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A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer NATURE GENETICS Aminkeng, F., Bhavsar, A. P., Visscher, H., Rassekh, S. R., Li, Y., Lee, J. W., Brunham, L. R., Caron, H. N., van Dalen, E. C., Kremer, L. C., van der Pal, H. J., Amstutz, U., Rieder, M. J., Bernstein, D., Carleton, B. C., Hayden, M. R., Ross, C. J. 2015; 47 (9): 1079-?

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.

View details for DOI 10.1038/ng.3374

View details for Web of Science ID 000360394100020

View details for PubMedID 26237429

View details for PubMedCentralID PMC4552570