title: Elevated plasma PCSK9 level is equally detrimental for patients with nonfamilial hypercholesterolemia and heterozygous familial hypercholesterolemia, irrespective of low-density lipoprotein receptor defects.
abstract: OBJECTIVE
  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.affiliation: 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.
authors.forename: Gilles
authors.initials: G
authors.lastname: Lambert
authors.affiliation: Lipid Research Group, Heart Research Institute, Sydney, Australia; Centre for Vascular Research, University of New South Wales, Sydney, Australia.
authors.forename: Francine
authors.initials: F
authors.lastname: Petrides
authors.affiliation: Faculté de Médecine, Université de Nantes, UMR PhAN 1280, Nantes, France.
authors.forename: Mathias
authors.initials: M
authors.lastname: Chatelais
authors.affiliation: Lipidology Division of Internal Medicine, MRC Cape Heart Group, University of Cape Town Health Science Faculty, Cape Town, South Africa.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Blom
authors.affiliation: Lipid Research Group, Heart Research Institute, Sydney, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Choque
authors.affiliation: Lipid Research Group, Heart Research Institute, Sydney, Australia; Centre for Vascular Research, University of New South Wales, Sydney, Australia.
authors.forename: Fatiha
authors.initials: F
authors.lastname: Tabet
authors.affiliation: Lipid Research Group, Heart Research Institute, Sydney, Australia.
authors.forename: Gida
authors.initials: G
authors.lastname: Wong
authors.affiliation: Lipid Research Group, Heart Research Institute, Sydney, Australia; Centre for Vascular Research, University of New South Wales, Sydney, Australia.
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.affiliation: 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.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Hooper
authors.affiliation: 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.
authors.forename: John R
authors.initials: JR
authors.lastname: Burnett
authors.affiliation: Lipid Research Group, Heart Research Institute, Sydney, Australia; Centre for Vascular Research, University of New South Wales, Sydney, Australia.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Barter
authors.affiliation: Chemical Pathology Division of Clinical Laboratory Sciences, MRC Cape Heart Group, University of Cape Town Health Science Faculty, Cape Town, South Africa.
authors.forename: A David
authors.initials: AD
authors.lastname: Marais
mesh_terms: D000328:Adult; D005260:Female; D006579:Heterozygote; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood* / Q000235:genetics; D006938:Hyperlipoproteinemia Type II / Q000097:blood* / Q000235:genetics; D008297:Male; D009154:Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood*; D011973:Receptors, LDL / Q000235:genetics; D012697:Serine Endopeptidases / Q000097:blood*
chemical_list: D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: LDL-cholesterol; LDL receptor; PCSK9; familial hypercholesterolemia