ArticleScientific reports2020
Variation in RARG increases susceptibility to doxorubicin-induced cardiotoxicity in patient specific induced pluripotent stem cell-derived cardiomyocytes.
Article in Scientific reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 2 of them syntheses that pooled it.
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Who cites it
27 citing papers in PubMed, 2 syntheses or guidelines pooled it, 46 citations in OpenAlex.
- Pharmacogenetics of chemotherapy treatment response and -toxicities in patients with osteosarcoma: a systematic review.BMC cancer · 2022Pooled it
- Using human induced pluripotent stem cell-derived cardiomyocytes to understand the mechanisms driving cardiomyocyte maturation.Frontiers in cardiovascular medicine · 2022Pooled it
- Organ-on-a-Chip and Lab-on-a-Chip Technologies in Cardiac Tissue Engineering.Biomimetics (Basel, Switzerland) · 2025Review
- SNP's use as a potential chemotoxicity stratification tool in breast cancer: from bench to clinic.Functional & integrative genomics · 2025Review
- Cardiovascular Toxicity in Cancer Therapy: Protecting the Heart while Combating Cancer.Current cardiology reports · 2024Review
- Risk of anthracycline-induced cardiac dysfunction in adolescent and young adult (AYA) cancer survivors: role of genetic susceptibility loci.The pharmacogenomics journal · 2024Article
- Anthracyclines induce cardiotoxicity through a shared gene expression response signature.PLoS genetics · 2024Article
- hiPSC-derived cardiomyocytes as a model to study the role of small-conductance CaFrontiers in cell and developmental biology · 2024Review
- The Essential Strategies to Mitigate Cardiotoxicity Caused by Doxorubicin.Life (Basel, Switzerland) · 2023Review
- Doxorubicin-Induced Cardiomyopathy: A Preliminary Study on the Cardioprotective Benefits of 7-Hydroxyflavanone.International journal of molecular sciences · 2023Article
- Review
- Pharmacogenomics for Prediction of Cardiovascular Toxicity: Landscape of Emerging Data in Breast Cancer Therapies.Cancers · 2022Review
- Novel molecular biomarkers of cancer therapy-induced cardiotoxicity in adult population: a scoping review.ESC heart failure · 2022Article
- Doxorubicin impacts chromatin binding of HMGB1, Histone H1 and retinoic acid receptor.Scientific reports · 2022Article
- RARG S427L attenuates the DNA repair response to doxorubicin in induced pluripotent stem cell-derived cardiomyocytes.Stem cell reports · 2022Article
- Pharmacogenomics in drug-induced cardiotoxicity: Current status and the future.Frontiers in cardiovascular medicine · 2022Review
- All-trans retinoic acid (ATRA) regulates key genes in the RARG-TOP2B pathway and reduces anthracycline-induced cardiotoxicity.PloS one · 2022Article
- Deciphering pathogenicity of variants of uncertain significance with CRISPR-edited iPSCs.Trends in genetics : TIG · 2021Review
- Article
- Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Doxorubicin is a potent anticancer drug used to treat a variety of cancer types. However, its use is limited by doxorubicin-induced cardiotoxicity (DIC). A missense variant in the RARG gene (S427L; rs2229774) has been implicated in susceptibility to DIC in a genome wide association study. The goal of this study was to investigate the functional role of this RARG variant in DIC. We used induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from patients treated with doxorubicin. iPSC-CMs from individuals who experienced DIC (cases) showed significantly greater sensitivity to doxorubicin compared to iPSC-CMs from doxorubicin-treated individuals who did not develop DIC (controls) in cell viability and optical mapping experiments. Using CRISPR/Cas9, we generated isogenic cell lines that differed only at the RARG locus. Genetic correction of RARG-S427L to wild type resulted in reduced doxorubicin-induced double stranded DNA breaks, reactive oxygen species production, and cell death. Conversely, introduction of RARG-S427L increased susceptibility to doxorubicin. Finally, genetic disruption of the RARG gene resulted in protection from cell death due to doxorubicin treatment. Our findings suggest that the presence of RARG-S427L increases sensitivity to DIC, establishing a direct, causal role for this variant in DIC.
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Registered trials
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