title: Pharmacogenetic analyses of cisplatin-induced nephrotoxicity indicate a renoprotective effect of ERCC1 polymorphisms.
abstract: OBJECTIVE
  We investigated whether genetic polymorphisms may contribute to the interpatient variability of cisplatin-induced nephrotoxicity.
  
  
  METHODS
  Polymorphisms in the candidate genes GSTM1, GSTT1, OCT1, OCT2, LARP2, ERCC1, XRCC1 and EPO were analyzed for associations with nephrotoxicity in 79 cancer patients receiving cisplatin-containing chemotherapy.
  
  
  RESULTS
  Higher cisplatin dose was associated with strongly decreased estimated glomerular filtration rates (eGFR) (r(2) = 0.205). Two highly genetically linked polymorphisms in the ERCC1 gene, 8092C>A and Asn118Asn, were significantly associated with change in eGFR, accounting for an additional 13% of interindividual variability. Homozygous carriers of the 8092A allele in ERCC1 showed no reduction in eGFR, compared with the 11.5% mean eGFR decrease in C allele carriers (p = 0.004). Homozygous carriers of the C allele of Asn118Asn showed no reduction in eGFR, compared with the 12.8% mean eGFR decrease seen in T allele carriers (p = 0.047). Polymorphisms in the other candidate genes were not associated with cisplatin-induced nephrotoxicity.
  
  
  CONCLUSIONS
  Genetic polymorphisms in ERCC1 may be valuable predictors of cisplatin-induced nephrotoxicity.
authors: Department of Clinical Pharmacology, University Medical Center, Georg-August-University, Robert-Koch-Strasse 40, Göttingen, Germany. mtzvetk@gwdg.de
authors: Mladen V
authors: MV
authors: Tzvetkov
authors: Gerrit
authors: G
authors: Behrens
authors: Valerie P
authors: VP
authors: O'Brien
authors: Karin
authors: K
authors: Hohloch
authors: Jürgen
authors: J
authors: Brockmöller
authors: Peter
authors: P
authors: Benöhr
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D002945:Cisplatin / Q000009:adverse effects* / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D005919:Glomerular Filtration Rate / Q000187:drug effects* / Q000235:genetics*; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D004268:DNA-Binding Proteins; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin