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Genetic variants in SLC22A17 and SLC22A7 are associated with anthracycline-induced cardiotoxicity in children

    Henk Visscher

    Centre for Molecular Medicine & Therapeutics, Child & Family Research Institute, Department of Medical Genetics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada

    ,
    S Rod Rassekh

    Division of Pediatric Hematology/Oncology/BMT, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada

    ,
    George S Sandor

    Division of Pediatric Cardiology, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada

    ,
    Huib N Caron

    Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands

    ,
    Elvira C van Dalen

    Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands

    ,
    Leontien C Kremer

    Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands

    ,
    Helena J van der Pal

    Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands

    Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands

    ,
    Paul C Rogers

    Division of Pediatric Hematology/Oncology/BMT, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada

    ,
    Michael J Rieder

    Department of Paediatrics, Children's Hospital/London Health Sciences Centre, London, ON, Canada

    ,
    Bruce C Carleton

    Division of Translational Therapeutics, Department of Pediatrics, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada

    ,
    Michael R Hayden

    Centre for Molecular Medicine & Therapeutics, Child & Family Research Institute, Department of Medical Genetics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada

    ,
    Colin J Ross

    *Author for correspondence:

    E-mail Address: cjross@cmmt.ubc.ca

    Centre for Molecular Medicine & Therapeutics, Child & Family Research Institute, Department of Medical Genetics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada

    Division of Translational Therapeutics, Department of Pediatrics, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada

    &
    Published Online:https://doi.org/10.2217/pgs.15.61

    Aim: To identify novel variants associated with anthracycline-induced cardiotoxicity and to assess these in a genotype-guided risk prediction model. Patients & methods: Two cohorts treated for childhood cancer (n = 344 and 218, respectively) were genotyped for 4578 SNPs in drug ADME and toxicity genes. Results: Significant associations were identified in SLC22A17 (rs4982753; p = 0.0078) and SLC22A7 (rs4149178; p = 0.0034), with replication in the second cohort (p = 0.0071 and 0.047, respectively). Additional evidence was found for SULT2B1 and several genes related to oxidative stress. Adding the SLC22 variants to the prediction model improved its discriminative ability (AUC 0.78 vs 0.75 [p = 0.029]). Conclusion: Two novel variants in SLC22A17 and SLC22A7 were significantly associated with anthracycline-induced cardiotoxicity and improved a genotype-guided risk prediction model, which could improve patient risk stratification.

    Original submitted 26 November 2014; Revision submitted 12 May 2015.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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