Plasma Proteomic Profiling Reveals Distinct Roles of Apolipoprotein B-containing Lipoproteins in Atherosclerosis

All apolipoprotein B-containing lipoproteins are established causal factors for coronary artery disease (CAD). However, triglyceride-rich lipoproteins (TRL) and lipoprotein(a) [Lp(a)] exhibit greater per-particle atherogenicity than low-density lipoprotein (LDL) through mechanisms that remain unclear. To elucidate these mechanisms, we combined observational and Mendelian randomization analyses in UK Biobank to identify plasma proteomic signatures of LDL, TRL, and Lp(a). We identified 30, 471, and 53 proteins robustly associated with LDL, TRL, and Lp(a) concentrations, respectively. TRL and Lp(a) signatures were distinct from the LDL signature and substantially overlapped with each other (36 proteins), with shared enrichment in inflammatory pathways. Multi-protein scores summarizing each signature showed that TRL (HR 1.16, 95%CI 1.08-1.24) and Lp(a) (HR 1.09, 95%CI 1.03-1.15), but not LDL (HR 0.95, 95%CI 0.89-1.02), were associated with CAD risk after adjustment for measured lipoprotein concentrations. Mediation analysis implicated inflammation as a major mediator (proportion mediated: 62%) of the excess TRL-associated CAD risk. Main analyses were replicated in the Multi-Ethnic Study of Atherosclerosis. Our findings provide deeper insight into the biological processes triggered by atherogenic lipoproteins that extend beyond lipid deposition in the arterial wall.