Orgil Buyan-Ochir, Bajpai Akhilesh K, Alberson Neely, Lander Morgan, Enkhzul Batsaikhan, Martinez Hugo R, Towbin Jeffrey A, Lu Lu, Purevjav Enkhsaikhan
University of Tennessee Health Science Center.
The University of Texas at Austin.
Res Sq. 2025 Apr 15:rs.3.rs-6224399. doi: 10.21203/rs.3.rs-6224399/v1.
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 (, , , , , ) as well as EF% and LV volumes (, , , , ) 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.
蒽环类药物引起的心脏毒性（ACT）是癌症幸存者面临的一个重大问题。由于生活方式和环境因素对人体研究的影响，ACT的遗传基础仍不清楚。本研究采用源自DBA/2J（D2）和C57BL/6J（B6）杂交的BXD重组近交系小鼠遗传参考群体（GRP），通过系统遗传学方法定位与多柔比星（DOX）诱导的心脏毒性表型相关的数量性状基因座（QTL）。
为模拟ACT的变异性，对58个BXD品系以及亲本B6和D2小鼠（每组性别≥4只小鼠，3 - 4月龄）进行腹腔注射DOX（20 mg/kg）。监测10天的存活率和体重（BW）。在治疗前和治疗后第5天进行超声心动图检查。采用遗传图谱和孟德尔随机化（MR）分析来确定与DOX诱导的性状和严重程度相关的QTL和候选基因。
亲本B6品系的存活率为60%，而在第10天只有24%的D2小鼠存活。在BXD品系中，中位生存期各不相同，BXD77在第4天显示出最低的生存期。超声心动图显示存在限制性功能障碍和类似于ACT患者中观察到的“格林奇综合征”的小心脏表型。位于10号染色体（86 - 94 Mb）、19号染色体（52.5 - 54.2 Mb）和14号染色体（103 - 120 Mb）上的显著QTL分别与存活率、平均体重减轻以及左心室（LV）容积和射血分数（EF%）相关。MR分析确定了DOX处理后的BXD小鼠中涉及体重减轻（……）以及EF%和LV容积（……）的基因与人类心力衰竭（HF）结局之间存在显著的因果关联。
在接受DOX治疗的BXD小鼠中，存活率、体重减轻和超声心动图参数有很大差异，表明遗传背景对这些性状的表达有显著影响。确定了几个可能调节ACT易感性和HF的候选基因，为心脏肿瘤学中基于遗传的风险分层和治疗提供了基础。
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