title: A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.
abstract: Anthracyclines are used in over 50% of childhood cancer treatment protocols, but their clinical usefulness is limited by anthracycline-induced cardiotoxicity (ACT) manifesting as asymptomatic cardiac dysfunction and congestive heart failure in up to 57% and 16% of patients, respectively. Candidate gene studies have reported genetic associations with ACT, but these studies have in general lacked robust patient numbers, independent replication or functional validation. Thus, the individual variability in ACT susceptibility remains largely unexplained. We performed a genome-wide association study in 280 patients of European ancestry treated for childhood cancer, with independent replication in similarly treated cohorts of 96 European and 80 non-European patients. We identified a nonsynonymous variant (rs2229774, p.Ser427Leu) in RARG highly associated with ACT (P = 5.9 × 10(-8), odds ratio (95% confidence interval) = 4.7 (2.7-8.3)). This variant alters RARG function, leading to derepression of the key ACT genetic determinant Top2b, and provides new insight into the pathophysiology of this severe adverse drug reaction.
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.|Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Folefac
authors.initials: F
authors.lastname: Aminkeng
authors.affiliation: Child and Family Research Institute, Vancouver, British Columbia, Canada.|Department of Pediatrics, Division of Translational Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Amit P
authors.identifier: http://orcid.org/0000-0003-3336-9288
authors.initials: AP
authors.lastname: Bhavsar
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: Visscher
authors.affiliation: Child and Family Research Institute, Vancouver, British Columbia, Canada.|Department of Pediatrics, Division of Pediatric Hematology/Oncology/Blood and Marrow Transplantation, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Shahrad R
authors.initials: SR
authors.lastname: Rassekh
authors.affiliation: Child and Family Research Institute, Vancouver, British Columbia, Canada.|Department of Pediatrics, Division of Translational Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.|Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Jong W
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Translational Laboratory in Genetic Medicine, National University of Singapore and Association for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Liam R
authors.initials: LR
authors.lastname: Brunham
authors.affiliation: Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Huib N
authors.initials: HN
authors.lastname: Caron
authors.affiliation: Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Elvira C
authors.initials: EC
authors.lastname: van Dalen
authors.affiliation: Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Leontien C
authors.initials: LC
authors.lastname: Kremer
authors.affiliation: Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, the Netherlands.|Department of Medical Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Helena J
authors.initials: HJ
authors.lastname: van der Pal
authors.affiliation: Child and Family Research Institute, Vancouver, British Columbia, Canada.|Department of Pediatrics, Division of Translational Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ursula
authors.initials: U
authors.lastname: Amstutz
authors.affiliation: Department of Pediatrics, University of Western Ontario, London, Ontario, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rieder
authors.affiliation: Division of Pediatric Cardiology, Stanford University, Palo Alto, California, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.affiliation: Child and Family Research Institute, Vancouver, British Columbia, Canada.|Department of Pediatrics, Division of Translational Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.|Pharmaceutical Outcomes Programme, British Columbia Children's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Carleton
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.|Child and Family Research Institute, Vancouver, British Columbia, Canada.|Translational Laboratory in Genetic Medicine, National University of Singapore and Association for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.|Child and Family Research Institute, Vancouver, British Columbia, Canada.|Department of Pediatrics, Division of Translational Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.|Pharmaceutical Outcomes Programme, British Columbia Children's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Colin J D
authors.initials: CJ
authors.lastname: Ross
mesh_terms: D000293:Adolescent; D018943:Anthracyclines / Q000009:adverse effects* / Q000627:therapeutic use; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000235:genetics; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000235:genetics*; D000097768:Retinoic Acid Receptor gamma
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D018168:Receptors, Retinoic Acid; D000097768:Retinoic Acid Receptor gamma