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Genetic Variants of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Implications for Low-Density Lipoprotein Cholesterol (LDL-C) © 2014 Amgen Inc.

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Presentation on theme: "Genetic Variants of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Implications for Low-Density Lipoprotein Cholesterol (LDL-C) © 2014 Amgen Inc."— Presentation transcript:

1 Genetic Variants of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Implications for Low-Density Lipoprotein Cholesterol (LDL-C) © 2014 Amgen Inc. All rights reserved. Not for Reproduction. USA (1)

2 PCSK9 Mutations Are Involved in Familial Hypercholesterolemia Familial hypercholesterolemia (FH) characterized by 1 : –Severely elevated LDL-C levels Mutations of three genes are primarily responsible for FH* 2 1. van der Graaf A, et al. Circulation. 2011;123: Seidah NG, et al. J Mol Med. 2007;85: *Autosomal Dominant Hypercholesterolemia form of FH 67% LDLR 16.7% Others 2.3% PCSK9 14% ApoB 2

3 PCSK9 is a Key Regulator of LDLR Recycling PCSK9 mediates degradation of the LDLR by interacting with the extracellular domain and targeting the receptor for degradation 1 1. Horton JD, et al. J Lipid Res. 2009;50:S172-S Qian YW, et al. J Lipid Res. 2007;48: Zhang DW, et al. J Biol Chem. 2007;282: LDL = low-density lipoprotein; LDLR = low-density lipoprotein receptor LDLR/PCSK9 routed to lysosome Lysosomal degradation PCSK9 secretion Decreased LDLR surface concentration 3

4 Regulation of PCSK9 is Dynamic 1. Horton JD, et al. J Lipid Res. 2009;50:S172-S Lopez D. Biochem Biophys Acta. 2008;1781: Abifadel M, et al. Hum Mutat. 2009;30:supplementary information. 4. Abifadel M, et al. In: Toth PP. The Year in Lipid Disorders. Vol. 2. Oxford, UK: Atlas Medical Publishing Ltd. 2010:3-23. PCSK9 is produced primarily by the liver, kidney, and intestine 1 Dietary and cellular cholesterol 4 Long-term fasting 1 Bile acids 3,4 Plasma PCSK9 Downregulates PCSK9 Upregulates PCSK9 Cholesterol depletion 2,3 Cholestyramine 2 Sterol regulatory element- binding protein 2 1,3,4 Statins 3,4 4

5 Genetic Variants of PCSK9 Demonstrate its Importance in Regulating LDL Levels PCSK9 Gain of Function = Less LDLRs 1 PCSK9 Loss of Function = More LDLRs 1 1. Steinberg D, et al. PNAS. 2009;106: Cohen JC, et al. N Engl J Med. 2006;354: Benn M, et al. J Am Coll Cardiol. 2010;55: Mutations in the human PCSK9 gene that lead to a loss of PCSK9 function are found in 1% to 3% of the representative populations 2,3 Lysosomal degradation of LDLR Gain-of-function PCSK9 Loss-of-function PCSK9 Recycling of LDLR

6 PCSK9 GOF Mutations

7 Clinical Outcomes Associated With Genetic Mutations for Gain of PCSK9 Function FH-associated physical abnormalities 1 PCSK9 Function 1 1. Abifadel M, et al. In: Toth PP. The Year in Lipid Disorders. Vol. 2. Oxford, UK: Atlas Medical Publishing Ltd. 2010:

8 Case Reports Highlight Hypercholesterolemia Associated With PCSK9 GOF Mutations 1. Abifadel M, et al. Nat Genet. 2003;34: Abifadel M, et al. In: Toth PP. The Year in Lipid Disorders. Vol. 2. Oxford, UK: Atlas Medical Publishing Ltd. 2010: Abifadel M, et al. Hum Mutat. 2009;30: Durrington P. Lancet. 2003;362: F216L mutation 1,2 French proband Age: 49 years TC: 441 mg/dL LDL-C: 356 mg/dL R218S mutation 3 TC: 402 mg/dL LDL-C: 293 mg/dL French proband presented with tendinous xanthoma and arcus corneae Age: 45 years Tendon xanthoma 4 TC = total cholesterol Reprinted from The Lancet, Vol. 362, Durrington P, Copyright 2003, with permission from Elsevier. 8

9 GOF Mutations Are Associated With Increased ApoB-Containing Lipoproteins in Humans –PCSK9 S127R subjects had a 3-fold increase in apoB-100 vs normal controls, with a 5-fold increase in LDL Increases in TC concentration of LDL were also observed Adapted from Ouguerram K, et al. Arterioscler Thromb Vasc Biol. 2004;24: Subject Lipoprotein Composition (mg/dL) LDL ‡ Subject GenotypeTCTGApoB S1 PCSK9 S127R S2 PCSK9 S127R FH* subjects SD Controls SD *Similar trends for increases in TC concentration and apoB-100 were seen in VLDL and IDL but not HDL 9 IDL = intermediate-density lipoprotein; VLDL = very-low-density lipoprotein; HDL = high-density lipoprotein; S1 = subject 1; S2 = subject 2; SD = standard deviation *FH subjects carrying heterozygous LDL-R mutation.

10 PCSK9 GOF Mutations Associated With FH* 1 1. Lopez D. Biochem Biophys Acta. 2008;1781: Horton JD, et al. J Lipid Res. 2009;50: S172-S Abifadel M, et al. Nat Genet. 2003;34: Abifadel M, et al. Hum Mutat. 2009;30: Cunningham D, et al. Nat Struct Mol Biol. 2007;14: PCSK9 Genotype Mutation Type Biochemical Phenotype Clinical/Biochemical Phenotype S127RMissense 5x higher affinity for LDLR; decreased LDLR expression and activity; may interfere with trafficking of LDLR to the cell surface 1,2 Cholesterol levels in 90th percentile; tendon xanthomas 3 D129GMissense Leads to decreased LDLR expression and activity 1 Elevated LDL-C 1 R218SMissense Normal processing and secretion but loss of PCSK9 enzymatic activity 1 Tendon xanthomas, arcus corneae 4 D374YMissense 10 ‒ 25x higher affinity for LDLR; decreased LDLR recycling and increased degradation 1,5 Tendon xanthomas 4 Please refer to Lopez et al (2008) and Abifadel et al (2009) for comprehensive lists of PCSK9 mutations and variants. *Autosomal Dominant Hypercholesterolemia form of FH 10

11 PCSK9 LOF Mutations

12 Clinical Outcomes Associated With Genetic Mutations for Loss of PCSK9 Function 1. Abifadel M, et al. Hum Mutat. 2009;30: Abifadel M, et al. Hum Mutat. 2009;30:supplementary information. 3. Abifadel M, et al. In: Toth PP. The Year in Lipid Disorders. Vol. 2. Oxford, UK: Atlas Medical Publishing Ltd. 2010: Benn M, et al. J Am Coll Cardiol. 2010;55:2833:2842. Reduced plasma levels of TC and LDL-C 1,2, 3,4 PCSK9 Function 12

13 PCSK9 LOF Mutations Are Associated With Decreased Plasma LDL-C Concentrations 81% of PCSK9 Y142X and PCSK9 C679X subjects had mean plasma LDL-C below 50th percentile Distribution of Plasma LDL-C in Black Subjects (mg/dL) Distribution of Plasma LDL-C in White Subjects (mg/dL) Moderate mean plasma LDL-C-lowering effect in PCSK9 R46L allele carriers No Nonsense Mutation (N = 3,278)  50th Percentile Frequency (%) PCSK9 Y142X or PCSK9 C679X (N = 85)  50th Percentile No PCSK9 R46L Allele (N = 9,223)  50th Percentile PCSK9 R46L Allele (N = 301)  50th Percentile Frequency (%) Adapted from Cohen JC, et al. New Engl J Med. 2006;354:

14 PCSK9 LOF Mutations and Variants Associated With Hypocholesterolemia 1. Lopez D. Biochem Biophys Acta. 2008;1781: Benn M, et al. J Am Coll Cardiol. 2010;55: Cunningham D, et al. Nat Struct Mol Biol. 2007;14: Mayne J, et al. Clin Chem. 2011;57: Abifadel M, et al. Hum Mutat. 2009;30: Zhao Z, et al. Am J Hum Genet. 2006;79: Abifadel M, et al. In: Toth PP. The Year in Lipid Disorders. Vol. 2. Oxford, UK: Atlas Medical Publishing Ltd. 2010:3-23. PCSK9 Genotype Mutation Type Biochemical PhenotypeClinical/Biochemical Phenotype R46LMissense Polymorphism No effect on processing or secretion 1 11% ‒ 16% reduction in LDL-C 2 G106RMissenseDefective protein that is not secreted 1 Reduced LDL-C 1 Y142XNonsenseDisrupted protein synthesis resulting in no detectable protein 3 40% reduction in LDL-C 1 Q152HMissenseDefective autocatalytic cleavage and secretion 4 48% decrease in LDL-C; 79% decrease in plasma PCSK9 4 L253FMissensePoorly cleaved and secreted 1 30% reduction in LDL-C 3,5 A443TMissense Polymorphism Normally cleaved and secreted; higher susceptibility to cleavage 1 Modest (2%) reduction in LDL-C 6 Q554EMissensePoorly cleaved and secreted 1 Reduced LDL-C 7 C679XNonsenseDisrupted protein folding; impaired protein secretion 1 40% reduction in LDL-C 1 Please refer to Lopez et al (2008) and Abifadel et al (2009) for comprehensive lists of PCSK9 mutations and variants. 14

15 PCSK9 LOF Compound Heterozygote With No Detectable Circulating PCSK9 Adapted from Zhao Z, et al. Am J Hum Genet. 2006;79: Paternal allele: PCSK9 ΔR97 (disrupted processing/secretion) LDL-C: 39 mg/dL Maternal allele: PCSK9 Y142X (disrupted synthesis) LDL-C: 49 mg/dL Compound heterozygote: No immunodetectable circulating PCSK9 Mutation prevented autocatalytic cleavage and secretion of PCSK9 LDL-C: 14 mg/dL PCSK9-Y142X PCSK9-  R97 LDL-C (mg/dL): Percentile 39 < 1 49 < < 1 30 < 1 37 < A B C 15

16 PCSK9 C679X -Associated Cholesterol Lowering in a Population With Low LDL-C –A total of 653 young black women from Zimbabwe, a population in which basal LDL-C is already low, were examined –C679X mutation occurred in 3.7% of subjects (24 out of 653) One homozygous PCSK9 C679X/C679X subject was identified PCSK9 C679X was associated with a 27% reduction in LDL-C (carriers [heterozygotes] versus noncarriers) Adapted from Hooper AJ, et al. Atherosclerosis. 2007;193: *Total deficiency in PCSK9; no adverse clinical sequelae were reported in this individual. † P < ǂ P < Normal C679C/C679C (CC) mean (SD) Homozygous* C679X/C679X (XX) Heterozygous C679C/C679X (CX) mean (SD) n Age (y)24 (5)2125 (5) Cholesterol (mmol/L)3.6 (0.7) (0.7) † Triglyceride (mmol/L)0.7 (0.3) (0.2) LDL-C (mmol/L)2.2 (0.7) (0.3) ǂ HDL-C (mmol/L)1.2 (0.4) (0.4) 16

17 Summary –Genetic variants resulting in changes in PCSK9 function provide evidence for the role of PCSK9 in regulating LDLR for cholesterol homeostasis 1 PCSK9 genetic mutations are associated with LDL variances 1. Abifadel M, et al. In: Toth PP. The Year in Lipid Disorders. Vol. 2. Oxford, UK: Atlas Medical Publishing Ltd. 2010: Horton JD, et al. J Lipid Res. 2009;50:S172-S Lakoski SG, et al. J Clin Endocrinol Metab. 2009;94: Abifadel M, et al. Hum Mutat. 2009;30: Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106: PCSK9 Gain of Function (GOF): 2-5 Less LDLRs More LDL-C PCSK9 Gain of Function (GOF): 2-5 Less LDLRs More LDL-C PCSK9 Loss of Function (LOF): 2,4 More LDLRs Less LDL-C PCSK9 Loss of Function (LOF): 2,4 More LDLRs Less LDL-C 17


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