Plasma proteins and onset of atherosclerosis: Integrating human plasma proteogenomics, transcriptomics and in vivo evidence

Backgroud: Atherosclerosis, a leading driver of cardiovascular disease (CVD), lacks effective early therapeutic targets. Leveraging plasma proteome-wide Mendelian randomization (MR), this study identifies novel causal proteins implicated in atherosclerosis pathogenesis. Method: Genome-wide MR was conducted using cis-pQTLs from deCODE and UKB-PPP cohorts (approximately 90,000 individuals) as instrumental variables, integrating colocalization, summary-data-based MR (SMR), and HEIDI tests to validate causal proteins. Key findings were replicated in coronary artery disease (CAD) and CVD from CARDIoGRAMplusC4D and FinnGen cohorts. Proteins passing replication MR were subjected to phenome-wide association study (PheWAS). Single cell-type expression, transcriptome analyses, histological staining, and ELISA assays were used to identify candidate proteins' expression in specific cells or tissues. Results: Among 2711 proteins, 28 exhibited robust genetic associations with atherosclerosis. Five proteins (ADK, ANGPTL4, CD4, MGAT1, SYT11) passed colocalization (PP.H4>0.8) and SMR validation. Replication MR and PheWAS analyses confirmed ADK, CALB2, and COMT's causal role in CAD and CVD. CALB2 was specifically enriched in mast cells in plaques and adipose tissue, with elevated plasma levels in patients with severe carotid artery stenosis (CAS). Conclusions: We identified 28 potential therapeutic targets for atherosclerosis and verified elevated plasma CALB2 levels in severe CAS patients, offering a novel therapeutic targets for future drug development.