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Functional Validation of Doxorubicin-Induced Cardiotoxicity-Related Genes

心脏毒性 生物 基因 表型 候选基因 遗传学 全基因组关联研究 诱导多能干细胞 PDGFRB公司 基因敲除 阿霉素 计算生物学 单核苷酸多态性 胚胎干细胞 基因型 化疗
作者
Hananeh Fonoudi,Mariam Jouni,Romina B. Cejas,Tarek Magdy,Malorie Blancard,Ning Ge,Disheet Shah,Davi M. Lyra‐Leite,Achal Neupane,Mennat Gharib,Zhengxin Jiang,Yadav Sapkota,Paul W. Burridge
出处
期刊:JACC: Cardiooncology [Elsevier BV]
卷期号:6 (1): 38-50 被引量:10
标识
DOI:10.1016/j.jaccao.2023.11.008
摘要

Genome-wide association studies and candidate gene association studies have identified more than 180 genetic variants statistically associated with anthracycline-induced cardiotoxicity (AIC). However, the lack of functional validation has hindered the clinical translation of these findings. The aim of this study was to functionally validate all genes associated with AIC using human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). Through a systemic literature search, 80 genes containing variants significantly associated with AIC were identified. Additionally, 3 more genes with potential roles in AIC (GSTM1, CBR1, and ERBB2) were included. Of these, 38 genes exhibited expression in human fetal heart, adult heart, and hiPSC-CMs. Using clustered regularly interspaced short palindromic repeats/Cas9–based genome editing, each of these 38 genes was systematically knocked out in control hiPSC-CMs, and the resulting doxorubicin-induced cardiotoxicity (DIC) phenotype was assessed using hiPSC-CMs. Subsequently, functional assays were conducted for each gene knockout on the basis of hypothesized mechanistic implications in DIC. Knockout of 26 genes increased the susceptibility of hiPSC-CMs to DIC. Notable genes included efflux transporters (ABCC10, ABCC2, ABCB4, ABCC5, and ABCC9), well-established DIC-associated genes (CBR1, CBR3, and RAC2), and genome-wide association study–discovered genes (RARG and CELF4). Conversely, knockout of ATP2B1, HNMT, POR, CYBA, WDR4, and COL1A2 had no significant effect on the in vitro DIC phenotype of hiPSC-CMs. Furthermore, knockout of the uptake transporters (SLC28A3, SLC22A17, and SLC28A1) demonstrated a protective effect against DIC. The present findings establish a comprehensive platform for the functional validation of DIC-associated genes, providing insights for future studies in DIC variant associations and potential mechanistic targets for the development of cardioprotective drugs.
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