title: Plasma proprotein convertase subtilisin kexin type 9 is a heritable trait of familial combined hyperlipidaemia.
abstract: The aim of the present study was to investigate the relationship between circulating PCSK9 (proprotein convertase subtilisin kexin type 9) and FCHL (familial combined hyperlipidaemia) and, when positive, to determine the strength of its heritability. Plasma PCSK9 levels were measured in FCHL patients (n=45), NL (normolipidaemic) relatives (n=139) and their spouses (n=72). In addition, 11 FCHL patients were treated with atorvastatin to study the response in PCSK9 levels. PCSK9 levels were higher in FCHL patients compared with NL relatives and spouses: 96.1 compared with 78.7 and 82.0 ng/ml (P=0.004 and P=0.002 respectively). PCSK9 was significantly associated with both TAG (triacylglycerol) and apolipoprotein B levels (P<0.001). The latter relationship was accounted for by LDL (low-density lipoprotein)-apolipoprotein B (r=0.31, P=0.02), not by VLDL (very-low-density lipoprotein)-apolipoprotein B (r=0.09, P=0.49) in a subgroup of subjects (n=59). Heritability calculations for PCSK9 using SOLAR and FCOR software yielded estimates of 67-84% respectively (P<0.0001). PCSK9 increased from 122 to 150 ng/ml in 11 FCHL patients treated with atorvastatin (40 mg) once daily for 8 weeks (P=0.018). In conclusion, plasma PCSK9 is a heritable trait associated with both FCHL diagnostic hallmarks. These results, combined with the significant rise in PCSK9 levels after statin therapy, warrant further studies in order to unravel the exact role of PCSK9 in the pathogenesis and treatment of this highly prevalent genetic dyslipidaemia.
authors.affiliation: Department of Internal Medicine, Division of General Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands. martijn.brouwers@maastrichtuniversity.nl
authors.forename: Martijn C G J
authors.initials: MC
authors.lastname: Brouwers
authors.forename: Marleen M J
authors.initials: MM
authors.lastname: van Greevenbroek
authors.forename: Jason S
authors.initials: JS
authors.lastname: Troutt
authors.forename: Angela
authors.initials: A
authors.lastname: Bonner Freeman
authors.forename: Ake
authors.initials: A
authors.lastname: Lu
authors.forename: Nicolaas C
authors.initials: NC
authors.lastname: Schaper
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Konrad
authors.forename: Coen D A
authors.initials: CD
authors.lastname: Stehouwer
mesh_terms: D000328:Adult; D000368:Aged; D001055:Apolipoproteins B / Q000378:metabolism; D000069059:Atorvastatin; D015992:Body Mass Index; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics*; D007333:Insulin Resistance; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011758:Pyrroles / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000097:blood* / Q000235:genetics*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000096:biosynthesis
chemical_list: D001055:Apolipoproteins B; D006538:Heptanoic Acids; D008079:Lipoproteins, VLDL; D011758:Pyrroles; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D000069059:Atorvastatin; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases