Abstract Body (Do not enter title and authors here): Background Calcific aortic valve disease (CAVD) is a degenerative disease characterized by aortic valve fibrosis and calcification with no medications available for treatment. Multi-omics research is highly beneficial for identifying disease targets. In this study, we aimed to identify potential therapeutic targets for CAVD through Mendelian randomization (MR) and summary data-based Mendelian randomization (SMR) combined with transcriptomic analysis.
Methods Protein quantitative trait locis (pQTLs) from two whole plasma protein databases deCODE and UK biobank pharma proteomics project (UKB-PPP) were utilized as the exposure. Three large CAVD cohorts from FinnGen (9,870 cases and 402,311 controls), the UK Biobank (3,552 cases and 425,855 controls) and France (3,123 cases and 6,531 controls) served as the outcome. MR and SMR was used to screen potential causal targets for CAVD. Colocalization analysis was performed to determine whether CAVD and target proteins shared common causal SNPs. Single-cell and bulk RNA sequencing was further used to detect the cell-type specific and differential expression of target proteins. Drug prediction and molecular docking was applied to discover potential medications.
Results 15 plasma proteins were identified via MR and SMR analysis with 6 strongly supported via colocalization analysis. Among them, angiopoietin-related protein 4 (ANGPTL4) and integrin alpha-V (ITGAV) were validated in the replication CAVD cohorts from the UK Biobank or France as well as the bulk RNA sequencing data. Both of ANGPTL4 (OR = 1.963, 95% CI: 1.460-2.641, P_FDR = 7.30E-03) and ITGAV (OR = 1.579,95% CI: 1.257-1.985, P_FDR = 3.48E-02) were risk factors of CAVD and the protein levels of ANGPTL4 and ITGAV was upregulated in valvular interstitial cells as proved by Western blot. Molecular docking suggested a stable binding between the target proteins and medications.
Conclusions In a combination of proteome-wide MR and RNA sequencing analysis, ANGPTL4 and ITGAV were identified as the pivotal protein targets associated with the progression of CAVD.