Cardiovascular diseases (CVDs) remain a leading cause of global morbidity and mortality, with significant residual risk unexplained by traditional factors. The discovery of novel therapeutic targets or the repurposing of existing drug targets could improve the prevention and treatment for different CVDs. However, previous studies have encountered different analytic challenges, such as failing to cover the whole spectrum of CVDs, not including cardiovascular magnetic resonance imaging (CMR) traits or lack of large-scale replication analysis and multidimensional downstream analysis.
A recent study published in Life Metabolism led by Prof. Zhongshang Yuan at Shandong University, leverages integrative omics analysis incorporating CMR imaging to pinpoint potentially druggable plasma proteins for CVDs. By combining proteome-wide association study (PWAS), Mendelian randomization (MR), and colocalization approaches, the research identifies key proteins like AGER, CCN3, FER, and SPON1 that associate with both CVDs and CMR traits, offering novel insights into pathogenesis and therapeutic development.
The study employed a systematic pipeline using pQTL data from the ARIC study (1,348 plasma proteins) and GWAS summary statistics for 19 CVDs (from FinnGen) and 82 CMR traits (from UK Biobank). Discovery analysis involved PWAS to screen protein-disease associations, followed by MR and colocalization to infer causality. Replication was conducted with independent deCODE pQTL data, and observational associations were assessed using UK Biobank individual-level data (Figure 1).
PWAS revealed 342 protein-CVD pairs and 115 protein-CMR pairs, with MR and colocalization confirming 66 and 39 potentially causal pairs, respectively. External replication validated 51 protein-CVD and 33 protein-CMR associations. Notably, the study points out four specific plasma proteins, AGER, CCN3, FER, and SPON1, as high-priority candidates due to their consistent associations with both clinical CVDs (e.g., MI, AA) and structural CMR traits (e.g., LVCO, LVESV). Single-cell RNA sequencing analysis further supported these findings by showing differential FER expression in aortic tissues, specifically highlighting its role in cell types like smooth muscle and endothelial cells.
This research underscores the value of integrating CMR into omics frameworks to uncover therapeutic targets. The findings provide genetic evidence for future drug development and repurposing, particular within the emerging field of cardio-immunology. While the researchers note that the current data is primarily derived from European populations and requires further validation in diverse groups, the study marks a major step forward in understanding CVD pathogenesis. Overall, the study paves the way for improved CVD prevention and treatment strategies.
Life Metabolism
Experimental study
Not applicable
Integrative omics analysis incorporating cardiovascular magnetic resonance imaging pinpoints potentially druggable plasma proteins for cardiovascular diseases
7-Jan-2026