title: Circulating PCSK9 is a strong determinant of plasma triacylglycerols and total cholesterol in homozygous carriers of apolipoprotein ε2.
abstract: Homozygous carriers of the apolipoprotein ε2 allele are at risk of type III hyperlipidaemia, but do not necessarily develop this lipid disorder. In the present study, we have investigated the role of circulating PCSK9 (pro-protein convertase subtilisin kexin type 9), an important regulator of LDL (low-density lipoprotein) receptor expression, in the development of this hyperlipidaemic phenotype. In an observational study, plasma PCSK9 was measured in homozygous carriers of apolipoprotein ε2 (ε2/ε2; n=12), normal controls (n=72) and hypertriglyceridaemic patients with FCHL (familial combined hyperlipidaemia; n=38), who served as a hyperlipidaemic reference group. Cholesterol, triacylglycerols (triglycerides) and apolipoprotein B content in VLDL (very-low-density lipoprotein) and LDL particles was determined by ultracentrifugation in ε2/ε2 and FCHL patients. Median circulating PCSK9 levels did not differ between ε2/ε2 carriers compared with controls and hypertriglyceridaemic FCHL patients (84.5 compared with 82.0 and 84.9 ng/ml; P=0.2 and 0.6 respectively). Circulating PCSK9 was associated with total cholesterol and triacylglycerols levels in ε2/ε2 carriers (P<0.05). These associations were stronger in ε2/ε2 carriers when compared with controls (P values for interaction=0.01 and 0.02 respectively). A direct comparison with FCHL patients demonstrated a similar discrepancy for the association with plasma triacylglycerols and also VLDL-apolipoprotein B, cholesterol and triacylglycerols (P value for interaction=0.01, 0.01, 0.03 and 0.03 respectively). Plasma PCSK9 is associated with type III hyperlipidaemia. Its strong relationship with plasma triacylglycerols and total cholesterol distinguishes ε2/ε2 carriers from controls and another type of dyslipidaemia, which provides valuable information regarding the pathogenesis of this complex dyslipidaemia. Furthermore, these results suggest that patients with type III hyperlipidaemia may benefit from PCSK9-antagonizing therapy.
authors.affiliation: *Department of Internal Medicine, Divisions of General Internal Medicine and Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maasctricht, The Netherlands.
authors.forename: Martijn C G J
authors.initials: MC
authors.lastname: Brouwers
authors.affiliation: *Department of Internal Medicine, Divisions of General Internal Medicine and Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maasctricht, The Netherlands.
authors.forename: Marleen M J
authors.initials: MM
authors.lastname: van Greevenbroek
authors.affiliation: †Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IA 46285, U.S.A.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Konrad
authors.affiliation: †Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IA 46285, U.S.A.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Troutt
authors.affiliation: *Department of Internal Medicine, Divisions of General Internal Medicine and Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maasctricht, The Netherlands.
authors.forename: Nicolaas C
authors.initials: NC
authors.lastname: Schaper
authors.affiliation: *Department of Internal Medicine, Divisions of General Internal Medicine and Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maasctricht, The Netherlands.
authors.forename: Coen D A
authors.initials: CD
authors.lastname: Stehouwer
mesh_terms: D000328:Adult; D053329:Apolipoprotein E2 / Q000235:genetics*; D016022:Case-Control Studies; D002784:Cholesterol / Q000097:blood*; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood*; D012697:Serine Endopeptidases / Q000097:blood*; D014280:Triglycerides / Q000097:blood*
chemical_list: D053329:Apolipoprotein E2; D014280:Triglycerides; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases