A non-coding GWAS variant impacts anthracycline-induced cardiotoxic phenotypes in human iPSC-derived cardiomyocytes

Xi Wu, Fei Shen, Guanglong Jiang, Gloria Xue, Santosh Philips, Laura Gardner, Geneva Cunningham, Casey Bales, Erica Cantor and Bryan Paul Schneider ()
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Xi Wu: Indiana University School of Medicine
Fei Shen: Indiana University School of Medicine
Guanglong Jiang: Indiana University School of Medicine
Gloria Xue: Indiana University School of Medicine
Santosh Philips: Indiana University School of Medicine
Laura Gardner: Indiana University School of Medicine
Geneva Cunningham: Indiana University School of Medicine
Casey Bales: Indiana University School of Medicine
Erica Cantor: Indiana University School of Medicine
Bryan Paul Schneider: Indiana University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Anthracyclines, widely used to treat breast cancer, have the potential for cardiotoxicity. We have previously identified and validated a germline single nucleotide polymorphism, rs28714259, associated with an increased risk of anthracycline-induced heart failure. We now provide insights into the mechanism by which rs28714259 might confer increased risk of cardiac damage. Using hiPSC-derived cardiomyocyte cell lines with either intrinsic polymorphism or CRISPR-Cas9-mediated deletion of rs28714259 locus, we demonstrate that glucocorticoid receptor signaling activated by dexamethasone pretreatment prior to doxorubicin exposure preserves cardiomyocyte viability and contractility in cardiomyocytes containing the major allele. Homozygous loss of the rs28714259 major allele diminishes dexamethasone’s protective effect. We further demonstrate that the risk allele of rs28714259 disrupts glucocorticoid receptor and rs28714259 binding affinity. Finally, we highlight the activation of genes and pathways involved in cardiac hypertrophy signaling that are blocked by the risk allele, suggesting a decreased adaptive survival response to doxorubicin-related stress.

Date: 2022
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DOI: 10.1038/s41467-022-34917-y

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