Plasma Proteomic Assessment of Calcific Aortic Valve Disease in Older Adults.
Summary
Aptamer-based proteomics (~5000 proteins) in CHS identified proteins associated with AVC; CXCL12, KLKB1, and leptin replicated in AGES-RS. Mendelian randomization supported a causal, protective association of higher KLKB1 with lower AVC, nominating KLKB1 as a potential therapeutic target for calcific aortic valve disease.
Key Findings
- Six proteins were significantly associated with AVC in CHS; CXCL12, KLKB1, and leptin replicated in AGES-RS.
- Mendelian randomization supported a causal association: higher KLKB1 linked to lower AVC (protective).
- CXCL6 showed a significant positive association with incident AS; CXCL12 and KLKB1 associations highlighted novel biology.
Clinical Implications
While not yet a clinical test, KLKB1 pathway modulation could be explored as a preventive strategy for CAVD; proteins like CXCL12 and leptin refine risk biology and may inform biomarker panels.
Why It Matters
This work bridges population proteomics, replication, and genetic causality to propose KLKB1 as a modifiable pathway in valve calcification, addressing a major unmet need in AS prevention.
Limitations
- Aptamer-based proteomics may have platform-specific biases; limited functional validation.
- Observational cohorts with residual confounding; MR limited to available instruments and outcomes.
Future Directions
Mechanistic studies of KLKB1 in valvular interstitial cells and animal models; drug discovery/repurposing targeting kallikrein pathways; prospective validation of proteomic panels for CAVD risk.
Study Information
- Study Type
- Cohort
- Research Domain
- Pathophysiology
- Evidence Level
- III - Observational multi-cohort proteomics with replication and genetic causal inference.
- Study Design
- OTHER