Apolipoprotein C‐III as a Potential Modulator of the Association Between HDL‐Cholesterol and Incident Coronary Heart Disease

Background High‐density lipoproteins (HDL) are structurally and metabolically heterogeneous and subclasses with differential effects on coronary heart disease (CHD) might exist. Apolipoprotein (apo) C‐III, a small proinflammatory protein that resides on the surface of lipoproteins, enhances the atherogenicity of VLDL and LDL particles, but little is known about the role apoC‐III on HDL. We investigated whether the presence or absence of apoC‐III differentiates HDL into subtypes with nonprotective or protective associations with risk of future CHD. Methods and Results High‐density lipoprotein cholesterol (HDL‐C) levels were measured in plasma separated according to apoC‐III (by immunoaffinity chromatography) in two prospective case‐control studies nested within the Nurses’ Health and the Health Professionals Follow‐Up Studies. Baseline was in 1990 and 1994, and 634 incident CHD cases were documented through 10 to 14 years of follow‐up. The relative risk of CHD per each standard deviation of total HDL‐C was 0.78 (95% confidence intervals, 0.63–0.96). The HDL‐C subtypes were differentially associated with risk of CHD, HDL‐C without apoC‐III inversely and HDL‐C with apoC‐III directly (P=0.02 for a difference between the HDL types). The relative risk per standard deviation of HDL‐C without apoC‐III was 0.66 (0.53 to 0.93) and 1.18 (1.03 to 1.34) for HDL‐C with apoC‐III. HDL‐C with apoC‐III comprised ~13% of the total HDL‐C. Adjustment for triglycerides and apoB attenuated the risks; however, the two HDL‐C subgroups remained differentially associated with risk of CHD (P=0.05). Conclusion Separating HDL‐C according to apoC‐III identified two types of HDL with opposing associations with risk of CHD. The proatherogenic effects of apoC‐III, as a component of VLDL and LDL, may extend to HDL. (J Am Heart Assoc. 2012;1:jah3‐e000232 doi: 10.1161/JAHA.111.000232.)