Conserved RNA-protein modules link early anthracycline responses to atrial fibrillation risk

Anthracycline chemotherapeutics increase risk for cardiovascular disease. The early molecular events that link inherited risk to cardiac dysfunction remain poorly defined. We therefore exposed iPSC-derived cardiomyocytes from six individuals to three anthracyclines and an anthracenedione, which act as topoisomerase inhibitors (TOP2i) to induce DNA damage, and generated proteomics data following three and 24 hours of TOP2i treatment. We constructed a 19 module co-expression network and identified four protein modules that associate with response to all TOP2i. Integration with a co-expression network generated from paired transcriptomic data revealed that the two most drug-responsive protein modules are preserved in the RNA network. The most preserved RNA module is enriched for p53 motifs in associated active regulatory regions and p53 target genes, which propagates to enrichment of p53 targets in the most drug-responsive preserved protein module. Integration of the protein network with genome-wide association studies across hundreds of cardiovascular traits identified a preserved protein module enriched for genetic risk of atrial fibrillation, PR interval, and longitudinal strain, suggesting that the molecular response to TOP2i is linked to genetic variation influencing cardiac electrophysiology and contractile performance. Differential protein abundance in this module associates with impaired calcium handling in cardiomyocytes thereby linking molecular effects to cellular decline. Together, these results define a TOP2i-induced gene regulatory response propagated to the proteome that underlies early cardiotoxicity, and demonstrate how a multi-level network architecture can provide insight into genetically mediated susceptibility to drug-induced stress.