Abstract
BackgroundPrevious studies have reported high plasma concentrations of both intestinal apolipoprotein (apo) B-48-containing lipoproteins and PCSK9 in subjects with familial hypercholesterolemia (FH). However, the extent to which LDL receptor deficiency and PCSK9 levels influence plasma apoB-48 concentrations in humans remains to be fully characterized. The objective of the study was to assess the independent association between FH, PCSK9 concentrations and plasma apoB-48 levels in a large cohort of genetically defined FH heterozygotes (HeFH) and homozygotes (HoFH).MethodsA total of 118 HeFH, 6 HoFH, and 117 controls were included in the study. Plasma PCSK9 and apoB-48 concentrations were measured in the fasting state.ResultsPlasma PCSK9 and apoB-48 levels were higher in FH subjects compared with controls (PCSK9: HoFH: 642.6 ± 246.9 vs. HeFH: 324.9 ± 119.8 vs. controls: 194.5 ± 65.9 ng/mL, P < 0.0001; apoB-48: HoFH: 14.71 ± 4.36 vs. HeFH: 6.55 ± 4.24 vs. controls: 3.03 ± 2.07 μg/mL; P < 0.0001). There were no correlations between apoB-48 and PCSK9 plasma levels in both controls (ρ = 0.06, P = 0.5) and HeFH subjects (ρ = 0.07, P = 0.4). Multiple linear regression analysis showed that the FH status was the only independent factor associated with apoB-48 levels, contributing to 28.7% of the variance (P < 0.0001).ConclusionsThese data indicate that the elevation in plasma apoB-48 levels associated with FH is independent of PCSK9 levels.Trial registrationNCT02225340.
Highlights
Previous studies have reported high plasma concentrations of both intestinal apolipoprotein B48-containing lipoproteins and proprotein convertase subtilisin/kexin type 9 (PCSK9) in subjects with familial hypercholesterolemia (FH)
Familial hypercholesterolemia (FH) is an autosomal codominant single-gene disorder caused by mutations in the LDL receptor (LDLR) gene, its ligand apolipoprotein B, or proprotein convertase subtilisin/kexin type 9 (PCSK9) that disrupt normal clearance of LDLs [1, 2]
The objective of the present study was to determine the independent association between FH, plasma PCSK9 levels and apoB-48 levels in a large cohort of HeFH, heterozygotes (HeFH) and homozygotes (HoFH) and healthy control subjects
Summary
Previous studies have reported high plasma concentrations of both intestinal apolipoprotein (apo) B48-containing lipoproteins and PCSK9 in subjects with familial hypercholesterolemia (FH). The objective of the study was to assess the independent association between FH, PCSK9 concentrations and plasma apoB-48 levels in a large cohort of genetically defined FH heterozygotes (HeFH) and homozygotes (HoFH). Homozygous (HoFH) or compound heterozygous patients have plasma LDL-C concentrations that are 6- to 8-folds higher than normal and usually manifest a CHD event before the age of 20 years [3]. Chylomicron remnants have been shown to impair normal endothelial function [10], to be chemically modified and to accumulate in the subendothelial space the same way than apoB-100-containing lipoproteins [7, 11]. There is accumulating evidence reporting that FH patients have increased fasting apoB-48 levels [13,14,15,16,17], but data on the underlying mechanisms in cause are mixed
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