Abstract 11566: Beyond LDL Cholesterol: Carriers of the PCSK9 R46L Variant Are Characterized by an Anti-Atherogenic Lipoprotein Profile Assessed by Nuclear Magnetic Resonance Spectroscopy

Abstract

Background: Carriers of the PCSK9 R46L genetic variant are characterized by low levels of low-density lipoprotein (LDL) cholesterol and a decreased risk of cardiovascular disease (CVD). Whether these individuals are characterized by other features of a more beneficial lipoprotein-lipid profile is unknown. Methods and Results: We measured the lipoprotein-lipid profile of 2373 participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study by nuclear magnetic resonance spectroscopy. Among them, 77 participants carried at least one allele of the R46L genetic variant. Carriers and non-carriers had comparable clinical characteristics (age, body mass index, blood pressure, smoking and diabetes prevalence). As expected, carriers had lower LDL cholesterol levels compared to non-carriers (3,75±0,99 vs. 4,16±1,01 mmol/L, p<0.001 in carriers vs. non-carriers, respectively). Carriers were characterized by a lower very low-density lipoprotein (VLDL) particle concentration and a lower LDL particle concentration of any size (Table). Total high-density lipoprotein (HDL) particle concentration was not different in carriers vs. non-carriers. However, carriers had a higher concentration of large HDL particles and a higher mean HDL particle size. We also found that carriers were characterized by a lower secretory phospholipase A2 (sPLA2) activity (4,21±0,88 vs. 4,61±1,26, nmol/ml/min p=0.004 in carriers vs. non-carriers, respectively) and a lower lipoprotein-associated phospholipase A2 (Lp-PLA2) activity (47,5±14,1 vs. 52,4±16,2 nmol/ml/min, p=0.008 in carriers vs. non-carriers, respectively). Conclusions: Results of this study suggest that on top of having low LDL cholesterol levels, carriers of the PCSK9 R46L genetic variant have a lower VLDL and LDL particle concentration, a higher concentration of large HDL particles and lower sPLA2 and Lp-PLA2 activity. This anti-atherogenic profile may explain to a certain extent the reduced CVD risk observed in carriers of the PCSK9 R46L genetic variant.