Elevated Plasma PCSK9 Level Is Equally Detrimental for Patients With Nonfamilial Hypercholesterolemia and Heterozygous Familial Hypercholesterolemia, Irrespective of Low-Density Lipoprotein Receptor Defects

被引：47

作者：

Lambert, Gilles ^{[1
,2
]}

Petrides, Francine ^{[2
,3
]}

Chatelais, Mathias ^{[1
]}

Blom, Dirk J. ^{[4
]}

Choque, Benjamin ^{[2
]}

Tabet, Fatiha ^{[2
,3
]}

Wong, Gida ^{[2
]}

Rye, Kerry-Anne ^{[2
,3
]}

Hooper, Amanda J. ^{[5
,6
,7
]}

Burnett, John R. ^{[5
,7
]}

Barter, Philip J. ^{[2
,3
]}

Marais, A. David ^{[8
]}

机构：

[1] Univ Nantes, Fac Med, UMR PhAN 1280, Nantes, France

[2] Heart Res Inst, Lipid Res Grp, Sydney, NSW, Australia

[3] Univ New S Wales, Ctr Vasc Res, Sydney, NSW, Australia

[4] Univ Cape Town, Fac Hlth Sci, MRC Cape Heart Grp, Lipidol Div Internal Med, ZA-7925 Cape Town, South Africa

[5] Royal Perth Hosp, Dept Clin Biochem, PathWest Lab Med WA, Perth, WA 6001, Australia

[6] Univ Western Australia, Sch Pathol & Lab Med, Perth, WA 6009, Australia

[7] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia

[8] Univ Cape Town, Fac Hlth Sci, MRC Cape Heart Grp, Chem Pathol Div Clin Lab Sci, ZA-7925 Cape Town, South Africa

来源：

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY | 2014年 / 63卷 / 22期

基金：

英国医学研究理事会;

关键词：

familial hypercholesterolemia; LDL-cholesterol; LDL receptor; PCSK9; SUBTILISIN/KEXIN TYPE 9; MONOCLONAL-ANTIBODY; LDL RECEPTORS; AMG; 145; APO-B; CHOLESTEROL; MUTATIONS; HYPOBETALIPOPROTEINEMIA; DEGRADATION; THERAPY;

D O I：

10.1016/j.jacc.2014.02.538

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objectives Do elevated proprotein convertase subtilisin/kexin type 9 (PCSK9) levels constitute an even greater risk for patients who already have reduced low-density lipoprotein receptor (LDLR) levels, such as those with heterozygous familial hypercholesterolemia (HeFH)? Background As a circulating inhibitor of LDLR, PCSK9 is an attractive target for lowering LDL-cholesterol (LDL-C) levels. Methods Circulating PCSK9 levels were measured by enzyme-linked immunosorbent assay in nontreated patients with HeFH carrying a D206E (n = 237), V408M (n = 117), or D154N (n = 38) LDLR missense mutation and in normolipidemic controls (n 152). Skin fibroblasts and lymphocytes were isolated from a subset of patients and grown in 0.5% serum and mevastatin with increasing amounts of recombinant PCSK9. LDLR abundance at the cell surface was determined by flow cytometry. Results PCSK9 reduced LDLR expression in a dose-dependent manner in control and FH fibroblasts to similar extents, by up to 77 +/- 8% and 82 +/- 7%, respectively. Likewise, PCSK9 reduced LDLR abundance by 39 +/- 8% in nonfamilial hypercholesterolemia (non-FH) and by 45 +/- 10% in HeFH lymphocytes, irrespective of their LDLR mutation status. We found positive correlations of the same magnitude between PCSK9 and LDL-C levels in controls (beta 0.22; p = 0.0003), D206E (beta 0.20; p = 0.0002), V408M (beta 0.24; p = 0.0002), and D154N (beta 0.25; p = 0.048) patients with HeFH. The strengths of these associations were all similar. Conclusions Elevated PCSK9 levels are equally detrimental for patients with HeFH or non-FH: a 100-ng/ml increase in PCSK9 will lead to an increase in LDL-C of 0.20 to 0.25 mmol/l in controls and HeFH alike, irrespective of their LDLR mutation. This explains why patients with non-FH or HeFH respond equally well to monoclonal antibodies targeting PCSK9. (C) 2014 by the American College of Cardiology Foundation

引用

页码：2365 / 2373

页数：9

共 30 条

[1] Non-denaturing polyacrylamide gradient gel electrophoresis for the diagnosis of dysbetalipoproteinemia [J].

Blom, DJ ;

Byrnes, P ;

Jones, S ;

Marais, AD .

JOURNAL OF LIPID RESEARCH, 2003, 44 (01) :212-217

[2] Missense mutations in APOB within the βα1 domain of human APOB-100 result in impaired secretion of ApoB and ApoB-containing lipoproteins in familial hypobetalipoproteinemia [J].

Burnett, John R. ;

Zhong, Shumei ;

Jiang, Zhenghui G. ;

Hooper, Amanda J. ;

Fisher, Eric A. ;

McLeod, Roger S. ;

Zhao, Yang ;

Barrett, P. Hugh R. ;

Hegele, Robert A. ;

van Bockxmeer, Frank M. ;

Zhang, Hongyu ;

Vance, Dennis E. ;

McKnight, C. James ;

Yao, Zemin .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (33) :24270-24283

[3] A novel nontruncating APOB gene mutation, R463W, causes familial hypobetalipoproteinemia [J].

Burnett, JR ;

Shan, J ;

Miskie, BA ;

Whitfield, AJ ;

Yuan, J ;

Tran, K ;

McKnight, CJ ;

Hegele, RA ;

Yao, ZM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (15) :13442-13452

[4] Serum levels of proprotein convertase subtilisin/kexin type 9 in subjects with familial hypercholesterolemia indicate that proprotein convertase subtilisin/kexin type 9 is cleared from plasma by low-density lipoprotein receptor-independent pathways [J].

Cameron, Jamie ;

Bogsrud, Martin P. ;

Tveten, Kristian ;

Strom, Thea Bismo ;

Holven, Kirsten ;

Berge, Knut Erik ;

Leren, Trond P. .

TRANSLATIONAL RESEARCH, 2012, 160 (02) :125-130

[5] Effects of AMG 145 on Low-Density Lipoprotein Cholesterol Levels Results From 2 Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Phase 1 Studies in Healthy Volunteers and Hypercholesterolemic Subjects on Statins [J].

Dias, Clapton S. ;

Shaywitz, Adam J. ;

Wasserman, Scott M. ;

Smith, Brian P. ;

Gao, Bing ;

Stolman, Dina S. ;

Crispino, Caroline P. ;

Smirnakis, Karen V. ;

Emery, Maurice G. ;

Colbert, Alexander ;

Gibbs, John P. ;

Retter, Marc W. ;

Cooke, Blaire P. ;

Uy, Stephen T. ;

Matson, Mark ;

Stein, Evan A. .

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2012, 60 (19) :1888-1898

[6] Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters [J].

Dong, Bin ;

Wu, Minhao ;

Li, Hai ;

Kraemer, Fredric B. ;

Adeli, Khosrow ;

Seidah, Nabil G. ;

Park, Sahng Wook ;

Liu, Jingwen .

JOURNAL OF LIPID RESEARCH, 2010, 51 (06) :1486-1495

[7] Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia [J].

Dubuc, G ;

Chamberland, A ;

Wassef, H ;

Davignon, J ;

Seidah, NG ;

Bernier, L ;

Prat, A .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2004, 24 (08) :1454-1459

[8]

Firth JC, 2008, SAMJ S AFR MED J, V98, P99

[9] Low-density lipoprotein receptor structure and folding [J].

Gent, J ;

Braakman, I .

CELLULAR AND MOLECULAR LIFE SCIENCES, 2004, 61 (19-20) :2461-2470

[10] Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa [J].

Homer, Vivienne M. ;

Marais, A. David ;

Charlton, Francesca ;

Laurie, Andrew D. ;

Hurndell, Nicola ;

Scott, Russel ;

Mangili, Fabien ;

Sullivan, David R. ;

Barter, Philip J. ;

Rye, Kerry-Anne ;

George, Peter M. ;

Lamberte, Gilles .

ATHEROSCLEROSIS, 2008, 196 (02) :659-666

← 1 2 3 →