# Unraveling the Genetic Blueprint of Doxorubicin-Induced Cardiotoxicity Through Systems Genetics Approaches

## TL;DR

This study uses mice to identify genetic factors linked to heart damage caused by a cancer drug, revealing genes that could help predict and treat this side effect.

## Contribution

The study identifies novel genetic loci and candidate genes associated with doxorubicin-induced cardiotoxicity using a systems genetics approach in mice.

## Key findings

- BXD77 mice showed the lowest survival after doxorubicin treatment, highlighting genetic variability in cardiotoxicity.
- QTLs on Chromosomes 10, 19, and 14 were linked to survival, weight loss, and heart function changes.
- Candidate genes like ADD3, HSPA12A, and GPC6 were associated with cardiotoxicity traits and human heart failure outcomes.

## Abstract

Anthracycline-induced cardiotoxicity (ACT) is a significant concern for cancer survivors. The genetic basis of ACT remains unclear because of the impact of lifestyle and environmental factors in human studies. 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 cardiotoxic phenotypes through systems genetics approaches.

To model variability in ACT, 58 BXD strains and parental B6 and D2 mice (N ≥ 4 mice/sex, 3–4 months 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. Genetic mapping and Mendelian randomization (MR) analyses were used for identifying QTLs and candidate genes associated with DOX-induced traits and severity.

Parental B6 strain had 60% survival, whereas only 24% of D2 mice survived on Day 10. Among BXD strains, median survival varied, with BXD77 showing the lowest at four days. Echocardiography revealed restrictive dysfunction and a small-heart phenotype resembling “Grinch syndrome” observed in 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, HSPA12A, SLC18A2, PDZD8, DUSP5, CASP7) as well as EF% and LV volumes (GPC6, UGGT2, SLAIN1, POU4F1, MBNL2) in BXD mice post-DOX and heart failure (HF) outcomes in humans.

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 HF were identified, providing a foundation for genetic-based risk stratification and therapeutics in cardio-oncology.