Cardiovascular diseases (CVDs) stubbornly persist as the foremost cause of death and disability worldwide, despite decades of advances in prevention and treatment. Conventional risk factors such as hypertension, smoking, and hyperlipidemia only partially explain the complex nature of these diseases. Consequently, unveiling novel biological pathways and therapeutic targets remains an urgent challenge. A groundbreaking study recently published in Life Metabolism by Prof. Zhongshang Yuan and colleagues at Shandong University has moved the needle by harnessing an integrated omics approach enriched with cardiovascular magnetic resonance (CMR) imaging to identify plasma proteins that are potentially druggable for a broad spectrum of cardiovascular conditions.
This ambitious investigation integrates multi-layered datasets, including proteomic quantitative trait loci (pQTL) data drawn from approximately 1,348 plasma proteins in the ARIC cohort alongside genome-wide association study (GWAS) summary statistics for 19 distinct cardiovascular diseases procured from FinnGen and 82 CMR-derived phenotypes from the UK Biobank. This meticulous design allows an unprecedented high-resolution molecular dissection of CVD pathogenesis, bridging genetic associations, protein expression, and structural heart traits demarcated through advanced imaging.
Initially, a proteome-wide association study (PWAS) scanned the landscape to pinpoint protein-disease correlations across the cardiovascular clinical phenotypes and magnetic resonance imaging traits. Following this, Mendelian randomization (MR) and colocalization analyses were deployed to differentiate correlation from causality, a critical distinction to prioritize protein targets that plausibly contribute to disease mechanisms rather than simply reflecting downstream effects. Importantly, this pipeline included an external layer of replication through the independent deCODE genetics dataset, strengthening the robustness of these discoveries.
The results were compelling, unveiling 342 significant protein-CVD associations and 115 protein-CMR relationships in the discovery phase. MR and colocalization trimmed these to 66 and 39 putative causal pairs respectively. The replication analysis further bolstered confidence by validating 51 protein-disease and 33 protein-imaging associations. Among these, four plasma proteins—AGER, CCN3, FER, and SPON1—emerged as particularly striking candidates due to their consistent genetic linkage with both clinical cardiovascular events such as myocardial infarction (MI) and aortic aneurysm (AA), and intermediate imaging phenotypes like left ventricular cardiac output (LVCO) and left ventricular end-systolic volume (LVESV).
AGER (advanced glycosylation end product-specific receptor), known for mediating inflammatory responses, was implicated through its plasma abundance in modulating structural and functional cardiac remodeling. Likewise, CCN3 (cellular communication network factor 3), a matricellular protein influencing cell adhesion and signaling, was identified as a nexus point between extracellular matrix dynamics and cardiovascular health. FER, a non-receptor tyrosine kinase with emerging roles in immune regulation, demonstrated differential expression at single-cell resolution in aortic tissue, especially within endothelial and smooth muscle cells, highlighting its plausible involvement in vascular integrity and inflammation. SPON1 (spondin-1), an extracellular matrix protein with functions in cell adhesion and neural development, also showed promising associations, warranting further biological exploration.
The incorporation of cardiovascular magnetic resonance imaging added a transformative dimension to this omics study. CMR provides exquisitely detailed phenotyping of cardiac morphology and function beyond traditional clinical diagnoses, enabling the capture of subclinical and intermediate traits. By relating plasma protein levels to quantitative CMR metrics, this study elucidated not only disease associations but also underlying pathophysiological mechanisms, bridging molecular and anatomical domains.
Single-cell RNA sequencing analyses further enriched the context by delineating the cellular specificity of critical proteins within cardiovascular tissues. This high-resolution cellular map revealed, for instance, how FER expression varies among vascular cell types, supporting roles in both vascular remodeling and immune cell interactions. Such insights deepen mechanistic understanding and open avenues for targeted interventions that modulate specific cell populations in the cardiovascular milieu.
From a translational perspective, the study advances the burgeoning field of cardio-immunology by linking systemic immune-related proteins to cardiovascular structure and disease risk. This integrative framework offers a compendium of prioritized plasma proteins that could serve as therapeutic targets or biomarkers, potentially accelerating drug development pipelines. Moreover, by leveraging genetic instruments and large-scale biobanks, the approach circumvents common pitfalls of confounding and reverse causation that have long plagued observational research.
However, the researchers prudently acknowledge several limitations. The cohorts studied predominantly consist of individuals of European ancestry, underscoring the need for validation in diverse populations to ensure generalizability and equity in therapeutic advances. Additionally, while the multi-omics approach robustly implicates proteins in disease processes, functional experiments remain essential to unravel precise molecular mechanisms and to test pharmacologic modifiability.
Looking forward, the integration of cardiovascular imaging with omics modalities represents a powerful paradigm for biomarker discovery and drug target prioritization. This fusion of genomic, proteomic, and phenotypic data elevates precision medicine efforts in cardiology, enabling stratification of disease subtypes and personalized therapy strategies. As cardiovascular diseases continue to represent a global health burden, such innovative methodologies pave the way toward more effective prevention and treatment, moving beyond traditional risk factor frameworks.
In conclusion, this landmark study exemplifies how comprehensive multi-omics coupled with advanced imaging can unravel the intricate biological networks underlying cardiovascular diseases. By spotlighting druggable plasma proteins like AGER, CCN3, FER, and SPON1, it charts a promising course for future research and therapeutic innovation. The findings herald a new era in cardiovascular medicine, where integrative analyses illuminate pathogenesis and catalyze breakthroughs against this pervasive, devastating group of diseases.
Subject of Research: Not applicable
Article Title: Integrative omics analysis incorporating cardiovascular magnetic resonance imaging pinpoints potentially druggable plasma proteins for cardiovascular diseases
News Publication Date: 7-Jan-2026
Web References: http://dx.doi.org/10.1093/lifemeta/loag001
Image Credits: HIGHER EDUCATION PRESS
Keywords: Cell biology
