Department of Medical Genetics, University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada.
Nat Genet. 2009 Dec;41(12):1345-9. doi: 10.1038/ng.478. Epub 2009 Nov 8.
Cisplatin is a widely used and effective chemotherapeutic agent, although its use is restricted by the high incidence of irreversible ototoxicity associated with it. In children, cisplatin ototoxicity is a serious and pervasive problem, affecting more than 60% of those receiving cisplatin and compromising language and cognitive development. Candidate gene studies have previously reported associations of cisplatin ototoxicity with genetic variants in the genes encoding glutathione S-transferases and megalin. We report association analyses for 220 drug-metabolism genes in genetic susceptibility to cisplatin-induced hearing loss in children. We genotyped 1,949 SNPs in these candidate genes in an initial cohort of 54 children treated in pediatric oncology units, with replication in a second cohort of 112 children recruited through a national surveillance network for adverse drug reactions in Canada. We identified genetic variants in TPMT (rs12201199, P value = 0.00022, OR = 17.0, 95% CI 2.3-125.9) and COMT (rs9332377, P value = 0.00018, OR = 5.5, 95% CI 1.9-15.9) associated with cisplatin-induced hearing loss in children.
顺铂是一种广泛应用且有效的化疗药物，但其使用受到与之相关的不可逆耳毒性发生率高的限制。在儿童中，顺铂耳毒性是一个严重且普遍的问题，超过 60%接受顺铂治疗的儿童会受到影响，从而影响语言和认知发育。候选基因研究先前报告了顺铂耳毒性与编码谷胱甘肽 S-转移酶和巨球蛋白的基因中的遗传变异之间的关联。我们报告了对 220 个药物代谢基因的关联分析，这些基因与儿童顺铂诱导的听力损失的遗传易感性有关。我们在儿科肿瘤病房接受治疗的 54 名儿童的初始队列中对这些候选基因中的 1,949 个 SNP 进行了基因分型，并在加拿大国家药物不良反应监测网络招募的 112 名儿童的第二个队列中进行了复制。我们确定了 TPMT（rs12201199，P 值=0.00022，OR=17.0，95%CI 2.3-125.9）和 COMT（rs9332377，P 值=0.00018，OR=5.5，95%CI 1.9-15.9）中的遗传变异与儿童顺铂诱导的听力损失有关。
