Abstract 427: Plasma PCSK9 Levels Are Positively Correlated With LDL-Cholesterol Concentrations in Familial Hypercholesterolemia

Abstract

Autosomal dominant familial hypercholesterolemia (FH) is caused by mutations in the LDL receptor (LDLR), its ligand apoB or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. PCSK9 regulates LDL-C levels by binding to LDLR, thereby enhancing its intracellular degradation. Although PCSK9 levels have been shown to be elevated in FH subjects, the extent to which PCSK9 levels correlate with LDL-C concentrations in FH has not been examined. Therefore, the objective of the present study was to assess the relationship between PCSK9 and LDL-C levels in a large cohort of genetically defined French-Canadian (FC) FH subjects. A total of 292 FH heterozygotes (heFH) carrying one of the nine FC mutations in the LDLR gene were recruited. 226 subjects were carriers of a negative receptor (NR) mutation in the LDLR gene, while the other 66 were carriers of a defective (DR) LDLR gene mutation. 56 control subjects matched for gender and body mass index (BMI) were also recruited. Fasting blood samples were collected after a 6-week period without lipid lowering medication. PCSK9 levels were significantly higher in the heFH group than in the control group (317.9 ng/ml vs 203.3 ng/ml; P<0.001). In the heFH group, PCSK9 levels were positively and independently correlated with LDL-C concentrations and predicted 8.1% (P<0.001) of the variability in LDL-C levels. Age, the type of LDLR mutation (NR vs DR), and BMI were also significantly associated with the variability in LDL-C levels, predicting 13.6% (P<0.001), 3.9% (P<0.001), and 1.8% (P=0.02) of the LDL-C variance, respectively. Interestingly, PCSK9 levels were also positively correlated with lipoprotein(a) levels in heFH (r=0.20; P<0.001). These results indicate that PCSK9 levels are positively correlated with LDL-C and lipoprotein(a) concentrations in heFH.