Insights in association plasma apo CIII levels with CAD risk
Apolipoprotein CIII Levels and Incident Coronary Artery Disease Risk: The EPIC-Norfolk Prospective Population StudyVan Capelleveen JC, Bernelot Moens SJ, Yang X, et al. - Arterioscler Thromb Vasc Biol. 2017; 37: published online ahead of print
Apo CIII is a key regulator of the metabolism of triglyceride-rich lipoproteins and has been associated with increased coronary artery disease (CAD) risk [1,2]. According to genetic studies, the loss-of-function mutations in APOC3 result in a favorable lipid profile with reduced triglyceride and VLDL levels, whereas Mendelian randomization studies showed a causal relationship between genetic variation in APOC3 and CAD risk [3-5]. However, it is not clear yet, which factors mediate the impact of elevated apo CIII on CAD risk.
In this large prospective EPIC-Norfolk nested case–control study with 2711 healthy participants (of whom 832 developed CAD), the associations between apo CIII levels, detailed lipoprotein analyses, inflammatory markers and CAD risk were evaluated to explore which lipoprotein subfractions contribute to the relationship between apoCIII and CAD risk.
- At baseline, apo CIII levels were correlated with total cholesterol (r=0.23, P<0.001), LDL-C (r=0.13, P<0.001), triglycerides (r=0.39, P<0.001), VLDL particle number and size (r=0.24 and r=0.27, P<0.001), large VLDL/chylomicron-sized particle number (r= 0.39, P<0.001), IDL particle number (r=0.23, P<0.001), LDL particle number (r=0.26, P<0.001), LDL particle size (r=−0.22, P<0.001), apolipoprotein AV levels (r=0.21, P<0.001), LPL mass (r=−0.13, P<0.001), HDL particle number (r=0.20, P<0.001), HDL particle size (r=−0.23, P<0.001), cholesterol efflux capacity (r=0.08, P<0.001), lecithin–cholesterol acyltransferase mass (r=0.13, P<0.001) and high-sensitivity C-reactive protein levels (r=0.15, P<0.001).
- The OR for incident CAD was 1.91 (95% CI 1.48–2.48) for the highest apo CIII quintile compared with the lowest quintile and this association remained significant after adjustment for cardiovascular risk factors (OR 1.47, 95% CI 1.11–1.94), as well as after further adjustment for LDL-C (OR 1.35, 95% CI 1.01–1.81) and HDL-C (OR 1.41, 95% CI 1.05–1.88). The significance was lost after adjustment for triglycerides (OR 1.17, 95% CI 0.87–1.58).
- Apo CIII levels were not as strongly associated with CAD risk, in subjects with LDL-C level below the median compared with subjects with LDL-C over the median. Moreover, apo CIII levels were not significantly associated with CAD risk in subjects with triglycerides below the median.
- Plasma triglyceride levels explained a major part of the association between apo CIII and CAD risk (55%), followed by apoB levels (31%). VLDL and LDL particle numbers both explained 24% of the association between apo CIII and CAD risk, whereas the association observed for LDL particles was due to small dense LDL particles (24%).
There is a strong association between elevated plasma apo CIII levels with CAD risk, independently of traditional cardiovascular disease risk factors, which may be explained by elevated levels of remnant lipoproteins, small dense LDL and low-grade inflammation.