Abstract
Background: Anthracycline-induced cardiotoxicity (ACT) occurs in 57% of treated cancer patients. Effects of genetic variations to individual susceptibility to ACT is emerging. However, diverse lifestyle and environmental factors combined with small sample sizes in human cohorts remain as limitations to effectively clarify the genetic susceptibility to ACT. This study employed a murine genetic reference population (GRP) of BXD mice derived from crosses between DBA/2J and C57BL/6J strains for mapping of quantitative trait loci (QTLs) associated with doxorubicin (DOX)-induced traits using systems genetics methods. Methods: To model the variability in ACT to DOX, 56 BXD strains (N≥3 mice/sex, 3-4 month-old) were injected intraperitonially once with DOX (20 mg/kg). Survival and body weight (BW) were monitored daily for 10 Days (D). Echocardiography was performed before and on D5 after DOX. Genetic mapping was performed using WebQTL (www.genenetwork.org) and multi-criteria scoring was used for filtering candidate genes associated with DOX-induced traits. Results: Varied body weight loss, proportions and median survival rates were found among DOX-treated BXDs. Parental C57BL/6J strain had 100% survival, while 75% of DBA/2J mice survived on D10. Among BXDs tested, 47 strains had median survival of 6±1 D, with the lowest seen in BXD77 (4 D). Echocardiography revealed abnormal small heart and restrictive dysfunction in BXDs, resembling Grinch syndrome seen in ACT patients. A significant QTL (LRS = 17.11) at 86~94 Mb of Chromosome (Chr) 10 was identified (genome wide P < 0.05). Further filtering identified Gnptab , Slc25a3 , Uhrf1bp1l, and Chpt1 as top candidate genes associated with the survival of DOX-treated BXDs. Mapping of QTLs associated with echocardiography values and weight loss are in a progress. Conclusions: Survival, BW loss, and echocardiography parameters significantly varied among DOX-treated BXDs suggesting an influence of genetic background on expression of those traits. Gnptab , Slc25a3, Uhrf1bp1l, and Chpt1 (Chr 10) are associated with DOX-induced survival traits in BXDs of GRP, suggesting that these genes are involved in modulating ACT severity in humans and require further functional and biological validation.
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