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通过系统遗传学方法解析阿霉素诱导的心脏毒性的遗传蓝图。

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

作者信息

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

机构信息

Department of Pediatrics, The Heart Institute, University of Tennessee Health Science Center, Memphis, TN, USA.

Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN, USA.

出版信息

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

DOI:10.1186/s40959-025-00349-y

PMID:40462234

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12131464/

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.

摘要

背景

蒽环类药物诱导的心脏毒性（ACT）是癌症幸存者的一个重大担忧，而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绘制与多柔比星（DOX）诱导的表型相关的数量性状基因座（QTL）。

方法

为模拟ACT的变异性，对58个BXD品系以及亲本B6和D2小鼠（n≥4只小鼠/性别/品系，3 - 4月龄）进行腹腔注射DOX（20mg/kg）。监测10天的生存率和体重（BW）。在治疗前和治疗后第5天进行超声心动图检查，随后进行遗传定位和孟德尔随机化分析，以鉴定与DOX诱导的性状和严重程度相关的QTL和候选基因。

结果

亲本B6品系的生存率为60%，而D2小鼠在第10天的生存率为24%。在BXD品系中，中位生存期各不相同，BXD77在第4天显示出最低生存率。超声心动图显示心脏功能障碍和类似于ACT患者的小心脏表型。10号染色体（86 - 94Mb）、19号染色体（52.5 - 54.2Mb）和14号染色体（103 - 120Mb）上的显著QTL分别与生存率、平均体重减轻以及左心室（LV）容积和射血分数（EF%）相关。孟德尔随机化分析确定了BXD小鼠在接受DOX后体重减轻（ADD3、HSPA12A、SLC18A2、PDZD8、DUSP5、CASP7）以及EF%和LV容积（GPC6、UGGT2、SLAIN1、POU4F1、MBNL2）相关基因与人类心力衰竭结局之间的显著因果关联。根据单细胞RNA测序数据，大多数顶级候选基因显示出心肌细胞特异性表达。