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

TitleA coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer
Publication TypeJournal Article
Year of Publication2015
AuthorsAminkeng F, Bhavsar AP, Visscher H, Rassekh SR, Li Y, Lee JW, Brunham LR, Caron HN, van Dalen EC, Kremer LC, van der Pal HJ, Amstutz U, Rieder MJ, Bernstein D, Carleton BC, Hayden MR, Ross CJD
Corporate AuthorsCanadian Pharmacogenomics Network for Drug Safety Consortium
JournalNat Genet
Volume47
Issue9
Pagination1079-84
Date Published09/2015
ISSN1546-1718
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.

DOI10.1038/ng.3374
Alternate JournalNat. Genet.
PubMed ID26237429
PubMed Central IDPMC4552570
Grant List1R21HL123655-01 / HL / NHLBI NIH HHS / United States
HL123655 / HL / NHLBI NIH HHS / United States
R21 HL123655 / HL / NHLBI NIH HHS / United States