Key result
Higher proteomic score for triglyceride-rich lipoproteins is linked to ~16% higher CAD risk per SD.
Why the study?
All apolipoprotein B-containing lipoproteins are causal factors for CAD, but distinct proteomic signatures and biological processes underlying their per-particle atherogenicity remain unclear.
Do plasma proteomic signatures of triglyceride-rich lipoproteins and lipoprotein(a) predict incident coronary artery disease in a primary prevention population?
Cohort (n=35,269)
Yes
Do plasma proteomic signatures of triglyceride-rich lipoproteins and lipoprotein(a) predict incident coronary artery disease in a primary prevention population?
Hazard Ratio: 1.16 (95% CI 1.08–1.24)
Proteomic signatures of TRL and Lp(a) reflect immune activation and vascular remodeling pathways, highlighting non-cholesterol inflammatory mechanisms that may explain their disproportionate per-particle atherogenicity compared to LDL.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Lowering LDL cholesterol remains a cornerstone of prevention. Our findings point to biological processes that may help explain some of the risk that remains beyond LDL. The next step is to establish whether measuring or targeting these processes can improve prevention alongside existing treatments.”
“The overlap for TRL and Lp(a) is one of the most interesting findings. It suggests that these particles may affect some of the same inflammatory and vascular processes. This could help identify targets for more precisely directed prevention in the future.”
TRL and Lp(a) proteomic scores may refine CAD risk assessment beyond LDL; leaves open whether inflammatory pathways warrant targeted intervention in primary prevention.
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.
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Morze et al. (2026) conducted a cohort in Primary prevention of coronary artery disease (n=35,269). Triglyceride-rich lipoproteins (TRL) and lipoprotein(a) multi-protein scores was evaluated on Incident coronary artery disease (first hospitalization or death due to myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention) (HR 1.16, 95% CI 1.08-1.24). Higher plasma proteomic multi-protein scores for triglyceride-rich lipoproteins (HR 1.16 per 1-SD) and lipoprotein(a) (HR 1.09 per 1-SD) were significantly associated with incident coronary artery disease.
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