title: Evidence for association of SNPs in ABCB1 and CBR3, but not RAC2, NCF4, SLC28A3 or TOP2B, with chronic cardiotoxicity in a cohort of breast cancer patients treated with anthracyclines.
abstract: OBJECTIVE
  Validation of associations for SNPs in RAC2, NCF4 and SLC28A3, identification of a novel association with a TOP2B SNP and screening 23 SNPs putatively relevant to anthracycline-induced cardiotoxicity.
  
  
  METHODS
  A total of 166 breast cancer patients treated with doxorubicin underwent echocardiogram, including 19 cases with systolic dysfunction (ejection fraction <55%) and 147 controls. Four high priority SNPs were tested in the primary analysis, with appropriate statistical correction, and 23 additional SNPs were screened in an uncorrected secondary analysis.
  
  
  RESULTS
  Previously reported associations for RAC2, NCF4 and SLC28A3 could not be validated and a novel association with TOP2B was not discovered in this cohort (all p > 0.05), likely due to inadequate power. Two SNPs were identified in the uncorrected secondary analysis including a protective SNP in ABCB1 (3435C>T, p = 0.049) and a risk allele in CBR3 (V244M, p = 0.012).
  
  
  CONCLUSIONS
  The associations reported in prior publications and those discovered in this secondary analysis require further replication in independent cohorts.
authors.affiliation: Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Hertz
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Megan V
authors.initials: MV
authors.lastname: Caram
authors.affiliation: Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
authors.forename: Kelley M
authors.initials: KM
authors.lastname: Kidwell
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Jacklyn N
authors.initials: JN
authors.lastname: Thibert
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Gersch
authors.affiliation: Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Seewald
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Smerage
authors.affiliation: Department of Internal Medicine, Division of Cardiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Melvyn
authors.initials: M
authors.lastname: Rubenfire
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: N Lynn
authors.initials: NL
authors.lastname: Henry
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.|Department of Urology, University of Michigan Health System, Ann Arbor, MI 48109, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Cooney
authors.affiliation: Department of Internal Medicine, Division of Cardiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Leja
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Griggs
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.|Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000429:Alcohol Oxidoreductases / Q000235:genetics*; D018943:Anthracyclines / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D066126:Cardiotoxicity / Q000235:genetics*; D016022:Case-Control Studies; D002908:Chronic Disease; D003430:Cross-Sectional Studies; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics; D019255:NADPH Oxidases / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D020641:Polymorphism, Single Nucleotide; D020744:rac GTP-Binding Proteins / Q000235:genetics; D000097766:RAC2 GTP-Binding Protein
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000429:Alcohol Oxidoreductases; D018943:Anthracyclines; D000970:Antineoplastic Agents; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D026901:Membrane Transport Proteins; D019255:NADPH Oxidases; D000075223:Poly-ADP-Ribose Binding Proteins; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein; C513055:ABCB1 protein, human; C065171:cif nucleoside transporter; C531130:CBR3 protein, human; C113333:NCF4 protein, human; C000618814:TOP2B protein, human
keywords: ABCB1; CBR3; NCF4; RAC2; SLC28A3; TOP2B; anthracycline; cardiotoxicity; doxorubicin; pharmacogenetic; systolic dysfunction