Plasma proprotein convertase subtilisin kexin type 9 is a heritable trait of familial combined hyperlipidemia

Objective: To study the relation between circulating proprotein convertase subtilisin kexin type 9 (PCSK9) and familial combined hyperlipidemia (FCHL) and - when positive - to determine the strength of its heritability. Methods: Plasma PCSK9 levels were measured in FCHL patients (n=45), normolipidemic relatives (n=139) and their spouses (n=72). In addition, eleven FCHL patients were treated with atorvastatin to study the response in PCSK9 levels. Results: PCSK9 levels were higher in FCHL patients versus normolipidemic relatives and spouses: 96.1 versus 78.7 and 82.0 ng/mL, p=0.004 and p=0.002, respectively. PCSK9 was significantly associated with both triglycerides and apolipoprotein B levels (p<0.001). The latter relation was accounted for by LDL-apoliprotein B (r=0.31, p=0.02), not by VLDL-apolipoprotein B (r=0.09, p=0.49) in a subgroup of subjects (n=59). Heritability calculations for PCSK9 using SOLAR and FCOR yielded estimates of 67-84%, respectively (p<0.0001). PCSK9 increased from 122 to 150 ng/mL in eleven FCHL patients treated with atorvastatin 40mg once daily for 8 weeks (p=0.018). Conclusions: 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 to unravel the exact role of PCSK9 in the pathogenesis and treatment of this highly prevalent genetic dyslipidemia.