Abstract
The extent of hypercholesterolemia varies considerably in patients with familial hypercholesterolemia (FH). We hypothesized that the variability of the FH phenotype might be partly explained by variation in proprotein convertase subtilisin kexin type 9 (PCSK9) activity. Individuals between 18 and 53 years of age who had been tested for a pathogenic LDLR or APOB mutation were eligible. Mutation carriers with a LDL-C level below the 75(th) percentile (called "FH low") were selected, as well as those with LDL-C above the 90(th) percentile (called "FH high"). Relatives who tested negative for the mutation were the "controls." PCSK9 plasma levels were assessed in 267 individuals who did not receive cholesterol-lowering treatment at the time of the study. Mean PCSK9 plasma levels (95% CI) were lower in the FH-low group compared with the FH-high group [152 (137-167) ng/ml vs. 186 (165-207) ng/ml, P = 0.010] and the control group [177 (164-190) ng/ml, P = 0.013]. Mean PCSK9 levels did not statistically differ between the FH-high and control groups (P = 0.50). Plasma PCSK9 levels are positively associated with LDL-C levels in FH patients and might contribute to the phenotypic severity in this disorder. Therefore, the results of pharmaceutical inhibition of PCSK9 in FH patients are eagerly awaited.
Highlights
The extent of hypercholesterolemia varies considerably in patients with familial hypercholesterolemia (FH)
A total of 421 individuals provided written informed consent to participate in the original study. Of these 421 individuals, 378 were included for the subanalysis of proprotein convertase subtilisin kexin type 9 (PCSK9) levels: 13 individuals without FH were excluded because they were older than 53 years, and for 30 individuals, we did not have spare plasma to measure PCSK9
low-density lipoprotein cholesterol (LDL-C) levels were comparable between the individuals from the FH-low and control groups, whereas levels were significantly higher in the FH-high group
Summary
The extent of hypercholesterolemia varies considerably in patients with familial hypercholesterolemia (FH). The identification of a mutation that underlies FH in a particular kindred enables genetic testing of family members for the presence of the same mutation and makes it possible to initiate effective medical management before the cardiovascular consequences of FH become clinically manifest [4] This notion has led to the implementation of a nationwide genetic cascade screening program for FH in the Netherlands, and since 1994, approximately 20,000 individuals with FH have been found and treated [6]. The reasons why some individuals with a confirmed FH genotype lack the hypercholesterolemia phenotype are largely unknown We hypothesized that such nonpenetrance of an FH mutation could, in part, be explained by variation in PCSK9 activity.
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