HDL Subspecies Defined by Presence of Apolipoprotein C-III and Incident Coronary Heart Disease in Four Cohorts
Background—The causal role of high density lipoprotein (HDL) cholesterol in cardioprotection has been questioned by genetic and randomized studies. Novel measures that relate to HDL function may contribute new information to prediction of cardiovascular risk. Apolipoprotein C-III (apoC-III) is a key regulator of lipoprotein metabolism. We investigated whether subspecies of HDL defined by apoC-III are associated with coronary heart disease (CHD).
Methods—We used immuno-affinity chromatography to measure the apoA-I concentrations of HDL that contains and lacks apoC-III in two prospective studies of adults free of CHD. In the Multi-Ethnic Study of Atherosclerosis (MESA), 5,657 participants (52% women; age 52-72 y) were followed for risk of CHD from 2000-2002 through 2013. In a case-cohort study nested within the Danish Diet, Cancer and Health (DCH) study, 3,642 participants (47% women; age 51-64 y) were followed from 1994-1997 through 2010. Subsequently, we conducted a meta-analysis that combined these results with the previously published findings from two cohort studies that used similar laboratory methodology to measure lipoproteins, totaling 2,997 incident cases.
Results—ApoC-III was found on 6-8% of apoA-I. The two HDL subspecies showed opposing associations with risk of CHD in each of the individual cohorts and in the meta-analysis (p-heterogeneity between the two subspecies <0.01). HDL that contains apoC-III was associated with higher risk of CHD (pooled relative risk [RR] per SD = 1.09, 95% confidence interval [95% CI] = 1.01 to 1.18), whereas HDL that lacks apoC-III was associated with lower risk (RR= 0.76; 95% CI = 0.70 to 0.83). The relative risk for HDL lacking apoC-III was even more negative than the relative risk for total HDL (RR= 0.80; 95% CI = 0.74 to 0.87).
Conclusions—Our findings from four prospective studies support the hypothesis that apoC-III may mark a subfraction of HDL that is associated with higher risk of CHD. New measures reflecting HDL structure and function may provide novel insights for cardiovascular risk that extend beyond traditional plasma HDL cholesterol concentrations.
- prospective cohort study
- coronary heart disease
- high-density lipoprotein cholesterol
- Received August 23, 2017.
- Revision received October 27, 2017.
- Accepted October 31, 2017.