Single-Nucleotide Polymorphisms in Aldo-Keto and Carbonyl Reductase Genes Are Not Associated with Acute Cardiotoxicity after Daunorubicin Chemotherapy

Background: Evidence suggests that interpatient variability in anthracycline metabolic rate may contribute to the cardiotoxicity associated with anthracycline-based chemotherapy. Therefore, polymorphisms in the anthracycline metabolizing enzymes have been proposed as potential biomarkers of anthracycline-induced cardiotoxicity (AIC). Methods: We have previously shown that 13 of the naturally occurring nonsynonymous single-nucleotide polymorphisms (nsSNP) in the aldo keto reductases (AKR) and carbonyl reductases (CBR) reduce anthracycline metabolic rate in vitro. Here, we test these SNPs individually and jointly for association with daunorubicin-induced cardiotoxicity in patients with acute myeloid leukemia (AML). Results: Five of the 13 nsSNPs exhibiting an in vitro effect on anthracycline metabolism were detected among the 185 patients with AML. No association was found between the SNPs and daunorubicin-induced cardiotoxicity in either individual or joint effect analyses. Conclusions: Despite the shown in vitro effect of nsSNPs in reductase genes on anthracycline metabolic rate, on their own these SNPs do not explain enough variability in cardiotoxicity to be useful markers of this adverse event. Impact: The results of this study provide important information for biomarker studies on side effects of anthracycline chemotherapy. Cancer Epidemiol Bionlarkers Prey; 21(11); 2118-20. (C) 2012 AACR.