Julian C van Capelleveen1, Sophie J Bernelot Moens1, Xiaohong Yang1, John J P Kastelein1, Nicholas J Wareham1, Aeilko H Zwinderman1, Erik S G Stroes1, Joseph L Witztum1, G Kees Hovingh1, Kay-Tee Khaw1, S Matthijs Boekholdt1, Sotirios Tsimikas2. 1. From the Department of Vascular Medicine (J.C.v.C., S.J.B.M., J.J.P.K., E.S.G.S., G.K.H.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), and Department of Cardiology (S.M.B.), Academic Medical Center, Amsterdam, The Netherlands; Vascular Medicine Program, Division of Cardiology (X.Y., S.T.) and Division of Endocrinology and Metabolism (J.L.W.), Department of Medicine, University of California San Diego, La Jolla; Medical Research Council Epidemiology Unit, Cambridge, United Kingdom (N.J.W.); and Department of Public Health and Primary Care, University of Cambridge, United Kingdom (K.-T.K.). 2. From the Department of Vascular Medicine (J.C.v.C., S.J.B.M., J.J.P.K., E.S.G.S., G.K.H.), Department of Clinical Epidemiology and Biostatistics (A.H.Z.), and Department of Cardiology (S.M.B.), Academic Medical Center, Amsterdam, The Netherlands; Vascular Medicine Program, Division of Cardiology (X.Y., S.T.) and Division of Endocrinology and Metabolism (J.L.W.), Department of Medicine, University of California San Diego, La Jolla; Medical Research Council Epidemiology Unit, Cambridge, United Kingdom (N.J.W.); and Department of Public Health and Primary Care, University of Cambridge, United Kingdom (K.-T.K.). stsimikas@ucsd.edu.
Abstract
OBJECTIVE: Apolipoprotein C-III (apoC-III) is a key regulator of triglyceride metabolism. Elevated triglyceride-rich lipoproteins and apoC-III levels are causally linked to coronary artery disease (CAD) risk. The mechanism(s) through which apoC-III increases CAD risk remains largely unknown. The aim was to confirm the association between apoC-III plasma levels and CAD risk and to explore which lipoprotein subfractions contribute to this relationship between apoC-III and CAD risk. APPROACH AND RESULTS: Plasma apoC-III levels were measured in baseline samples from a nested case-control study in the European Prospective Investigation of Cancer (EPIC)-Norfolk study. The study comprised 2711 apparently healthy study participants, of whom 832 subsequently developed CAD. We studied the association of baseline apoC-III levels with incident CAD risk, lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy and inflammatory biomarkers. ApoC-III levels were significantly associated with CAD risk (odds ratio, 1.91; 95% confidence interval, 1.48-2.48 for highest compared with lowest quintile), retaining significance after adjustment for traditional CAD risk factors (odds ratio, 1.47; 95% confidence interval, 1.11-1.94). ApoC-III levels were positively correlated with triglyceride levels, (r=0.39), particle numbers of very-low-density lipoprotein (r=0.25), intermediate-density lipoprotein (r=0.23), small dense low-density lipoprotein (r=0.26), and high-sensitivity C-reactive protein (r=0.15), whereas an inverse correlation was observed with large low-density lipoprotein particle number (r=-0.11), P<0.001 for each. Mediation analysis indicated that the association between apoC-III and CAD risk could be explained by triglyceride elevation (triglyceride, very-low-density lipoprotein, and intermediate-density lipoprotein particles), small low-density lipoprotein particle size, and high-sensitivity C-reactive protein. CONCLUSIONS: ApoC-III levels are significantly associated with incident CAD risk. Elevated levels of remnant lipoproteins, small dense low-density lipoprotein, and low-grade inflammation may explain this association.
OBJECTIVE:Apolipoprotein C-III (apoC-III) is a key regulator of triglyceride metabolism. Elevated triglyceride-rich lipoproteins and apoC-III levels are causally linked to coronary artery disease (CAD) risk. The mechanism(s) through which apoC-III increases CAD risk remains largely unknown. The aim was to confirm the association between apoC-III plasma levels and CAD risk and to explore which lipoprotein subfractions contribute to this relationship between apoC-III and CAD risk. APPROACH AND RESULTS: Plasma apoC-III levels were measured in baseline samples from a nested case-control study in the European Prospective Investigation of Cancer (EPIC)-Norfolk study. The study comprised 2711 apparently healthy study participants, of whom 832 subsequently developed CAD. We studied the association of baseline apoC-III levels with incident CAD risk, lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy and inflammatory biomarkers. ApoC-III levels were significantly associated with CAD risk (odds ratio, 1.91; 95% confidence interval, 1.48-2.48 for highest compared with lowest quintile), retaining significance after adjustment for traditional CAD risk factors (odds ratio, 1.47; 95% confidence interval, 1.11-1.94). ApoC-III levels were positively correlated with triglyceride levels, (r=0.39), particle numbers of very-low-density lipoprotein (r=0.25), intermediate-density lipoprotein (r=0.23), small dense low-density lipoprotein (r=0.26), and high-sensitivity C-reactive protein (r=0.15), whereas an inverse correlation was observed with large low-density lipoprotein particle number (r=-0.11), P<0.001 for each. Mediation analysis indicated that the association between apoC-III and CAD risk could be explained by triglyceride elevation (triglyceride, very-low-density lipoprotein, and intermediate-density lipoprotein particles), small low-density lipoprotein particle size, and high-sensitivity C-reactive protein. CONCLUSIONS:ApoC-III levels are significantly associated with incident CAD risk. Elevated levels of remnant lipoproteins, small dense low-density lipoprotein, and low-grade inflammation may explain this association.
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