Druggable proteins influencing cardiac structure and function: Implications for heart failure therapies and cancer...

Area of Science:

• Genetics
• Cardiology
• Pharmacology

Background:

• Ventricular dysfunction is a major cause of heart failure (HF), leading to significant morbidity and mortality.
• Cardiac magnetic resonance (CMR) imaging provides detailed insights into biventricular structure and function.

Purpose of the Study:

• To conduct a genome-wide association study (GWAS) on 16 CMR imaging traits.
• To utilize cis-Mendelian randomization (MR) to identify plasma proteins associated with cardiac traits and outcomes.
• To discover potential therapeutic targets and understand mechanisms of cardiotoxicity.

Main Methods:

• Performed a GWAS on 16 CMR imaging measurements of biventricular function and structure.
• Employed cis-Mendelian randomization (MR) to link plasma proteins with CMR traits and cardiac outcomes (HF, cardiomyopathy, atrial fibrillation, coronary heart disease).

Main Results:

• Prioritized 33 plasma proteins associated with cardiac traits and outcomes.
• Identified potential drug repurposing candidates for dilated cardiomyopathy (DCM) and/or HF, including IL18R, I17RA, GPC5, LAMC2, PA2GA, CD33, and SLAF7.
• Found that 52% of druggable proteins identified are linked to existing cancer drugs, suggesting shared mechanisms.

Conclusions:

• The study provides novel insights into the genetic underpinnings of biventricular function and structure.
• Identified 33 plasma proteins as potential therapeutic targets for heart diseases like HF and DCM.
• Suggests that cardiotoxicities observed in cancer treatments may be mechanism-based adverse effects, offering avenues for drug development and risk mitigation.