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oai:repisalud.isciii.es:20.500.12105/165712024-09-27T08:02:50Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Gómez-Vecino, Aurora author Corchado-Cobos, Roberto author Blanco-Gómez, Adrián author García-Sancha, Natalia author Castillo-Lluva, Sonia author Martín-García, Ana author Mendiburu-Eliçabe, Marina author Prieto, Carlos author Ruiz-Pinto, Sara author Pita, Guillermo author Velasco-Ruiz, Alejandro author Patino-Alonso, Carmen author Galindo-Villardón, Purificación author Vera-Pedrosa, María Linarejos author Jalife, Jose author Mao, Jian-Hua author Macías de Plasencia, Guillermo author Castellanos-Martín, Andrés author Sáez-Freire, María Del Mar author Fraile-Martín, Susana author Rodrigues-Teixeira, Telmo author García-Macías, Carmen author Galvis-Jiménez, Julie Milena author García-Sánchez, Asunción author Isidoro-García, María author Fuentes, Manuel author García-Cenador, María Begoña author García-Criado, Francisco Javier author García-Hernández, Juan Luis author Hernández-García, María Ángeles author Cruz-Hernández, Juan Jesús author Rodríguez-Sánchez, César Augusto author García-Sancho, Alejandro Martín author Pérez-López, Estefanía author Pérez-Martínez, Antonio author Gutiérrez-Larraya, Federico author Cartón, Antonio J author García-Sáenz, José Ángel author Patiño-García, Ana author Martín, Miguel author Alonso-Gordoa, Teresa author Vulsteke, Christof author Croes, Lieselot author Hatse, Sigrid author Van Brussel, Thomas author Lambrechts, Diether author Wildiers, Hans author Chang, Hang author Holgado-Madruga, Marina author González-Neira, Anna author Sánchez, Pedro L author Pérez Losada, Jesús author 2023-07-27 Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management. Cells. 2023 Jul 27;12(15):1956. 10.3390/cells12151956 2073-4409 Cells 37566035 http://hdl.handle.net/20.500.12105/16571 Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.