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.

Effects of lipoprotein apheresis on PCSK9 levels

“…The reason for these differences remains unclear; although it is likely due to the different assays and standards used for quantitation of PCSK9 or the different matrix used. Generally, patients with FH [2,22] or familial combined hyperlipidemia [21] clearly showed elevated PCSK9 levels. Statin therapy increases PCSK9 levels [2,20,21,23] along with ezetimibe [23] and fibrates [24].…”

“…Generally, patients with FH [2,22] or familial combined hyperlipidemia [21] clearly showed elevated PCSK9 levels. Statin therapy increases PCSK9 levels [2,20,21,23] along with ezetimibe [23] and fibrates [24]. In another investigation by Novartis in 31 statin-treated patients mean serum PCSK9 concentrations were 215 ng/mL (sd 46 ng/mL, range 145e328 ng/ mL).…”

“…Though in other papers higher serum [2,3] or plasma [19,21] PCSK9 concentrations in healthy persons were given. In a study performed by Novartis (performing the assay which was also used in this study) in 65 healthy volunteers (HVs) the mean serum PCSK9 levels were 179 ng/mL (sd 45 ng/ mL, range 90e329 ng/mL).…”

Circulating PCSK9 is a strong determinant of plasma triacylglycerols and total cholesterol in homozygous carriers of apolipoprotein ε2

“…Carriers of the ε2/ε2 genotype underwent the same study protocol as recently described for patients with FCHL (familial combined hyperlipidaemia) and their spouses [14,15]. The latter group was included as a normal control population.…”

“…Plasma total cholesterol, HDL (high-density lipoprotein)-cholesterol, triacylglycerols, AST (aspartate aminotransferase), ALT (alanine aminotransferase), glucose, insulin, apolipoprotein B and PCSK9 levels were measured as described previously [14,16]. In nine ε2/ε2 patients and all of the FCHL patients, we additionally determined cholesterol, triacylglycerols and apolipoprotein B levels in the VLDL and LDL subfractions isolated by ultracentrifugation; apolipoprotein B levels in the VLDL subfraction were measured by gel electrophoresis, and apolipoprotein B levels in the LDL subfraction were determined similarly as in total plasma [14].…”