1. Determining the genetic basis of anthracycline-cardiotoxicity by molecular response QTL mapping in induced cardiomyocytes
- Author
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Nadine Norton, Daniel J. Serie, Yoav Gilad, Kristen M. Patterson, David A. Knowles, Carole Ober, Courtney K Burrows, Jonathan K. Pritchard, and John D. Blischak
- Subjects
0301 basic medicine ,Anthracycline ,QH301-705.5 ,Science ,Quantitative Trait Loci ,Genome-wide association study ,oxidative damage ,030204 cardiovascular system & hematology ,Quantitative trait locus ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Anthracyclines ,Myocytes, Cardiac ,Doxorubicin ,Biology (General) ,Gene ,Cells, Cultured ,Cardiotoxicity ,General Immunology and Microbiology ,Sequence Analysis, RNA ,Gene Expression Profiling ,General Neuroscience ,General Medicine ,iPSC-derived differentiated cells ,030104 developmental biology ,Molecular Response ,Cancer research ,Medicine ,anthracycline-induced toxicity ,response expression QTL ,Genome-Wide Association Study ,medicine.drug - Abstract
Anthracycline-induced cardiotoxicity (ACT) is a key limiting factor in setting optimal chemotherapy regimes, with almost half of patients expected to develop congestive heart failure given high doses. However, the genetic basis of sensitivity to anthracyclines remains unclear. We created a panel of iPSC-derived cardiomyocytes from 45 individuals and performed RNA-seq after 24 hr exposure to varying doxorubicin dosages. The transcriptomic response is substantial: the majority of genes are differentially expressed and over 6000 genes show evidence of differential splicing, the later driven by reduced splicing fidelity in the presence of doxorubicin. We show that inter-individual variation in transcriptional response is predictive of in vitro cell damage, which in turn is associated with in vivo ACT risk. We detect 447 response-expression quantitative trait loci (QTLs) and 42 response-splicing QTLs, which are enriched in lower ACT GWASp-values, supporting the in vivo relevance of our map of genetic regulation of cellular response to anthracyclines.
- Published
- 2018