Mendelian randomization makes it possible to infer if a drug target protein will have an on-target effect on disease-relevant traits.
Investigators identified a set of 33 protein drug targets that affect cardiac magnetic resonance(CMR) traits and cardiac outcomes, according to a recent study published in Science Advances.
“By leveraging orthogonal lines of evidence on mRNA expression, protein interactions, and drug compound indications and side effects, we were able to identify a robust set of proteins affecting CMR and cardiac outcomes,” wrote study authors in the article.
CMR is the gold standard for measuring morphology and right ventricle (RV) or left ventricle (LV) function—the disfunction of which leads to heart failure (HF). CMR is used as a diagnostic tool for cardiac disease (CD).
Proteins make up most CD drug targets, with assays used to measure plasma proteins. Together, proteins and CMR measurements can be leveraged for drug target validation. During the study, investigators aimed to identify proteins that affect CD outcomes.
The investigators conducted a genome-wide association study (GWAS) to find CMR measurements of the RV and LV structure and functions. Then they performed a cis-Mendelian randomization (MR) to identify plasma proteins that were associated with CMR traits andcardiac outcomes (HF, non-ischemic cardiomyopathy (non-ischemic CM), dilated cardiomyopathy (DCM), atrial fibrillation (AF), or coronary heart disease (CHD)). In terms of measurement, a protein could have a “beneficial,” “harmful,” or “mixed,” effect on CMR and cardiac outcomes.
Within the 33 proteins prioritized for cardiac outcomes, 9 affected HF, 13 DCM, 7 non-ischemic CM, 12 AF, and 9 CHD. Of the 25 proteins associated with HF, DCM, and non-ischemic CM, higher levels of the BAG family molecular chaperone regulator 3 (BAG3) protein represented areduced risk of HF and non-ischemic CM and it improved 6 CMR traits. Increased levels of tumor necrosis factor ligand superfamily member 12 (TNF12) reflected lower risk of non-ischemic CM.
The plasma endoplasmic reticulum aminopeptidase 1 protein, which is involved in cardiomyocyte pathogenesis, affects CHD, AF, and non-ischemic CM. Investigators also observed that proteins that promote interleukin 8 may be linked to lower risk of AF and HF. The results of this CMR GWA further suggest that TNR5, TNF12, milk fat globule membrane, CPC5, and BAG3 proteins affected HF and DCM and should be considered leads for drug development.
Of the 25 druggable proteins, 15 had known cardiovascular adverse events. For instance, the protein SLAM family member 7 is a current target for cancer, but it was found to be harmful andto increase risk of HF.
The investigators noted that there are limitations to the study. First, it may include population stratification bias because individuals without European ancestry were included. In addition, MR estimates are not always effective at tracking change across age, nor do they detect dose-specific effects, and the study cannot conclude that the proteins affect multiple CMR traits and cardiac outcomes.
“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,” study authors wrote in the article.
Schmidt A, Bourfiss M, Finan C, et al. Druggable proteins influencing cardiac structure and function: Implications for heart failure therapies and cancer cardiotoxicity. Sci Advances. April 26, 2023. doi:10.1126/sciadv.add4984