ApoC-III distribution in lipoproteins does not provide incremental predictive value for CAD

Relationship of lipoprotein-associated apolipoprotein C-III to lipid variables and coronary artery disease risk: The EPIC-Norfolk Prospective Population Study

Literature - van Capelleveen JC, Lee S-R, Verbeek R, et al. - J Clin Lipidol 2018; published online ahead of print

Introduction and methods

Apolipoprotein C-III (apoC-III) is a circulating apolipoprotein that inhibits the activation of lipoprotein lipase (LPL), thereby hindering triglyceride (TG) hydrolysis, and apoC-III plays an important role in the metabolism of triglyceride-rich lipoproteins (TRL).Several lines of evidence have suggested a causal relationship between apoC-III levels and coronary artery disease (CAD) [1-3]. The distribution of apoC-III among circulating lipoproteins and their respective predictive risk compared to apoC-III are unclear.

The association between lipoprotein-associated apoC-III levels and CAD risk was evaluated in a nested case-control analysis of the EPIC-Norfolk prospective population study [4]. For this purpose the apoC-III content on apolipoprotein B-100 (apoC-III-apoB), apolipoprotein A-I (apoC-III-apoAI), and lipoprotein(a) (apoC-III-Lp(a)) containing lipoproteins was determined in plasma samples (using the recently developed quantitative high-throughput sandwich chemiluminescent enzyme-linked immunoassays [ELISA]), and indices of “total apoC-III-apoB” and “total apoC-III-apoAI” were calculated by multiplying these measures with plasma apoB and apoA-I concentrations.

The EPIC-Norfolk cohort study includes 25,663 individuals, aged 45-79 years, who were recruited between 1993 and 1997. For the present analysis, 1,879 participants without a history of heart attack or stroke at baseline, who developed CAD during follow-up until 2003 were selected. Moreover, a control group (N=832) of apparently healthy study participants without CAD, was used for comparison. The duration of follow-up was 7.4 years.

Main results

  • At baseline, apoC-III-apoB, apoC-III-Lp(a), apoC-III-apoAI, and blood lipid values were significantly higher in CAD cases, compared with controls (all P values ≤0.005).
  • ApoCIII-apoAI was significantly associated with CAD risk (OR for highest compared to lowest quintile: 1.42; 95%CI: 1.09-1.84), but significance was lost after adjustment for CAD risk factors (OR: 1.14; 95%CI: 0.86-1.52).
  • ApoC-III-apoB was also associated with CAD risk when comparing highest to lowest quintile (OR: 1.46; 95%CI: 1.12-1.89), but significance was lost after adjusting for CAD risk factors (OR: 1.28; 95%CI: 0.96-1.70).
  • ApoC-III-Lp(a) was significantly associated with CAD risk before and after adjustment for CAD risk factors (OR: 1.66; 95%CI: 1.29-2.15; ORadj: 1.35; 95%CI: 1.02-1.78), but this significance was lost after additional adjustment for lipid variables and apoC-III.
  • ApoC-III content in apoA-I-containing lipoproteins was not associated with CAD risk (OR: 1.22; 95%CI: 0.92-1.63), while apoC-III content in apoB-containing lipoproteins was significantly associated with CAD risk (OR: 1.81; 95%CI: 1.38-2.38; OR adjusted for CAD risk factors: 1.57; 95%CI: 1.16-2.12), but the association lost its significance after further adjustment for lipid values.


Immuno-assay measurement of apoC-III on individual lipoproteins did not provide additional predictive information on the risk of CAD events in patients in the primary care setting, compared with total plasma apoC-III measurement. It remains to be established whether these biomarkers can predict future risk in individuals with established CVD.


1. Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45:1345-1352.

2. Ginsberg HN, Le NA, Goldberg IJ, et al. Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J Clin Invest.1986;78:1287-1295.

3. Gordts PL, Nock R, Son NH, et al. ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J Clin Invest. 2016;126:2855-2866.

4. Day N, Oakes S, Luben R, et al. EPIC-Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer. Br J Cancer. 1999;80 Suppl 1:95-103.

Find this article online at J Clin Lipidol

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