{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Fonoudi H"],"funding":["National Cancer Institute","NCI NIH HHS"],"pagination":["38-50"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10950437"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["6(1)"],"pubmed_abstract":["<h4>Background</h4>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.<h4>Objectives</h4>The aim of this study was to functionally validate all genes associated with AIC using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).<h4>Methods</h4>Through a systemic literature search, 80 genes containing variants significantly associated with AIC were identified. Additionally, 3 more genes with potential roles in AIC (<i>GSTM1</i>, <i>CBR1</i>, and <i>ERBB2</i>) 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.<h4>Results</h4>Knockout of 26 genes increased the susceptibility of hiPSC-CMs to DIC. Notable genes included efflux transporters (<i>ABCC10</i>, <i>ABCC2</i>, <i>ABCB4</i>, <i>ABCC5</i>, and <i>ABCC9</i>), well-established DIC-associated genes (<i>CBR1</i>, <i>CBR3</i>, and <i>RAC2</i>), and genome-wide association study-discovered genes (<i>RARG</i> and <i>CELF4</i>). Conversely, knockout of <i>ATP2B1</i>, <i>HNMT</i>, <i>POR</i>, <i>CYBA</i>, <i>WDR4</i>, and <i>COL1A2</i> had no significant effect on the in vitro DIC phenotype of hiPSC-CMs. Furthermore, knockout of the uptake transporters (<i>SLC28A3</i>, <i>SLC22A17</i>, and <i>SLC28A1</i>) demonstrated a protective effect against DIC.<h4>Conclusions</h4>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."],"journal":["JACC. CardioOncology"],"pubmed_title":["Functional Validation of Doxorubicin-Induced Cardiotoxicity-Related Genes."],"pmcid":["PMC10950437"],"funding_grant_id":["R01 CA261898","R01 CA220002"],"pubmed_authors":["Gharib M","Shah DA","Jouni M","Lyra-Leite DM","Cejas RB","Sapkota Y","Burridge PW","Ge N","Jiang Z","Neupane A","Fonoudi H","Magdy T","Blancard M"],"additional_accession":[]},"is_claimable":false,"name":"Functional Validation of Doxorubicin-Induced Cardiotoxicity-Related Genes.","description":"<h4>Background</h4>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.<h4>Objectives</h4>The aim of this study was to functionally validate all genes associated with AIC using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).<h4>Methods</h4>Through a systemic literature search, 80 genes containing variants significantly associated with AIC were identified. Additionally, 3 more genes with potential roles in AIC (<i>GSTM1</i>, <i>CBR1</i>, and <i>ERBB2</i>) 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.<h4>Results</h4>Knockout of 26 genes increased the susceptibility of hiPSC-CMs to DIC. Notable genes included efflux transporters (<i>ABCC10</i>, <i>ABCC2</i>, <i>ABCB4</i>, <i>ABCC5</i>, and <i>ABCC9</i>), well-established DIC-associated genes (<i>CBR1</i>, <i>CBR3</i>, and <i>RAC2</i>), and genome-wide association study-discovered genes (<i>RARG</i> and <i>CELF4</i>). Conversely, knockout of <i>ATP2B1</i>, <i>HNMT</i>, <i>POR</i>, <i>CYBA</i>, <i>WDR4</i>, and <i>COL1A2</i> had no significant effect on the in vitro DIC phenotype of hiPSC-CMs. Furthermore, knockout of the uptake transporters (<i>SLC28A3</i>, <i>SLC22A17</i>, and <i>SLC28A1</i>) demonstrated a protective effect against DIC.<h4>Conclusions</h4>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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Feb","modification":"2025-04-18T19:26:53.628Z","creation":"2025-04-07T07:10:28.749Z"},"accession":"S-EPMC10950437","cross_references":{"pubmed":["38510289"],"doi":["10.1016/j.jaccao.2023.11.008"]}}