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Recent experimental studies have found that apolipoprotein E (APOE) can promote the de novo biogenesis of high-density lipoprotein (HDL) particles in a pathway similar to that of apolipoprotein AI (APOAI) but independent of functional APOAI presence. APOE containing HDL (APOE-HDL) particle may be necessary to stimulate the reverse cholesterol transport process, an underpinning of the anti-atherogenic function of HDL. It thus far remains unclear whether APOE-HDL cholesterol is causally associated with coronary heart disease (CHD) incident risk, and further whether this association is independent of total HDL cholesterol. To explore whether APOE-HDL cholesterol is associated with CHD incident risk, and further whether this association is independent of total HDL cholesterol in a cardiovascular disease-free population.
APOE-HDL cholesterol and HDL cholesterol were measured in 5417 participants (women, 51.8%) aged 35-64 years at baseline in a community-based cohort study. HDLC and APOE-HDLC were categorized using a fixed increment method. For HDLC, the lowest cutoff point was defined by the criterion of low HDLC (<40 mg/dL for men and <50 mg/dL for women). Then, a fixed increment of 10 mg/dL was used to classify study participants into four groups. For APOE-HDLC, the lowest cutoff point was set at <4.0 mg/dl for men and <5.0 mg/dl for women. A fixed increment of 1 mg/dL was used and study participants classified into five groups. For APOE-HDLC/HDLC ratio, the lowest cutoff point was set at 8.60 %. A fixed increment of 0.7 % was used to classify study participants into four groups. Multivariate Cox regression was employed to assess the association between HDL related biomarkers and 10-year CHD incident risk.
Mean levels of baseline APOE-HDLC and APOE-HDLC/HDLC ratio were 5.15 ± 1.60 mg/dL and 9.05 ± 0.94%, respectively. HDL cholesterol was strongly correlated with APOE-HDL cholesterol (partial-r: 0.978), and moderately with APOE-HDLC/HDLC ratio (partial-r: 0.604). Total of 100 incident CHD events occurred during 10-year follow-up. Baseline HDL cholesterol, APOE-HDL cholesterol, APOE-HDLC/HDLC ratio were significantly associated with incident CHD risk (HDL cholesterol: hazard ratio [HR]=0.39; 95% confidence interval [CI]=0.18−0.88; APOE-HDL cholesterol: HR=0.42; 95% CI=0.20−0.86; APOE-HDLC/HDLC ratio: HR=0.26; 95% CI=0.10−0.71, respectively for participants with the highest level than those with the lowest level). There were no overlaps in 95% CI of absolute risk for the comparisons of APOE-HDLC/HDLC ratio (0.48, 95% CI=0.44-0.52) with APOE-HDL cholesterol (1.51, 95% CI=1.41-1.61) and HDL cholesterol (0.83, 95% CI=0.78-0.88) among participants with the highest level of these parameters. Among participants with different levels of HDL cholesterol, baseline APOE-HDLC/HDLC ratio was negatively associated with incident CHD risk, and participants in the highest category of HDL cholesterol had the lowest HR associated with APOE-HDLC/HDLC ratio.
Our findings revealed that APOE-HDLC/HDLC ratio was significantly associated with 10-year increased risk of incident CHD, suggesting that APOE containing HDL can serve as a better indicator for the anti-atherosclerotic function of HDL than total HDLC.