Mass-spectrometry method changes the Lp(a) proteome, but a 34-protein core is method-independent (J Clin Med 2026)

Background: Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD). Proteomic studies suggest that Lp(a)-associated proteins mediate inflammation, thrombosis, and vascular calcification, but methodological variability may influence proteome definition. Methods: Lp(a) was immunoprecipitated from human plasma using an apo(a)-specific monoclonal antibody and analyzed by mass spectrometry following either in-gel digestion or automated in-solution proteolysis. Proteins identified by ≥3 unique peptides and consistently detected across all samples by both methods were considered high confidence. Functional enrichment and interaction networks were assessed using STRING. Results: In-solution proteolysis identified 92 proteins and in-gel digestion identified 55 proteins, with 34 proteins shared between methods. These high-confidence proteins were enriched for pathways involved in lipoprotein remodeling, coagulation regulation, vesicle-mediated transport, lipid binding, and extracellular matrix organization, providing biological insight into mechanisms linking Lp(a) to inflammation, thrombosis, and calcification. Conclusions: Proteome composition of Lp(a) is method-dependent; however, a rigorously defined core proteome of 34 proteins was consistently identified across analytical approaches, highlighting biologically relevant pathways that may underlie Lp(a)-mediated ASCVD risk.