Circulating Plasma Proteins Influence the Risk of Aortic Dissection via Blood Pressure: A Network Mendelian Randomization and Multi-Omics Study

Background: The causal link between plasma proteins and aortic dissection (AD), and the role of blood pressure (BP) in this relationship, is not well understood. Methods: We applied an integrated network Mendelian randomization (MR) and multi-omics framework to investigate the causal effects of plasma proteins on AD and the mediating role of BP. Genetic instruments for plasma proteins were derived from deCODE genetics (n = 35,559), and genome-wide association studies (GWAS) data for BP and AD were sourced from UK Biobank (n = 458,855), Million Veteran Program (n = 449,042) and FinnGen (n = 464,256). We conducted proteome-wide MR, mediation MR, and colocalization analyses to pinpoint causal proteins and pathways. Robustness was checked through sensitivity and replication analyses. Validation was implemented by replication MR analyses and our proteomic sequencing of East Asian population. Downstream analyses, including single‑cell RNA sequencing analysis, drug target analysis and phenome-wide association study (PheWAS) analysis were performed. Results: Genetically predicted hypertension and diastolic BP were linked to a higher risk of AD. Proteome-wide MR identified 9 plasma proteins affecting both BP and AD, notably CCN3, COL6A3, NPPB, and NQO1, with BP mediating 5.43-22.74% of their effects on AD. Colocalization analysis showed shared genetic variants between CCN3 and DBP (PP.H4 = 92.10%), and COL6A3 and AD (PP.H4 = 71.60%). Subsequent analyses validated the mediating effects and expression tendency of candidate proteins, revealed their underlying molecular mechanisms, and identified potential targeted drugs. Conclusion: By mapping plasma proteins that affect AD risk and quantifying the mediation effect of BP, our work nominates CCN3, COL6A3, NPPB, and NQO1 as promising biomarkers and therapeutic targets, aiming to provide novel strategies for the early identification and intervention of AD.