Journal
NATURE GENETICS
Volume 41, Issue 12, Pages 1345-U118Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.478
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Funding
- Genome Canada
- Genome British Columbia
- Child and Family Research Institute
- University of British Columbia Faculty of Pharmaceutical Sciences
- Canadian Institutes of Health Research
- Canada Foundation for Innovation
- Canada Gene Cure Foundation
- Canadian Society of Clinical Pharmacology
- BC Clinical Genomics Network
- C17 Research Network and Childhood Cancer Foundation Candlelighters Canada
- Michael Smith Foundation for Health Research, Health Canada, Pfizer, Eli Lilly, Merck Frosst and Janssen-Ortho
- Genome Canada Applied Health Research Program
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Cisplatin is a widely used and effective chemotherapeutic agent, although its use is restricted by the high incidence of irreversible ototoxicity associated with it(1). In children, cisplatin ototoxicity is a serious and pervasive problem, affecting more than 60% of those receiving cisplatin(2-5) 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(6-8). 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.
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