Abstract 118: Phospholipid Transfer Protein, High Density Lipoprotein Particle Concentration and Cardiovascular Disease Risk

Abstract

High density lipoprotein (HDL) plays a key role in reverse cholesterol transport from arteries and protects against development of atherosclerosis by removing cholesterol from lipid loaded macrophages in atherosclerotic lesions. Low levels of HDL-cholesterol (HDL-C) strongly associate with increased risk of cardiovascular disease (CVD) in clinical and epidemiological studies. However, recent trials with drugs that elevate HDL-C failed to reduce CVD events. In contrast recent studies strongly suggested that HDL sterol efflux capacity-its ability to remove cholesterol from macrophages-predict incident cardiovascular disease risk. Moreover, CVD risk strongly associates with low levels of HDL particle concentration (HDL-P). However, the relations between HDL efflux capacity, HDL particle concentration and HDL composition are not well understood. Using proteomics analysis, we have previously identified over 50 proteins on HDL. Here we investigated the relationship of HDL composition, and HDL-P in two independent populations of people with and without CVD (Study 1, n=40, and Study 2, n=65). Using quantitative targeted multiplex MS/MS analysis quantifying majority (40) of HDL associated proteins, we found that phospholipid transfer protein (PLTP) and clusterin (CLU or ApoJ) strongly correlated in HDL (r = 0.9, P < 0.001) indicating that the two proteins likely coexist in a single population of HDL particles. Furthermore, abundance of these two proteins correlated strongly with the concentration of large HDL particles (PLTP r = 0.58; CLU r = 0.61, both P < 0.001) and negatively with the concentration of small HDL particles (both PLTP and CLU r = -0.49, P < 0.001) as determined by calibrated ion mobility analysis. Moreover, both PLTP and CLU were significantly decreased in CVD subjects, and both predicted CVD status after adjustment for age and sex (PLTP, OR 0.53, 95% CI, 0.28-0.94, P = 0.02). Collectively, this data supports the hypothesis that PLTP and CLU play important roles in determining HDL-P and that these are interrelated factors determining HDL’s anti-atherogenic properties.