Carriers of the PCSK9 R46L Variant Are Characterized by an Antiatherogenic Lipoprotein Profile Assessed by Nuclear Magnetic Resonance Spectroscopy—Brief Report

Abstract

Objective-Carriers of the PCSK9 (proprotein convertase subtilisin/kexin 9) R46L genetic variant (rs11591147) are characterized by low levels of low-density lipoprotein cholesterol and a decreased risk of cardiovascular disease. We studied the impact of the R46L variant on lipoprotein size and composition. Approach and Results-Lipoprotein size and composition were measured by nuclear magnetic resonance spectroscopy in 2373 participants of the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk study. DiscussionOur study shows that carriers of the PCSK9 R46L variant are characterized by lower levels of NMR-measured atherogenic lipoproteins and subfractions compared with noncarriers. The most prominent differences based on percentage change between carriers and noncarriers were observed with IDL-P (−18%) and medium VLDL-P (−16%; Figure). The most prominent differences based on change in SD between carriers and noncarriers were observed with apolipoprotein B ( who have reported a 15% reduction in LDL-C in carriers of the PCSK9 R46L variant in the ARIC study (Atherosclerosis Risk in Communities). The effect on other parameters of the lipoprotein-lipid profile was comparable, with in both studies significant lower levels of total cholesterol and no effect on high-density lipoprotein cholesterol.In a cross-sectional study of 52 healthy subjects, PCSK9 levels were found to correlate with total cholesterol, nonhigh-density lipoprotein cholesterol, LDL-C, triglycerides, and VLDL-P and LDL-P concentrations. 4 In a subsequent multivariable regression analysis, PCSK9 levels were only related to LDL-P concentration. Interestingly, in an analysis that included the 3 LDL subfractions, PCSK9 was only associated with IDL-P. The R46L variant examined in our study has been shown to be associated with lower levels of PCSK9, 5 and therefore, we expected a similar effect on NMR lipoprotein subfractions. Our study suggests that there is not only an association between PCSK9 and IDL-P but also with other lipoprotein particles. The effect of the R46L variant on lipoproteins in our study seemed to be comparable with the results of Chasman et al, 6 who showed a significant effect of the single-nucleotide polymorphism on large LDL-P, total LDL-P, small LDL-P, IDL-P, LDL-C, total VLDL-P, and small VLDL-P. Other groups also documented the effect of different single-nucleotide The relationship between LDL-C and CVD risk is strong and consistent, but evidence suggest that LDL-P concentrations could be more closely associated with CVD risk than LDL-C. 12 Because of a possible discordance between LDL-C and LDL-P concentrations, patients with LDL-C levels on target could be at increased CVD risk attributable to high LDL-P levels. 13 The American Association of Clinical Chemistry has suggested to strive for a LDL-P concentration treatment goal of <1100 nmol/L 14 or an equivalent LDL-C level of <100 mg/dL in patients at high CVD risk according to the National Cholesterol Education Program Adult Treatment Panel III. 15As w...

Efficacy and safety of proprotein convertase subtilisin/kexin 9 inhibitors in people with diabetes and dyslipidaemia

“…Specifically, plasma PCSK9 levels associate with (large) VLDLs, VLDL remnants and intermediate‐density lipoproteins (IDLs) in subjects with T2DM and/or metabolic syndrome . Genetic studies have also demonstrated that specific gain‐of‐function variants (notably p.S127R and p.D374Y) modestly increase plasma TG levels, whereas certain loss‐of‐function variants (p.Y142X, p.C679X, p.R46L) modestly lower plasma TG levels . One potential explanation for the positive relationship between plasma TG and plasma PCSK9 levels is an intracellular effect of PCSK9 on APOB/VLDL secretion.…”

“…44 Genetic studies have also demonstrated that specific gain-of-function variants (notably p.S127R and p.D374Y) modestly increase plasma TG levels, 45,46 whereas certain loss-of-function variants (p.Y142X, p.C679X, p.R46L) modestly lower plasma TG levels. 17,47,48 One potential explanation for the positive relationship between plasma TG and plasma PCSK9 levels is an intracellular effect of PCSK9 on APOB/VLDL secretion. Indeed, the over-expression of wild-type PCSK9 or the p.S127R and p.D374Y gain-of-function variants promoted the secretion of APOB from hepatocytes.…”

Genetic inhibition ofPCSK9, atherogenic lipoprotein concentrations, and calcific aortic valve stenosis

“…In the present study, we confirm these findings and expand the investigation of the lipoprotein-lipid profile to apolipoproteins and Lp(a). In a previous report of 2373 individuals included in a nested case-control design of the EPIC-Norfolk study, we have shown that carriers of the PCSK9 R46L variant had lower levels of nuclear magnetic resonance spectroscopy-measured VLDL and LDL particle concentrations and lower Lp(a) (23). In another study, Sliz et al (24) reported no impact of this variant on VLDL lipid measures.…”

A transient amphipathic helix in PCSK9’s prodomain facilitates low-density lipoprotein binding

“…Collectively, these data support that helical conformation in the prodomain N-terminus plays a larger role in LDL binding relative to its role in PCSK9-LDLR association and LDLR degradation. R46L substitution increases helix propensity in prodomain-derived peptides-The natural PCSK9 mutation R46L is a LOF variant associated with lowered plasma PCSK9 levels, an anti-atherogenic lipid profile and decreased incidence of CHD (5,35,36). Notably, an R46L substitution would extend the nonpolar face of the predicted AH motif in the IDR and reorient and increase the amplitude of the hydrophobic moment, as shown in helical wheel models ( Figure 6A).…”