Buyan-Ochir Orgil, Akhilesh K Bajpai, Neely Alberson, Morgan Lander, Batsaikhan Enkhzul, Hugo R Martinez, Jeffrey A Towbin, Lu Lu, Enkhsaikhan Purevjav
{"title":"通过系统遗传学方法揭示阿霉素诱导的心脏毒性的遗传蓝图。","authors":"Buyan-Ochir Orgil, Akhilesh K Bajpai, Neely Alberson, Morgan Lander, Batsaikhan Enkhzul, Hugo R Martinez, Jeffrey A Towbin, Lu Lu, Enkhsaikhan Purevjav","doi":"10.1186/s40959-025-00349-y","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":9804,"journal":{"name":"Cardio-oncology","volume":"11 1","pages":"53"},"PeriodicalIF":3.2000,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131464/pdf/","citationCount":"0","resultStr":"{\"title\":\"Unraveling the genetic blueprint of doxorubicin-induced cardiotoxicity through systems genetics approaches.\",\"authors\":\"Buyan-Ochir Orgil, Akhilesh K Bajpai, Neely Alberson, Morgan Lander, Batsaikhan Enkhzul, Hugo R Martinez, Jeffrey A Towbin, Lu Lu, Enkhsaikhan Purevjav\",\"doi\":\"10.1186/s40959-025-00349-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":9804,\"journal\":{\"name\":\"Cardio-oncology\",\"volume\":\"11 1\",\"pages\":\"53\"},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2025-06-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131464/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cardio-oncology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1186/s40959-025-00349-y\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cardio-oncology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1186/s40959-025-00349-y","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
Unraveling the genetic blueprint of doxorubicin-induced cardiotoxicity through systems genetics approaches.
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.
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