title: Elevated PCSK9 levels in untreated patients with heterozygous or homozygous familial hypercholesterolemia and the response to high-dose statin therapy.
abstract: BACKGROUND
  Proprotein convertase subtilisin kexin type 9 (PCSK9) is an enzyme that impairs low-density lipoprotein cholesterol (LDL-C) clearance from the plasma by promoting LDL receptor degradation. Patients with familial hypercholesterolemia (FH) have reduced or absent LDL receptors and should therefore have elevated PCSK9 levels.
  
  
  RESULTS
  Fasting lipograms and PCSK9 levels were measured 51 homozygous FH (HoFH), 20 heterozygous FH (HeFH), and 20 normocholesterolemic control subjects. Levels were repeated following high-dose statin therapy. LDL-C levels were significantly higher in untreated HoFH (13.4±0.7 mmol/L) and HeFH patients (7.0±0.2 mmol/L) compared with controls (2.6±0.1 mmol/L) (P<0.01). Statin therapy decreased LDL-C levels from 13.4±0.7 to 11.1±0.7 mmol/L in HoFH and from 7.0±0.2 to 3.6±0.2 mmol/L in HeFH patients (P<0.01). PCSK9 levels were higher in untreated HoFH (279±27 ng/mL) and HeFH (202±14 ng/mL) than in controls (132±10 ng/mL) (both P<0.01). High-dose statin therapy increased PCSK9 levels from 279±27 to 338±50 ng/mL in HoFH, and significantly so in the HeFH patients from 202±14 to 278±20 ng/mL (P<0.01). Linear regression analysis showed a correlation between PCSK9 and LDL-C (r=0.6769; P<0.0001); however, this was eliminated following statin therapy (r=0.2972; P=0.0625).
  
  
  CONCLUSIONS
  PCSK9 levels are elevated in untreated FH patients, particularly in those with HoFH. High-dose statin therapy further increases PCSK9 levels. PCSK9 inhibitors might be a beneficial therapy for FH patients, even in those with HoFH.
authors.affiliation: Carbohydrate and Lipid Metabolism Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa. frederick.raal@wits.ac.za
authors.forename: Frederick
authors.initials: F
authors.lastname: Raal
authors.forename: Vanessa
authors.initials: V
authors.lastname: Panz
authors.forename: Andrew
authors.initials: A
authors.lastname: Immelman
authors.forename: Gillian
authors.initials: G
authors.lastname: Pilcher
mesh_terms: D000328:Adult; D059168:Carotid Intima-Media Thickness; D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood* / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006938:Hyperlipoproteinemia Type II / Q000097:blood* / Q000188:drug therapy; D016014:Linear Models; D008297:Male; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood* / Q000187:drug effects; D011973:Receptors, LDL / Q000235:genetics*; D012697:Serine Endopeptidases / Q000097:blood* / Q000187:drug effects; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; D014280:Triglycerides; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
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