Identifying plasma proteomic biomarkers for risk prediction and therapeutic targets of abdominal aortic aneurysm: Prospective cohort and Mendelian randomization analyses
Atherosclerosis, 2025
Zhang Y., Huang Y., Gan X., Ye Z., Zhang Y., Yang S., Xiang H., Zhang Y., Wu Y., Qin X.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
CVD | Pathophysiology Patient Stratification | Plasma |  Olink Explore 3072/384 |
Abstract
Background and aims
Abdominal aortic aneurysm (AAA) lacks reliable circulating biomarkers and effective pharmacological therapies. This study aimed to investigate the observational and causal associations between plasma proteins and AAA to enhance understanding of its biological mechanisms, improve disease prediction, and identify potential therapeutic targets.
Methods
We included 51,381 participants from the UK Biobank(43,317 in the training set and 8064 in the test set) without aortic aneurysm or dissection. Observational associations between 2911 plasma proteins and incident AAA were assessed, and causal associations were evaluated using two-sample cis-Mendelian randomization (MR) analyses.
Results
Over a median follow-up of 13.1 years, 329 incident AAA cases were identified. 113 plasma proteins were significantly associated with AAA, enriched in collagen-containing extracellular matrix and pathways related to immune response, death receptor activity, cytokine-cytokine receptor interaction, and apoptosis. A simple predictive model incorporating MMP12(macrophage metalloelastase-12), CXCL17(CXC motif chemokine-17), IL6(interleukin-6), and WFDC2(WAP four-disulfide core domain protein-2)—alone or in combination—along with age and sex, demonstrated comparable predictive performance(C-index: 0.826–0.864) to the clinical risk factors model(C-index: 0.852). In cis-MR analyses, MMP12 (OR: 1.14; 95 %CI: 1.09–1.20), WFDC2 (OR:1.32; 95 %CI: 1.13–1.55), and NCR3LG1 (natural cytotoxicity triggering receptor 3 ligand 1; OR: 1.15; 95 %CI: 1.09–1.22) were causally associated with AAA. Notably, MMP12 is already a drug target for aortic aneurysm and other diseases.
Conclusions
MMP12, CXCL17, IL6, and WFDC2 are effective circulating biomarkers for AAA prediction, while MMP12, WFDC2, and NCR3LG1 represent promising therapeutic targets for AAA. These findings provide valuable insights into AAA pathogenesis and highlight potential avenues for drug development.