title: Genetic variants in SLC22A17 and SLC22A7 are associated with anthracycline-induced cardiotoxicity in children.
abstract: OBJECTIVE
  To identify novel variants associated with anthracycline-induced cardiotoxicity and to assess these in a genotype-guided risk prediction model.
  
  
  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]).
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Henk
authors.initials: H
authors.lastname: Visscher
authors.affiliation: Division of Pediatric Hematology/Oncology/BMT, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: S Rod
authors.initials: SR
authors.lastname: Rassekh
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: George S
authors.initials: GS
authors.lastname: Sandor
authors.affiliation: Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Huib N
authors.initials: HN
authors.lastname: Caron
authors.affiliation: Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Elvira C
authors.initials: EC
authors.lastname: van Dalen
authors.affiliation: Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Leontien C
authors.initials: LC
authors.lastname: Kremer
authors.affiliation: Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands.|Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Helena J
authors.initials: HJ
authors.lastname: van der Pal
authors.affiliation: Division of Pediatric Hematology/Oncology/BMT, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Rogers
authors.affiliation: Department of Paediatrics, Children's Hospital/London Health Sciences Centre, London, ON, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rieder
authors.affiliation: Division of Translational Therapeutics, Department of Pediatrics, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Carleton
authors.affiliation: 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.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: 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.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Ross
mesh_terms: D018943:Anthracyclines / Q000009:adverse effects*; D066126:Cardiotoxicity / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006331:Heart Diseases / Q000139:chemically induced* / Q000235:genetics*; D006801:Humans; D008297:Male; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012306:Risk
chemical_list: D018943:Anthracyclines; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; C518841:SLC22A17 protein, human; C490280:SLC22A7 protein, human
keywords: anthracyclines; association study; cardiotoxicity; childhood cancer; pharmacogenomics