Rutger Verbeek1, Marjorie Boyer1, S Matthijs Boekholdt1, G Kees Hovingh1, John J P Kastelein1, Nicholas Wareham1, Kay-Tee Khaw1, Benoit J Arsenault2. 1. From the Department of Vascular Medicine (R.V., G.K.H., J.J.P.K.) and Department of Cardiology (S.M.B.), Academic Medical Centre, Amsterdam, The Netherlands; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Canada (M.B., B.J.A.); Department of Medicine, Faculty of Medicine, Université Laval, Québec, Canada (M.B., B.J.A.); Medical Research Council Epidemiology Unit, Cambridge, United Kingdom (N.W.); and Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, United Kingdom (K.-T.K.). 2. From the Department of Vascular Medicine (R.V., G.K.H., J.J.P.K.) and Department of Cardiology (S.M.B.), Academic Medical Centre, Amsterdam, The Netherlands; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Canada (M.B., B.J.A.); Department of Medicine, Faculty of Medicine, Université Laval, Québec, Canada (M.B., B.J.A.); Medical Research Council Epidemiology Unit, Cambridge, United Kingdom (N.W.); and Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, United Kingdom (K.-T.K.). benoit.arsenault@criucpq.ulaval.ca.
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. 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.
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.
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