Circulating PCSK9 levels are positively correlated with NMR-assessed atherogenic dyslipidaemia in patients with high cardiovascular risk

Abstract

The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene regulates cholesterol homoeostasis by accelerating low-density lipoprotein receptor (LDLR) degradation resulting in the decreased catabolism of low-density lipoprotein (LDL) leading to hypercholesterolaemia. PCSK9 has also been related to other metabolic risk factors such as triglycerides (TGs) and glucose levels and body mass index (BMI). Therefore, our aim was to study the relationship between the PCSK9 and the lipid and lipoprotein profile. We studied 267 diabetic and metabolic syndrome patients who were not receiving any lipid-lowering therapy. We measured circulating lipids, cholesterol in remnant lipoproteins (RLPc) and PCSK9 levels. A detailed lipoprotein profile was determined based on NMR. Plasma PCSK9 levels were significantly and positively correlated with TG (r=0.136, P=0.033), total cholesterol (r=0.219, P<0.001) and apoB (apolipoprotein B; r=0.226, P=0.006) circulating levels and with an atherogenic profile of lipoprotein subclasses. In further detail, circulating PCSK9 levels were positively correlated with large very-low density lipoprotein (VLDL) particles, (r=0.210, P=0.001) and with their remnants, the intermediate-density lipoprotein (IDL) particles (r=0.206, P=0.001); positively correlated with smaller LDL particles (for small LDL: r=0.224, P<0.001; for medium small LDL: r=0.235, P<0.001; and for very small LDL: r=0.220, P<0.001); and with high-density lipoprotein (HDL) particles (r=0.146, P<0.001), which is mainly explained by the PCSK9 correlation with the smallest HDL particles (r=0.130, P=0.037). In addition, circulating PCSK9 levels were positively correlated with the pro-atherogenic circulating RLPc levels (r=0.171, P=0.006). All of the correlations were adjusted by age, gender and BMI. PCSK9 levels are significantly and positively correlated with atherogenic lipoproteins such as large VLDL, IDL, the smallest LDL, the smallest HDL particles and RLPc levels.

Plasma proprotein‐convertase‐subtilisin/kexin type 9 (PCSK9) and cardiovascular events in type 2 diabetes

“…[9][10][11][12][13][34][35][36] Other possible explanations for the effect of PCSK9 on CVD involve its impact on atherogenic lipoproteins independently of its impact on the LDLR pathway. Guardiola et al 16 recently reported that circulating PCSK9 levels were positively correlated with large very-low-density lipoprotein and their remnants, intermediate-density…”

“…Other possible explanations for the effect of PCSK9 on CVD involve its impact on atherogenic lipoproteins independently of its impact on the LDLR pathway. Guardiola et al recently reported that circulating PCSK9 levels were positively correlated with large very‐low‐density lipoprotein and their remnants, intermediate‐density lipoprotein particles known for their potent atherogenicity. In addition, PCSK9 was correlated with smaller LDL particles as well as with HDL particles, mainly explained by the correlation between PCSK9 and the smallest HDL particles.…”

“…Finally, circulating PCSK9 levels were positively correlated with pro‐atherogenic circulating remnant‐like particle cholesterol levels. Interestingly, all these findings were derived from a population of patients with type 2 diabetes or metabolic syndrome . Unfortunately, no detailed data are available concerning lipoproteins and particle characteristics in the DIABHYCAR or the SURDIAGENE cohorts to replicate these associations and to test whether they can mediate the observed association with future CV events.…”

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

“…Indeed, plasma PCSK9 levels positively associate with fasting plasma TG levels in adults and adolescents in the general population, and also in patients with T1DM and T2DM . 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 .…”

“…28 Specifically, plasma PCSK9 levels associate with (large) VLDLs, VLDL remnants and intermediatedensity lipoproteins (IDLs) in subjects with T2DM and/or metabolic syndrome. 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.…”