Mapping the Proteomic Landscape of Aortic Aneurysm and Dissection in the Context of Hypertension

BackgroundAortic aneurysm and dissection (AAD) are highly lethal conditions for which hypertension serves as a primary risk factor. The limited efficacy of conventional antihypertensive treatments suggests an inadequate understanding of the molecular mechanisms that connect these conditions. Despite their pivotal role in regulating biological functions, the specific proteomic signatures associated with both hypertension and AAD have not been extensively investigated. This study sought to conduct a comprehensive mapping of the plasma proteome to identify novel biomarkers and therapeutic targets for AAD within a hypertensive cohort. MethodsWe analyzed 2,923 plasma proteins in 26,690 hypertensive individuals without a prior history of AAD from the UK Biobank. LASSO and Cox regression analyses were employed to identify proteins associated with AAD, while a LightGBM algorithm was utilized to construct predictive models. Causal inference was conducted using two-sample Mendelian randomization (MR). Further mechanistic exploration included colocalization, single-cell RNA sequencing, functional enrichment, and drug-target analysis. ResultsAmong the core hypertension proteins, we identified 186 proteins independently associated with AAD risk, with MMP12 showing the strongest association. A streamlined model, which included the top five proteins alongside age and sex, exhibited superior predictive performance (AUC: 0.791) compared to traditional risk models. MR analysis confirmed causal relationships for 21 proteins with AAD, and colocalization provided high-confidence evidence for shared genetic architecture for MMP7, CCN3, and COL6A3. Mechanistically, single-cell analysis verified cell-type-specific aortic expression of candidate genes, functional enrichment implicated extracellular matrix (ECM) pathways. Furthermore, we identified 95 FDA-approved drugs targeting 11 of these causal proteins. ConclusionThis study presents the first comprehensive plasma proteomic landscape of AAD within a large hypertensive cohort, offering a high-performance predictive model, validating novel causal proteins, and identifying actionable drug targets. These findings provide crucial molecular insights into the pathogenesis of AAD and establish a solid foundation for developing early-detection strategies, improving risk stratification, and guiding precision medicine.