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Published on: November 17, 2018
PCSK9 R46L, lower LDL, and cardiovascular disease risk in familial hypercholesterolemia: a cross-sectional cohort
Yascara Grisel Luna Saavedra1, Robert Dufour1, Jean Davignon1
1From the Department of Medicine, Division of Experimental Medicine, Institut de Recherches Cliniques de Montréal (IRCM), Nutrition, Metabolism and Atherosclerosis Clinic, Montréal, Canada (Y.G.L.S., A.B.); Medicine Department, McGill University, Montréal, Canada (Y.G.L.S., R.D., J.D., A.B.); and Nutrition Department, University of Montreal, Montréal, Canada (R.D., J.D.).
Insights
The PCSK9 R46L variant in familial hypercholesterolemia (FH) patients significantly lowers LDL cholesterol and cardiovascular risk. This suggests PCSK9 inhibition could be a valuable therapeutic strategy for FH.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Biochemistry
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein receptor (LDLR) levels.
- Familial hypercholesterolemia (FH) is a genetic disorder characterized by high LDL cholesterol and premature cardiovascular disease.
- The PCSK9 R46L loss-of-function variant is a naturally occurring mutation with potential implications for lipid metabolism and cardiovascular risk.
Purpose of the Study:
- To investigate the association of the PCSK9 R46L loss-of-function variant with lipid profiles, xanthoma frequency, and cardiovascular risk in FH patients.
- To determine the clinical significance of this variant in a well-characterized cohort of FH individuals.
Main Methods:
- Cross-sectional cohort study of 582 FH patients with confirmed LDLR mutations.
- Genotyping to identify carriers of the PCSK9 R46L missense variant.
- Statistical analysis to compare lipid levels, xanthoma occurrence, and cardiovascular events between carriers and non-carriers.
Main Results:
- The R46L variant was present in 3% of the FH cohort.
- R46L carriers exhibited significantly lower LDL cholesterol (-11%), total cholesterol (-9%), apolipoprotein B (-10%), and non-HDL cholesterol (-12%) compared to non-carriers.
- Carriers had fewer xanthomata and a significantly reduced risk of cardiovascular events (86% lower odds).
Conclusions:
- The PCSK9 R46L variant attenuates the impact of LDLR mutations on lipid levels in FH patients.
- Carriage of the R46L variant is strongly associated with a substantially lower risk of cardiovascular disease.
- Targeting PCSK9 with novel therapies may offer a promising strategy to reduce cardiovascular risk in FH patients.
Objective:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a downregulator of the low density lipoprotein receptor. The aims of this cross-sectional cohort-study were to examine whether the PCSK9 R46L loss of function variant found in a cohort of familial hypercholesterolemia (FH) patients was associated with lower low density lipoprotein cholesterol, lower frequency of xanthomata, and cardiovascular risk.
Approach And Results:
We studied FH patients attending the IRCM (Institut de Recherches Cliniques de Montréal) Lipid Clinic and whose DNA genotyping was positive for a low density lipoprotein receptor mutation. The presence of the PCSK9 loss of function R46L missense variant was determined among a cohort of 582 FH patients by genotyping. Frequency of the R46L variant was 3%. Carriers had significantly lower low density lipoprotein cholesterol (11%, P=0.002), total cholesterol (9%, P=0.007), apolipoprotein B (10%, P=0.037), and non-high density lipoprotein (12%, P<0.001) concentrations compared with noncarriers. Furthermore, R46L carriers showed a decreased average number of xanthoma per individual compared with noncarriers (0.33 and 0.76, respectively; P<0.001). Importantly, the R46L genetic variant was associated with a significant 86% lower odd of presenting a cardiovascular event (odds ratio, 0.14; 95% confidence interval, 0.032-0.63; P=0.001).
Conclusions:
Even though the R46L variant was present in 3% of our FH population, carriers of this polymorphism showed attenuated effect of the low density lipoprotein receptor mutation on parameters, such as low density lipoprotein cholesterol, apolipoprotein B, total cholesterol, and non-high density lipoprotein. More importantly, this mutation is associated with a significant lower risk of cardiovascular disease compared with noncarriers. It is therefore likely that targeting PCSK9 in FH patients with novel anti-PCSK9 therapies will be useful in reducing cardiovascular risk in affected subjects.
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