Identification of (apo)lipoprotein subclasses causally underpinning atherosclerosis may lead to identification of novel drug targets for treatment of atherosclerotic cardiovascular disease (ASCVD). In this study, observational and genetic associations between (apo)lipoprotein profile and carotid intima-media thickness-assessed atherosclerosis, and risks of coronary artery disease (CAD) and ischemic stroke (IS) are assessed, using data from the UK Biobank study, with further exploration of potential drug target for these two ASCVD subtypes through multi-omics analysis integrating genetic, transcriptomic, and proteomic data. Cholesteryl ester content in medium high-density lipoprotein causally protective of atherosclerosis is identified, plus a target gene, PSRC1, with therapeutic potential for CAD, but not IS, supported by consistent evidence from multi-omics layers of data, which also reveals that such therapeutic potential may be through downregulation of circulating proteins including TRP1, GRNs, and Pla2g12b, and upregulation of Neo1. The results provide strong evidence as well as mechanistic clues of PSRC1's therapeutic potential for CAD.
Keywords: (apo)lipoprotein profiling; atherosclerotic cardiovascular disease; carotid intima‐media thickness; colocalization; mendelian randomization; multi‐omics.
© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.