Atheroprotective targets associated with high-density lipoprotein: phospholipid transfer protein, paraoxonase-1, and their effects on cerebrovascular disease

Abstract

The recent high-profile failures of clinical trials and Mendelian randomization studies to demonstrate a causal role of high-density lipoprotein cholesterol (HDL-C) in cardiovascular disease have shifted focus to other measures of HDL that may better reflect its cardioprotective properties. Here, I describe a series of work that first identified and validated that the smaller and denser HDL particles were more likely the source of HDL’s cardioprotective properties. I then explore specific proteins that co-localize with these small, dense HDL particles: phospholipid transfer protein (PLTP) and paraoxonase-1 (PON1). First, I demonstrate that commercially available assays of PLTP activity are only weakly correlated with the low-throughput, but gold-standard radiometric PLTP assay. Using a large collection of participants with radiometrically-measured PLTP activity, I then show that PLTP activity measured by this method is protective against carotid artery disease. Finally, I use data from the NHLBI Exome Sequencing Project (ESP) to demonstrate Mendelian randomization for the role of PON1 and cerebrovascular disease by identifying a rare variant that is associated with decreased PON1 activity and increased risk of ischemic stroke. These findings aid researchers and clinicians to narrow their focus onto specific functions and measures of HDL that may potentially be used as therapeutics.