Abstract 15805: PCSK9 R46L, Lower LDL and Cardiovascular Disease Risk in Familial Hypercholesterolemia
Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a down-regulator of the low density lipoprotein receptor (LDLR). Familial hypercholesterolemia (FH) is a autosomal monogenic disease associated with high LDL-C concentration and cardiovascular risk.
Hypothesis: This study aimed to examine whether the PCSK9 R46L loss of function mutation found in a cohort of FH patients will be associated with lower LDL-C and cardiovascular risk.
Methods: We studied FH patients attending the IRCM Lipid Clinic and whose DNA genotyping was positive for LDLR mutations. The presence of the PCSK9 loss of function R46L missense mutation was determined among a cohort of 582 FH patients by sequencing.
Results: Frequency of the R46L variant was 3%. Comparison of their lipid profile showed that carriers had significantly reduced LDL-C (11%, p<0.001), TC (9%, p<0.01), ApoB (10%, p<0.01) and non-HDL (12%, p<0.001) concentrations compared to non-carriers. The analysis of physical xanthomata among both groups, showed a decreased average number of xanthoma per individual in R46L carriers (0.33 and 0.76 respectively, p<0.001). Importantly, the R46L mutation was associated with a significant 66% (p=0.05) lower risk of cardiovascular events compared to non-carriers.
Conclusion: Our study showed that the presence of the PCSK9 loss of function R46L mutation in the genotype of FH patients is beneficial for the lipid homeostasis and down-regulate the effect of the LDLR mutation in terms of accumulation of LDL-C, ApoB , total cholesterol, non-HDL and thereby, lowers the coronary heart disease risk of PCSK9 LOF mutation carriers. It is therefore very likely that anti-PCSK9 therapy will be useful in reducing cardiovascular risk in FH patients.
Author Disclosures: A. Baass: None.
- © 2014 by American Heart Association, Inc.