Gilles Lambert1, Francine Petrides2, Mathias Chatelais3, Dirk J Blom4, Benjamin Choque5, Fatiha Tabet2, Gida Wong5, Kerry-Anne Rye2, Amanda J Hooper6, John R Burnett7, Philip J Barter2, A David Marais8. 1. Faculté de Médecine, Université de Nantes, UMR PhAN 1280, Nantes, France; Lipid Research Group, Heart Research Institute, Sydney, Australia. Electronic address: gilles.lambert@univ-nantes.fr. 2. Lipid Research Group, Heart Research Institute, Sydney, Australia; Centre for Vascular Research, University of New South Wales, Sydney, Australia. 3. Faculté de Médecine, Université de Nantes, UMR PhAN 1280, Nantes, France. 4. Lipidology Division of Internal Medicine, MRC Cape Heart Group, University of Cape Town Health Science Faculty, Cape Town, South Africa. 5. Lipid Research Group, Heart Research Institute, Sydney, Australia. 6. Royal Perth Hospital, Department of Clinical Biochemistry, PathWest Laboratory of Medicine WA, Perth, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia; School of Medicine and Pharmacology, University of Western Australia, Perth, Australia. 7. Royal Perth Hospital, Department of Clinical Biochemistry, PathWest Laboratory of Medicine WA, Perth, Australia; School of Medicine and Pharmacology, University of Western Australia, Perth, Australia. 8. Chemical Pathology Division of Clinical Laboratory Sciences, MRC Cape Heart Group, University of Cape Town Health Science Faculty, Cape Town, South Africa.
Abstract
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.
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.
Authors: Anke Loregger; Emma Claire Laura Cook; Jessica Kristin Nelson; Martina Moeton; Laura Jane Sharpe; Susanna Engberg; Madina Karimova; Gilles Lambert; Andrew John Brown; Noam Zelcer Journal: Mol Cell Biol Date: 2015-11-02 Impact factor: 4.272