Lp(a) proteomic signature associates with incident CAD and inflammatory pathways mediate 14% of risk (Eur Heart J 2026)

Background And Aims: All apolipoprotein B-containing lipoproteins are established causal factors for coronary artery disease (CAD). This study aimed to identify robust proteomic signatures of low-density lipoprotein (LDL), triglyceride-rich lipoproteins (TRL), and lipoprotein(a) [Lp(a)] and to evaluate whether these signatures illuminate biological processes underlying differences in per-particle atherogenicity.

Methods: Plasma proteins associated with LDL, TRL, and Lp(a) concentrations were identified using multivariable-adjusted regression across 2918 proteins in a primary prevention cohort based on UK Biobank (n=35,269), and findings were corroborated using one-sample Mendelian randomization. Proteins consistently identified by both approaches were summarized into lipoprotein-specific multi-protein scores and associated with incident CAD (n=1599 events) using Cox regression. High-dimensional mediation analysis quantified the proportion of lipoprotein-associated CAD risk explained by proteomic alterations. Findings were replicated in the Multi-Ethnic Study of Atherosclerosis (n=5915).

Results: Requiring concordance between observational and Mendelian randomization analyses (both Bonferroni-adjusted P<0.05), 30 proteins were identified as associated with LDL, 471 with TRL, and 53 with Lp(a). The TRL and Lp(a) signatures were distinct from the LDL signature yet overlapped substantially with each other (36 shared proteins), with common enrichment in inflammatory pathways. After adjustment for potential confounders and measured lipoprotein concentrations, the multi-protein scores for TRL (hazard ratio per 1-SD [HRSD], 1.16; 95% confidence interval [95%CI]: 1.08-1.24) and Lp(a) (HRSD, 1.09; 95%CI: 1.03-1.15), but not LDL (HRSD, 0.95; 95%CI: 0.89-1.02), were associated with incident CAD. Mediation analysis was consistent with immune activation and vascular remodeling markers mediating TRL-associated CAD risk (proportion mediated, 62%) and, in part, Lp(a)-associated risk (14%).

Conclusions: Beyond arterial lipid deposition, TRL and Lp(a) converge on inflammatory and vascular remodeling pathways that, under the assumptions of observational mediation analysis, may explain their excess per-particle atherogenicity compared with LDL.