The contribution of PCSK9 levels to the phenotypic severity of familial hypercholesterolemia is independent of LDL receptor genotype.

Unlabelled: Autosomal dominant familial hypercholesterolemia (FH) is caused by genetic mutations in the LDL receptor (LDLR), its ligand apolipoprotein (apo) B, or proprotein convertase subtilisin/kexin type 9 (PCSK9). Although PCSK9 levels have been shown to correlate with LDL-cholesterol (LDL-C) levels in FH, the extent to which PCSK9 levels modulate the phenotypic severity of this disease independent of LDLR genotype remains to be clarified.

Objective: To assess the relationship between LDLR genotype and the plasma levels of PCSK9, LDL-C, and lipoprotein (a) (Lp(a)) in a large cohort of genetically defined FH heterozygotes (HeFH).

Methods: A total of 292 HeFH carrying one of the nine French-Canadian mutations in the LDLR gene were recruited. The cohort included 226 carriers of a negative-receptor (NR) mutation and 66 carriers of a defective-receptor (DR) LDLR gene mutation. Fifty-six control subjects, who were matched with the HeFH subjects based on gender and body mass index, were also recruited.

Results: PCSK9 levels were higher in the HeFH group than in the control group (317.9±107.1 ng/mL vs. 203.3±59.8 ng/mL; P<0.0001). The strength of the association between PCSK9 and LDL-C levels was similar among controls (r=0.37; P=0.005) and HeFH (r=0.31; P<0.0001). Furthermore, a multiple linear regression analysis revealed that the positive correlation between PCSK9 and LDL-C levels remained significant after adjusting for LDLR genotype in the HeFH group.

Conclusion: These results suggested that the contribution of PCSK9 levels to the phenotypic severity in FH heterozygotes is independent of LDLR genotype.