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Nat Genet. 2015 Sep;47(9):1079-84. doi: 10.1038/ng.3374. Epub 2015 Aug 3.

A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.

Author information

1
Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
2
Child and Family Research Institute, Vancouver, British Columbia, Canada.
3
Department of Pediatrics, Division of Translational Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
4
Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
5
Department of Pediatrics, Division of Pediatric Hematology/Oncology/Blood and Marrow Transplantation, University of British Columbia, Vancouver, British Columbia, Canada.
6
Translational Laboratory in Genetic Medicine, National University of Singapore and Association for Science, Technology and Research (A*STAR), Singapore.
7
Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, the Netherlands.
8
Department of Medical Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, the Netherlands.
9
Department of Pediatrics, University of Western Ontario, London, Ontario, Canada.
10
Division of Pediatric Cardiology, Stanford University, Palo Alto, California, USA.
11
Pharmaceutical Outcomes Programme, British Columbia Children's Hospital, Vancouver, British Columbia, Canada.

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.

PMID:
26237429
PMCID:
PMC4552570
DOI:
10.1038/ng.3374
[Indexed for MEDLINE]
Free PMC Article

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