HDL‐3 is a Superior Predictor of Carotid Artery Disease in a Case‐Control Cohort of 1725 Participants

BACKGROUND: Recent data suggest that high‐density lipoprotein cholesterol (HDL‐C) levels are likely not in the causative pathway of atheroprotection, shifting focus from HDL‐C to its subfractions and associated proteins. This study's goal was to determine which HDL phenotype was the better predictor of carotid artery disease (CAAD). METHODS AND RESULTS: HDL‐2 and HDL‐3 were measured in 1725 participants of European ancestry in a prevalent case‐control cohort study of CAAD. Stratified analyses were conducted for men (n=1201) and women (n=524). Stepwise linear regression was used to determine whether HDL‐C, HDL‐2, HDL‐3, or apolipoprotein A1 was the best predictor of CAAD, while adjusting for the confounders of censored age, diabetes, and current smoking status. In both men and women, HDL‐3 was negatively associated with CAAD (P=0.0011 and 0.033 for men and women, respectively); once HDL‐3 was included in the model, no other HDL phenotype was significantly associated with CAAD. Addition of paraoxonase 1 activity to the aforementioned regression model showed a significant and independent (of HDL‐3) association with CAAD in men (P=0.001) but not in the smaller female subgroup. CONCLUSIONS: This study is the first to contrast the associations of HDL‐2 and HDL‐3 with CAAD. We found that HDL‐3 levels were more predictive of CAAD status than HDL‐2, HDL‐C, or apolipoprotein A1. In addition, for men, paraoxonase 1 activity improved the overall model prediction for CAAD independently and additively with HDL‐3 levels. Further investigation into the molecular mechanisms through which HDL‐3 is associated with protection from CAAD is warranted.