Anthracyclines are very effective chemotherapeutic agents; however, their use is hampered by the treatment-induced
cardiotoxicity. Genetic variants that help define patient's sensitivity to
anthracyclines will greatly improve the design of optimal chemotherapeutic regimens. However, identification of such variants is hampered by the lack of analytical approaches that address the complex, multi-genic character of
anthracycline induced
cardiotoxicity (AIC). Here, using a multi-SNP based approach, we examined 60 genes coding for
proteins involved in
drug metabolism and efflux and identified the P450
oxidoreductase (POR) gene to be most strongly associated with
daunorubicin induced
cardiotoxicity in a population of
acute myeloid leukemia (AML) patients (FDR adjusted p-value of 0.15). In this sample of
cancer patients, variation in the POR gene is estimated to account for some 11.6% of the variability in the drop of left ventricular ejection fraction (LVEF) after
daunorubicin treatment, compared to the estimated 13.2% accounted for by the cumulative dose and ethnicity. In post-hoc analysis, this association was driven by 3 SNPs-the rs2868177, rs13240755, and rs4732513-through their linear interaction with cumulative
daunorubicin dose. The unadjusted odds ratios (
ORs) and confidence intervals (CIs) for rs2868177 and rs13240755 were estimated to be 1.89 (95% CI: 0.7435-4.819; p = 0.1756) and 3.18 (95% CI: 1.223-8.27; p = 0.01376), respectively. Although the contribution of POR variants is expected to be overestimated due to the multiple testing performed in this small pilot study, given that cumulative
anthracycline dose is virtually the only factor used clinically to predict the risk of
cardiotoxicity, the contribution that genetic analyses of POR can make to the assessment of this risk is worthy of follow up in future investigations.