A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.
A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.
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DOI：
10.1038/ng.3374
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发表时间：
2015-09
期刊：
影响因子：
30.8
通讯作者：
Canadian Pharmacogenomics Network for Drug Safety Consortium
中科院分区：
文献类型：
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作者：
Aminkeng 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 CJ;Canadian Pharmacogenomics Network for Drug Safety Consortium
超过50%的儿童癌症治疗方案使用了蒽环类药物，但其临床有效性受到限制，分别高达57%和16%的患者表现为无症状性心功能障碍和充血性心力衰竭。候选基因研究已经报道了与ACT，，，但这些研究总体上缺乏可靠的患者数量，独立的复制或功能验证。因此，ACT易感性的个体差异在很大程度上仍未得到解释。我们对280名接受儿童癌症治疗的欧洲血统患者进行了全基因组关联研究，在96名接受类似治疗的欧洲患者和80名非欧洲患者组成的队列中独立复制。我们在RAR中发现了一个非同义变异(rs2229774，p.Ser427Leu)，与ACT高度相关(P=5.9×10−8，优势比(95%可信区间)=4.7(2.7-8.3))。这种变异改变了RARG功能，导致了关键的ACT基因决定因素Top2b的去抑制，并为这种严重药物不良反应的病理生理学提供了新的见解。
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) inRARGhighly 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 determinantTop2b, and provides new insight into the pathophysiology of this severe adverse drug reaction.