Untargeted lipidomics reveals novel HDL metabotypes and lipid-clinical correlates

Plasma high-density lipoprotein (HDL), originally studied for its role in lipid transport, is now appreciated to have wide-ranging biological functions that become defective during disease. While >200 lipids have collectively been detected in HDL, published HDL lipidomic analyses in different diseases have commonly been targeted to prespecified subsets of lipids. Here, we report the results of untargeted lipidomic analysis of HDL isolated from 101 subjects referred for computed tomographic coronary imaging for whom multiple additional clinical and lipoprotein metadata were measured. Unsupervised clustering of the total HDL lipidome revealed that the subjects fell into one of two discrete groups, herein referred to as HDL “metabotypes.” Patients in metabotype 1 were likelier to be female and tended to have a less atherogenic lipoprotein profile, higher HDL cholesterol efflux capacity (CEC), and lower-grade non-calcified burden on coronary imaging than metabotype 2 counterparts. Specific lipids were relatively enriched in metabotype 1 HDL. Linear modeling revealed that several of these lipids were positively associated with CEC, statin use, HDL size, and HDL particle number, and positively correlated with HDL apolipoprotein A-1, suggesting that they may be informative HDL biomarkers. Taken together, we posit a novel, clinically relevant categorization for HDL revealed by systems biology.