005 2654 2660
71. J.D. Neaton, H. Blackburn, D. Jacobs, L. Kuller, D.J. Lee, and R. Sherwin Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Trial Research Group Arch Intern Med 152 1992 1490 1500
72. M.A. Nguyen, T. Kosenko, and T.A. Lagace Internalized PCSK9 dissociates from recycling LDL receptors in PCSK9-resistant SV-589 fibroblasts J Lipid Res 55 2014 266 275
73. S. Poirier, G. Mayer, S. Benjannet, E. Bergeron, J. Marcinkiewicz, and N. Nassoury The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2 J Biol Chem 283 2008 2363 2372
74. S. Poirier, G. Mayer, V. Poupon, P.S. McPherson, R. Desjardins, and K. Ly Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route J Biol Chem 284 2009 28856 28864
75. E. Polisecki, I. Peter, M. Robertson, A.D. McMahon, I. Ford, and C. Packard Genetic variation at the PCSK9 locus moderately lowers low-density lipoprotein cholesterol levels, but does not significantly lower vascular disease risk in an elderly population Atherosclerosis 200 2008 95 101
76. I. Postmus, S. Trompet, A.J. de Craen, B.M. Buckley, I. Ford, and D.J. Stott PCSK9 SNP rs11591147 is associated with low cholesterol levels but not with cognitive performance or noncardiovascular clinical events in an elderly population J Lipid Res 54 2013 561 566
77. D. Preiss, S.R. Seshasai, P. Welsh, S.A. Murphy, J.E. Ho, and D.D. Waters Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis JAMA 305 2011 2556 2564
78. F. Raal, V. Panz, A. Immelman, and G. Pilcher Elevated PCSK9 levels in untreated patients with heterozygous or homozygous familial hypercholesterolemia and the response to high-dose statin therapy J Am Heart Assoc 2 2013 e000028
79. F. Raal, R. Scott, R. Somaratne, I. Bridges, G. Li, and S.M. Wasserman Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) Randomized Trial Circulation 126 2012 2408 2417
80. S. Rashid, D.E. Curtis, R. Garuti, N.N. Anderson, Y. Bashmakov, and Y.K. Ho Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9 Proc Natl Acad Sci U S A 102 2005 5374 5379
81. P.M. Ridker, A. Pradhan, J.G. MacFadyen, P. Libby, and R.J. Glynn Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial Lancet 380 2012 565 571
82. E.M. Roth, J.M. McKenney, C. Hanotin, G. Asset, and E.A. Stein Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia N Engl J Med 367 2012 1891 1900
83. A. Roubtsova, M.N. Munkonda, Z. Awan, J. Marcinkiewicz, A. Chamberland, and C. Lazure Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue Arterioscler Thromb Vasc Biol 31 2011 785 791
84. N. Sattar, D. Preiss, H.M. Murray, P. Welsh, B.M. Buckley, and A.J. de Craen Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials Lancet 375 2010 735 742
85. G. Schonfeld Familial hypobetalipoproteinemia: a review J Lipid Res 44 2003 878 883
86. N.G. Seidah, S. Benjannet, L. Wickham, J. Marcinkiewicz, S.B. Jasmin, and S. Stifani The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation Proc Natl Acad Sci U S A 100 2003 928 933
87. A.R. Sharrett, C.M. Ballantyne, S.A. Coady, G. Heiss, P.D. Sorlie, and D. Catellier Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study Circulation 104 2001 1108 1113
88. L.F. Soria, E.H. Ludwig, H.R. Clarke, G.L. Vega, S.M. Grundy, and B.J. McCarthy Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100 Proc Natl Acad Sci U S A 86 1989 587 591
89. E.A. Stein, D. Gipe, J. Bergeron, D. Gaudet, R. Weiss, and R. Dufour Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial Lancet 380 2012 29 36
90. E.A. Stein, and F. Raal Reduction of low-density lipoprotein cholesterol by monoclonal antibody inhibition of PCSK9 Annu Rev Med 65 2014 417 431
91. T.B. Strom, K. Tveten, and T.P. Leren PCSK9 acts as a chaperone for the LDL receptor in the endoplasmic reticulum Biochem J 457 2014 99 105
92. D. Sullivan, A.G. Olsson, R. Scott, J.B. Kim, A. Xue, and V. Gebski Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial JAMA 308 2012 2497 2506
93. X. Sun, R. Essalmani, R. Day, A.M. Khatib, N.G. Seidah, and A. Prat Proprotein convertase subtilisin/kexin type 9 deficiency reduces melanoma metastasis in liver Neoplasia 14 2012 1122 1131
94. H. Sun, A. Samarghandi, N. Zhang, Z. Yao, M. Xiong, and B.B. Teng Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor Arterioscler Thromb Vasc Biol 32 2012 1585 1595
95. H. Tavori, D. Fan, J.L. Blakemore, P.G. Yancey, L. Ding, and M.F. Linton Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor: evidence for a reciprocal regulation Circulation 127 2013 2403 2413
96. H. Tavori, I. Giunzioni, M.F. Linton, and S. Fazio Loss of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) after lipoprotein apheresis Circ Res 113 2013 1290 1295
97. K.M. Timms, S. Wagner, M.E. Samuels, K. Forbey, H. Goldfine, and S. Jammulapati A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree Hum Genet 114 2004 349 353
98. E.P. van Poelgeest, R.M. Swart, M.G. Betjes, M. Moerland, J.J. Weening, and Y. Tessier Acute kidney injury during therapy with an antisense oligonucleotide directed against PCSK9 Am J Kidney Dis 62 2013 796 800
99. Y. Wang, Y. Huang, H.H. Hobbs, and J.C. Cohen Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR J Lipid Res 53 2012 1932 1943
100. G. Welder, I. Zineh, M.A. Pacanowski, J.S. Troutt, G. Cao, and R.J. Konrad High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol J Lipid Res 51 2010 2714 2721
101. J.R. Wetterau, L.P. Aggerbeck, M.E. Bouma, C. Eisenberg, A. Munck, and M. Hermier Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia Science 258 1992 999 1001
102. A.J. Whitfield, P.H. Barrett, F.M. van Bockxmeer, and J.R. Burnett Lipid disorders and mutations in the APOB gene Clin Chem 50 2004 1725 1732
103. C. Xie, J.A. Richardson, S.D. Turley, and J.M. Dietschy Cholesterol substrate pools and steroid hormone levels are normal in the face of mutational inactivation of NPC1 protein J Lipid Res 47 2006 953 963
104. P. Yue, M. Averna, X. Lin, and G. Schonfeld The c.43-44insCTG variation in PCSK9 is associated with low plasma LDL-cholesterol in a Caucasian population Hum Mutat 27 2006 460 466
105. A. Zaid, A. Roubtsova, R. Essalmani, J. Marcinkiewicz, A. Chamberland, and J. Hamelin Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration Hepatology 48 2008 646 654
106. Z. Zhao, Y. Tuakli-Wosornu, T.A. Lagace, L. Kinch, N.V. Grishin, and J.D. Horton Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote Am J Hum Genet 79 2006 514 523