Apolipoprotein C-III Levels and Incident Coronary Artery Disease Risk: The EPIC-Norfolk Prospective Population Study

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.

Keywords: C-reactive protein; apolipoprotein CIII; coronary artery disease; lipoproteins; triglycerides.

Figure 1

Distribution of apoC-III in mg/dl (panel A) and triglycerides in mmol/l (panel B) as percentage of total cohort for cases (n=832) and controls (n=1,879).

Figure 2

Nuclear magnetic resonance spectroscopy measured lipoprotein subparticle numbers per apoC-III quintile. Bars display mean particle numbers in nmol/l and corresponding 95% confidence interval. A. VLDL (small, medium, large/chylomicron) particle numbers, total bar height represents total VLDL particle number. B. IDL particle numbers per apoC-III quintile. C. LDL (small and large) particle number per apoC-III, total bar height represents total LDL particle number. P-value for trend < 0.001 for all (sub)particle number associations.

Figure 3

Association of apoC-III quintiles and incident coronary artery disease risk. Data are odds ratios and corresponding 95% confidence interval. Model 1(open diamond) is matched for age and sex, model 2 (black square) is adjusted for age, sex, BMI, current smoking, diabetes mellitus, use of blood-pressure lowering and lipid lowering drugs. Model 3 (open circle) is model 2 additionally adjusted for triglyceride levels. ApoC-III range for each quintile was Q1 <3.27, Q2: 3.27–4.45, Q3: 4.45–5.79, Q4: 5.79–7.87, Q5 >7.87 mg/dL.