Key result
The PCSK9 p.R46L loss-of-function variant and p.D374Y gain-of-function mutation were both associated with significantly lower plasma PCSK9 concentrations compared to controls.
Why the study?
Do specific PCSK9 genetic variants (p.R46L and p.D374Y) affect plasma PCSK9 concentrations in healthy individuals and FH patients?
Cross-Sectional (n=490)
Do specific PCSK9 genetic variants (p.R46L and p.D374Y) affect plasma PCSK9 concentrations in healthy individuals and FH patients?
Both loss-of-function (p.R46L) and gain-of-function (p.D374Y) PCSK9 variants are associated with lower circulating PCSK9 concentrations, suggesting low plasma PCSK9 is not a useful screening tool for novel mutations in treated FH patients.
Plasma PCSK9 measurement should not screen for variants in treated FH; leaves open its biomarker utility pending prospective validation.
BACKGROUND: We measured plasma PCSK9 concentrations in healthy men with a PCSK9 (proprotein convertase subtilisin/kexin type 9) loss-of-function variant (p.R46L), in statin-treated patients with a clinical diagnosis of familial hypercholesterolemia (FH) and carrying a PCSK9 gain-of-function mutation (p.D374Y), and in statin-treated patients with FH due to different genetic causes. METHODS: PCSK9 was measured with a previously described ELISA. RESULTS: In 81 healthy middle-aged Caucasian men, the PCSK9 concentration was significantly associated with the concentrations of total cholesterol (r = 0.42; P < 0.0001), LDL cholesterol (r = 0.34; P = 0.01), and triglycerides (r = 0.25; P = 0.02). In p.R46L carriers, mean (SD) concentrations of PCSK9 were 15% lower than in RR individuals [65.5 microg/L (21.6 microg/L) vs 77.5 microg/L (18.2 microg/L); P = 0.03]. In patients with the p.D374Y variant (n = 7), the mean PCSK9 concentration was significantly lower than in the combined group of patients with an LDLR (low density lipoprotein receptor) mutation (n = 25), an APOB [apolipoprotein B (including Ag(x) antigen)] variant encoding p.R3527Q (n = 6), or no detectable mutation (n = 14) [96.4 microg/L (42.5 microg/L) vs 151.6 microg/L (69.6 microg/L); P = 0.02]. Two of the 14 patients with no mutation had PCSK9 concentrations below the mean for p.D374Y carriers; sequencing of the PCSK9 gene and promoter revealed no mutations. Among 409 FH patients, we identified 6 carriers of the promoter variant -287G>A (1.5%), a frequency similar to that (1.0%) previously reported for 2772 healthy men in the UK. In neither group was the -287G>A variant associated with differences in lipid traits. CONCLUSIONS: The loss-of-function p.R46L variant is associated with the expected lower concentrations of circulating PCSK9; the gain-of-function p.D374Y mutation is also associated with lower concentrations, presumably because of the higher affinity of this variant for the LDL receptor and its more rapid clearance. In treated FH patients, a low plasma PCSK9 concentration does not appear to be a useful screening tool for identifying novel PCSK9 mutations.
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Humphries et al. (2009) conducted a cross-sectional in Familial Hypercholesterolemia (n=490). PCSK9 p.R46L and p.D374Y variants vs. Individuals without these specific variants was evaluated on Plasma PCSK9 concentration (microg/L) (p=0.03). The PCSK9 p.R46L loss-of-function variant and p.D374Y gain-of-function mutation were both associated with significantly lower plasma PCSK9 concentrations compared to controls.
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