Mapping the Genetic Basis of Cardiac Sensitivity to Anthracyclines
David Knowles, postdoctoral scholar at Stanford University, will deliver the talk, "Mapping the Genetic Basis of Cardiac Sensitivity to Anthracyclines".
Abstract: Many chemotherapeutics, including anthracyclines, have side effects on the healthy functioning of the heart. This anthracycline cardiotoxicity (ACT) leads to chronic heart failure in a dose-dependent manner. ACT is therefore a key limiting factor in setting optimal chemotherapy regimes. However, the genetic basis of sensitivity to anthracyclines such as doxorubicin remains unclear. We created a panel of iPSC-derived cardiomyocytes from 45 individuals and performed RNA-seq after 24h exposure to varying levels of doxorubicin. Inter-individual variation in transcriptional response is predictive of in vitro cell damage, which in turn is associated with in vivo ACT risk. Using an efficient linear mixed model, suez, we detect 447 response-expression quantitative trait loci (QTLs). Combining suez with our RNA splicing quantification algorithm LeafCutter we find 42 response-splicing QTLs. These molecular response QTLs are enriched in lower ACT genome-wide association study p-values, further supporting the in vivo relevance of our map of genetic regulation of cellular response to anthracyclines.
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