Determining the genetic basis of anthracycline-cardiotoxicity by molecular response QTL mapping in induced cardiomyocytes

David A. Knowles, Courtney K. Burrows, John D. Blischak, Kristen M. Patterson, Daniel J. Serie, Nadine Norton, Carole Ober, Jonathan K. Pritchard, Yoav Gilad

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 GWAS p-values, supporting the in vivo relevance of our map of genetic regulation of cellular response to anthracyclines.

Original languageEnglish (US)
Article numbere33480
JournaleLife
Volume7
DOIs
StatePublished - May 8 2018

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Quantitative Trait Loci
Anthracyclines
Cardiac Myocytes
Doxorubicin
Genes
Chemotherapy
Genome-Wide Association Study
Heart Failure
Cells
Cardiotoxicity
RNA
Drug Therapy

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Knowles, D. A., Burrows, C. K., Blischak, J. D., Patterson, K. M., Serie, D. J., Norton, N., ... Gilad, Y. (2018). Determining the genetic basis of anthracycline-cardiotoxicity by molecular response QTL mapping in induced cardiomyocytes. eLife, 7, [e33480]. https://doi.org/10.7554/eLife.33480.001

Determining the genetic basis of anthracycline-cardiotoxicity by molecular response QTL mapping in induced cardiomyocytes. / Knowles, David A.; Burrows, Courtney K.; Blischak, John D.; Patterson, Kristen M.; Serie, Daniel J.; Norton, Nadine; Ober, Carole; Pritchard, Jonathan K.; Gilad, Yoav.

In: eLife, Vol. 7, e33480, 08.05.2018.

Research output: Contribution to journalArticle

Knowles, DA, Burrows, CK, Blischak, JD, Patterson, KM, Serie, DJ, Norton, N, Ober, C, Pritchard, JK & Gilad, Y 2018, 'Determining the genetic basis of anthracycline-cardiotoxicity by molecular response QTL mapping in induced cardiomyocytes', eLife, vol. 7, e33480. https://doi.org/10.7554/eLife.33480.001
Knowles, David A. ; Burrows, Courtney K. ; Blischak, John D. ; Patterson, Kristen M. ; Serie, Daniel J. ; Norton, Nadine ; Ober, Carole ; Pritchard, Jonathan K. ; Gilad, Yoav. / Determining the genetic basis of anthracycline-cardiotoxicity by molecular response QTL mapping in induced cardiomyocytes. In: eLife. 2018 ; Vol. 7.
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