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

No Thumbnail Available
Change log
Verbeek, R 
Boyer, M 
Boekholdt, SM 
Hovingh, GK 
Kastelein, JJP 

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. After adjusting for age, sex, and cardiovascular disease status, carriers of the R46L variant (n=77) were characterized by lower concentrations of very low-density lipoprotein particles (85.8±26.2 versus 99.0±33.3 nmol/L; P<0.001), low-density lipoprotein particles (1479.7±396.8 versus 1662.9±458.3 nmol/L; P<0.001), and lipoprotein(a) (11.1 [7.2-28.6] versus 12.4 [6.7-29.1] mg/dL; P<0.001) compared with noncarriers. Total high-density lipoprotein particle and very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein particle sizes were comparable in carriers and noncarriers. Carriers were characterized by lower secretory phospholipase A2 (4.2±0.9 versus 4.6±1.3 nmol/mL/min; P=0.004) and lipoprotein-associated phospholipase A2 activity (47.5±14.1 versus 52.4±16.2 nmol/mL/min; P=0.02) compared with noncarriers. CONCLUSIONS: Results of this study suggest that carriers of the PCSK9 R46L genetic variant have lower very low-density lipoprotein and low-density lipoprotein particle concentrations, lower lipoprotein(a) levels, and lower secretory phospholipase A2 and lipoprotein-associated phospholipase A2 activity compared with noncarriers.

PCSK9, R46L, lipoprotein(a), lipoproteins, nuclear magnetic resonance spectroscopy
Journal Title
Arteriosclerosis, Thrombosis, and Vascular Biology
Conference Name
Journal ISSN
Volume Title
American Heart Association
MRC (MC_PC_13048)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0512-10135)
Medical Research Council (MC_UU_12015/1)
Medical Research Council (MR/N003284/1)
Medical Research Council (G1000143)
Medical Research Council (G0401527)
Medical Research Council (MC_U106179471)
The EPIC-Norfolk Study is funded by Cancer Research UK grant number 14136 and the Medical Research Council grant number G1000143. R.V. is supported by a grant from the European Union [TransCard: FP7-603091-2]. B.J.A. holds a junior scholar award from the Fonds de recherche du Québec: Santé (FRQS). J.J.P.K. is a recipient of the Dutch Heart Foundation Lifetime Achievement Award (2010).