PCSK9 R46L, Lower LDL, and Cardiovascular Disease Risk in Familial Hypercholesterolemia

Abstract

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) LipidClinic 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. plasma LDL-C, total cholesterol and, importantly, showed also a decrease in coronary heart disease. 11 Additionally, important observations from meta-analysis have highlighted the association of the R46L carriers to a reduced risk of ischemic heart disease and of early-onset myocardial infarction. 22,23 Presently, statins are the first line medications used to lower LDL-C and the risk of CVD. Unfortunately, statins also upregulate the PCSK9 gene expression, therefore, compromising their LDL lowering effect. 24 Nevertheless, a previous report observed that compound carriers of the PCSK9 R46L variation and of a LDLR mutation associated with FH responded much better to statin therapy compared with controls. 25 A decade of scientific research on PCSK9 resulted in the development of neutralizing molecules, such as monoclonal antibodies. These molecules are currently undergoing phase II/III clinical trials and have been shown to lower LDL-C efficiently by ≈50% to 60%. 26,27,27a,27b Outcome trials are underway to test the ability of these drugs to reduce cardiovascular even...

The contribution of PCSK9 levels to the phenotypic severity of familial hypercholesterolemia is independent of LDL receptor genotype

“…This mutation is associated with decreased PCSK9 levels, LDL-C concentrations and CAD risk [29,31] in non-FH subjects. A recent study by Saavedra et al [34] showed that HeFH carrying the R46L had lower LDL-C levels and a reduced CVD risk compared with non-carriers. In the Dallas Heart Study cohort, the addition of the variant R46L in the linear model predicting PCSK9 levels only slightly increased by 1% the predictive value of the model [29].…”

Atherosclerosis

“…47-51 Profiling of carotid atherosclerosis from a human biobank using microarray technique found increased PCSK9 mRNA abundance in fibrous caps of symptomatic carotid atherosclerotic lesions. 52 Findings in human studies have led to development of PCSK9 inhibitors to reduce plasma cholesterol concentrations and risks for cardiovascular events.…”

Translational and Therapeutic Approaches to the Understanding and Treatment of Dyslipidemia

“…performed an observational cross-sectional cohort study of FH patients in a French Canadian population. 21 In that cohort, the presence of the R46L loss-of-function missense mutation among FH patients (3% of the FH population) was associated with lower plasma concentration of LDL-C (11%) compared with non-carrier FH patients. The PCSK9 R46L mutation was also associated with protection against CVD.…”