Identifying novel drug targets for calcific aortic valve disease through Mendelian randomization
Atherosclerosis, 2025
Xu D., Lu J., Yang Y., Hu W., Chen J., Xue J., Yang S., Cao N., Hu H., Qian N., Zhou D., Dai H., Wang J., Liu X.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
CVD | Pathophysiology | Plasma |  Olink Explore 3072/384 |
Abstract
Background and aims
Calcific aortic valve disease (CAVD) is characterized by progressive leaflet thickening and calcification, with no available pharmacological treatments. Plasma proteins play a pivotal role in disease regulation. This study aimed to uncover novel therapeutic targets for CAVD using Mendelian randomization (MR) integrated with transcriptomic analysis.
Methods
Protein quantitative trait loci (pQTL) from the deCODE and UK Biobank Pharma Proteomics Project (UKB-PPP) plasma protein databases were used as exposure data. The FinnGen cohort (9870 cases, 402,311 controls) served as the discovery set, while the TARGET cohort (13,765 cases, 640,102 controls) provided validation. MR and summary data-based Mendelian randomization (SMR) were employed to screen for potential causal targets of CAVD. Colocalization analysis was conducted to assess whether CAVD and target proteins shared common causal SNPs. Additional analyses included trancriptomic profiling at multiple RNA levels. Protein-level validation was conducted via Western blot and immunostaining.
Results
Six proteins (ANGPTL4, PCSK9, ITGAV, CTSB, GNPTG, and FURIN) with strong genetic colocalization were identified by MR and SMR analysis. Among these, cellular trancriptomic analysis revealed ANGPTL4 and ITGAV with significantly greater expression in osteogenic group, which was further validated in calcified aortic valves and osteogenic valvular interstitial cells in protein level.
Conclusions
This study identified six causal proteins with strong genetic colocalization for CAVD, with ANGPTL4 and ITGAV emerging as the most promising targets for further investigation.