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

Background: 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.

Methods: 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.

Results: 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 (, , , , , ) as well as EF% and LV volumes (, , , , ) in BXD mice post-DOX and heart failure (HF) outcomes in humans.

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