Format

Send to

Choose Destination
Elife. 2018 May 8;7. pii: e33480. doi: 10.7554/eLife.33480.

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

Author information

1
Department of Genetics, Stanford University, Stanford, United States.
2
Department of Radiology, Stanford University, Stanford, United States.
3
Department of Human Genetics, University of Chicago, Chicago, United States.
4
Department of Health Sciences Research, Mayo Clinic, Jacksonville, United States.
5
Department of Cancer Biology, Mayo Clinic, Jacksonville, United States.
6
Department of Biology, Stanford University, Stanford, United States.
7
Howard Hughes Medical Institute, Stanford University, Stanford, United States.
8
Department of Medicine, University of Chicago, Chicago, United States.
#
Contributed equally

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 [Formula: see text]-values, supporting the in vivo relevance of our map of genetic regulation of cellular response to anthracyclines.

KEYWORDS:

Doxorubicin; anthracycline-induced toxicity; evolutionary biology; genetics; genomics; human; human biology; iPSC-derived differentiated cells; medicine; oxidative damage; response expression QTL

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center