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 (TG) metabolism. Elevated TG 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 prospective EPIC-Norfolk study. The study comprised 2,711 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 (NMR) and inflammatory biomarkers.

ApoC-III levels were significantly associated with CAD risk (odds ratio 1.91 95% CI 1.48–2.48 for highest compared to lowest quintile), retaining significance after adjustment for traditional CAD risk factors (odds ratio 1.47, 95% CI 1.11–1.94). ApoC-III levels were positively correlated with TG levels, (r=0.39), particle numbers of very-low density lipoprotein (VLDL; r=0.25), intermediate-density lipoprotein (IDL; r=0.23), small dense LDL (r=0.26), and high-sensitivity C-reactive protein (hsCRP) (r=0.15), whereas an inverse correlation was observed with large LDL 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 TG-elevation (TG, VLDL and IDL particles), small LDL particle size and hsCRP.

Conclusions

ApoC-III levels are significantly associated with incident CAD risk. Elevated levels of remnant lipoproteins, small dense LDL and low-grade inflammation may explain this association.