Abstract
Mutations in the genes coding for the LDL-receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are now known to cause familial hypercholesterolaemia (FH). However, molecularly diagnosed FH patients do not always exhibit a hypercholesterolaemic phenotype. The reasons are largely unknown.
The authors postulated that such non-penetrance of the FH mutation could, in part, be explained by the variation in PCSK9 activity. PCSK9 binds to the hepatic LDLR and thereby directs it towards degradation. Low activity of PCSK9 could lead to the increased presence of LDLR at the hepatic cell surface and, consequently, to the increased clearance of plasma LDL-cholesterol (LDL-C).
Individuals (n = 267) not on lipid-lowering medications were included. Those who had a pathogenic mutation were categorized based on their untreated LDL-C concentration. Those with an LDL-C below the age- and sex-specific 75th percentile were referred to as ‘FH low’; those with an LDL-C above the 90th percentile were referred to as ‘FH high’. First-degree relatives negative for the mutation were included as ‘controls’. The study subjects also underwent examination of carotid arteries with ultrasound to assess intima-media thickness (cIMT).
Individuals from the FH-low group had a significantly lower mean PCSK9 concentration (152 [137–167] µg/L) compared with untreated individuals from the FH-high group (186 [165–207] µg/L, P = 0.010) and controls (177 [164–190] µg/L, P = 0.013). Results were true after adjustment for age, gender, body mass index and systolic blood pressure. PCSK9 concentration was positively associated with cIMT after adjustment for the lipid profile and other traditional cardiovascular risk factors.
The study was an observational study so a causal relationship between low plasma PCSK9 concentration and lower LDL-C could not be proven. However, plasma PCSK9 concentration may contribute to phenotypic variation in individuals with FH. Studies of pharmaceutical inhibition of PCSK9 in FH patients are eagerly awaited.