title: A discovery study of daunorubicin induced cardiotoxicity in a sample of acute myeloid leukemia patients prioritizes P450 oxidoreductase polymorphisms as a potential risk factor.
abstract: 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.
authors.affiliation: Department of Zoology, Life Sciences Institute, University of British Columbia Vancouver, BC, Canada ; Department of Statistics and Actuarial Science, Simon Fraser University Burnaby, BC, Canada.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Lubieniecka
authors.forename: Jinko
authors.initials: J
authors.lastname: Graham
authors.forename: Daniel
authors.initials: D
authors.lastname: Heffner
authors.forename: Randy
authors.initials: R
authors.lastname: Mottus
authors.forename: Ronald
authors.initials: R
authors.lastname: Reid
authors.forename: Donna
authors.initials: D
authors.lastname: Hogge
authors.forename: Tom A
authors.initials: TA
authors.lastname: Grigliatti
authors.forename: Wayne K
authors.initials: WK
authors.lastname: Riggs
keywords: P450 oxidoreductase variants; acute myeloid leukemia; adverse drug reactions; anthracycline induced cardiotoxicity; complex trait; daunorubicin; global test