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

• DOI: 10.1126/sciadv.add4984
• Publication Date: 2023-04-26T18:00:51Z
• Authors: Amand F. Schmidt; Mimount Bourfiss; Abdulrahman Alasiri; Esther Puyol-Anton; Sandesh Chopade; Marion van Vugt; Sander W. van der...; Christian Gross; Chris Clarkson; Albert Henry; Tom R. Lumbers; Pim van der Harst; Nora Franceschini; Joshua C. Bis; Birgitta K. Velthuis; Anneline S. J. M....; Aroon D. Hingorani; Bram Ruijsink; Folkert W. Asselb...; Jessica van Setten; Chris Finan
• Keywords: Heart Failure; Cardiomyopathy, Dilated; Glypicans; Neoplasms; Atrial Fibrillation; Journal Article; Humans; Biomedicine and Life Sciences; General; Cardiotoxicity; 3. Good health; Genome-Wide Association Study

Dysfunction of either the right or left ventricle can lead to heart failure (HF) and subsequent morbidity and mortality. We performed a genome-wide association study (GWAS) of 16 cardiac magnetic resonance (CMR) imaging measurements of biventricular function and structure. Cis- Mendelian randomization (MR) was used to identify plasma proteins associating with CMR traits as well as with any of the following cardiac outcomes: HF, non-ischemic cardiomyopathy, dilated cardiomyopathy (DCM), atrial fibrillation, or coronary heart disease. In total, 33 plasma proteins were prioritized, including repurposing candidates for DCM and/or HF: IL18R (providing indirect evidence for IL18), I17RA, GPC5, LAMC2, PA2GA, CD33, and SLAF7. In addition, 13 of the 25 druggable proteins (52%; 95% confidence interval, 0.31 to 0.72) could be mapped to compounds with known oncological indications or side effects. These findings provide leads to facilitate drug development for cardiac disease and suggest that cardiotoxicities of several cancer treatments might represent mechanism-based adverse effects.