Unraveling the genetic blueprint of doxorubicin-induced cardiotoxicity through systems genetics approaches

Buyan-Ochir Orgil; Akhilesh K Bajpai; Neely Alberson; Morgan Lander; Batsaikhan Enkhzul; Hugo R Martinez; Jeffrey A Towbin; Lu Lu; Enkhsaikhan Purevjav

doi:10.1186/s40959-025-00349-y

Unraveling the genetic blueprint of doxorubicin-induced cardiotoxicity through systems genetics approaches

Cardiooncology. 2025 Jun 3;11(1):53. doi: 10.1186/s40959-025-00349-y.

Authors

Buyan-Ochir Orgil^#^{1

2}, Akhilesh K Bajpai^#³, Neely Alberson^{1

2}, Morgan Lander^{1

2}, Batsaikhan Enkhzul⁴, Hugo R Martinez⁵, Jeffrey A Towbin^{1

2

6}, Lu Lu⁷, Enkhsaikhan Purevjav^{8

9}

Affiliations

¹ Department of Pediatrics, The Heart Institute, University of Tennessee Health Science Center, Memphis, TN, USA.
² Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN, USA.
³ Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA.
⁴ Department of Pharmacology, Toxicology and Addiction Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.
⁵ Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
⁶ Cardiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
⁷ Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA. llu@uthsc.edu.
⁸ Department of Pediatrics, The Heart Institute, University of Tennessee Health Science Center, Memphis, TN, USA. epurevja@uthsc.edu.
⁹ Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN, USA. epurevja@uthsc.edu.

^# Contributed equally.

Abstract

Background: Anthracycline-induced cardiotoxicity (ACT) is a significant concern for cancer survivors, while genetic basis of ACT remains unclear. This study employs a murine genetic reference population (GRP) of BXD recombinant inbred strains, derived from DBA/2J (D2) and C57BL/6J (B6) crosses, to map quantitative trait loci (QTLs) linked to doxorubicin (DOX)-induced phenotypes through systems genetics approaches.

Methods: To model variability in ACT, 58 BXD strains and parental B6 and D2 mice (n ≥ 4 mice/sex/strain, 3-4-month-old) underwent an intraperitoneal injection of DOX (20 mg/kg). Survival and body weight (BW) were monitored for 10 days. Echocardiography was performed before treatment and on Day 5 post-treatment, followed by genetic mapping and Mendelian randomization analyses for identifying QTLs and candidate genes associated with DOX-induced traits and severity.

Results: Parental B6 strain had 60% survival, whereas 24% of D2 mice survived on Day 10. Among BXD strains, median survival varied, with BXD77 showing the lowest at Day 4. Echocardiography revealed cardiac dysfunction and a small-heart phenotype resembling ACT patients. Significant QTLs on Chromosome 10 (86-94 Mb), Chromosome 19 (52.5-54.2 Mb) and on Chromosome 14 (103-120 Mb) were associated with the survival, mean BW loss, and left ventricular (LV) volumes and ejection fraction (EF%), respectively. MR analysis identified significant causal associations between the genes implicated in BW loss (ADD3, HSPA12 A, SLC18 A2, PDZD8, DUSP5, CASP7) as well as EF% and LV volumes (GPC6, UGGT2, SLAIN1, POU4 F1, MBNL2) in BXD mice post-DOX and heart failure outcomes in humans. Most of the top candidates showed cardiomyocyte specific expression based on scRNA-seq data.

Conclusions: Survival, BW loss, and echocardiography parameters considerably varied among DOX-treated BXDs, suggesting significant influence of genetic background on expression of those traits. Several candidate genes that may modulate ACT susceptibility and heart failure were identified, providing a foundation for genetic-based risk stratification and therapeutics in cardio-oncology.

Abstract

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