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

Aminkeng, Folefac; Bhavsar, Amit P; Visscher, Henk; Rassekh, Shahrad R; Li, Yuling; Lee, Jong W; Brunham, Liam R; Caron, Huib N; van Dalen, Elvira C; Kremer, Leontien C; van der Pal, Helena J; Amstutz, Ursula; Rieder, Michael J; Bernstein, Daniel; Carleton, Bruce C; Hayden, Michael R; Ross, Colin J D (2015). A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nature genetics, 47(9), pp. 1079-1084. Nature America 10.1038/ng.3374

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry

UniBE Contributor:

Amstutz, Ursula

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1061-4036

Publisher:

Nature America

Language:

English

Submitter:

Ursula Amstutz

Date Deposited:

10 Aug 2015 16:00

Last Modified:

26 Jun 2016 02:06

Publisher DOI:

10.1038/ng.3374

PubMed ID:

26237429

BORIS DOI:

10.7892/boris.70719

URI:

https://boris.unibe.ch/id/eprint/70719

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