Objective To investigate the association between plasma proteins and coronary artery disease (CAD) risk using data from the UK Biobank.

Methods Cox proportional hazards models were applied to assess prospective associations of 2, 911 proteins with CAD incidence. Pathway enrichment analysis was performed to identify relevant biological processes. Two-sample Mendelian randomization (MR) and colocalization analyses were conducted to infer causal relationships, and the clinical translational potential of key proteins was evaluated using DrugBank databases.

Results During a median follow-up of 14.52 years, 3, 760 incident CAD cases were documented. A total of 508 proteins were identified to be significantly associated with the risk of CAD, and these proteins were enriched in atherosclerosis-related pathways. MR analysis confirmed 27 proteins with causal evidence for CAD. Colocalization analysis supported shared causal genetic variants between CAD and PCSK9/IFI30 proteins. Drug target validation indicated existing pharmacological development potential for several proteins.

Conclusion This study identifies key plasma proteins associated with CAD risk and demonstrates their causal roles, providing a theoretical foundation for elucidating disease mechanisms and developing early prediction models and precision treatment strategies.