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A discovery study of daunorubicin induced cardiotoxicity in a sample of acute myeloid leukemia patients prioritizes P450 oxidoreductase polymorphisms as a potential risk factor.

Lubieniecka JM, Graham J, Heffner D, Mottus R, Reid R, Hogge D, Grigliatti TA, Riggs WK - Front Genet (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Results of gene-based tests of association with drop in LVEF. (A) Quantile-quantile plot of nominal p-values for the 60 genes included in analysis—the observed p-values are plotted against p-values expected under the  hypothesis.(B) Benjamini-Hochberg false-discovery rates (FDRs) for the 60 analyzed genes. The strongest signal was detected for the POR gene (FDR adjusted p-value = 0.15).
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Figure 2: Results of gene-based tests of association with drop in LVEF. (A) Quantile-quantile plot of nominal p-values for the 60 genes included in analysis—the observed p-values are plotted against p-values expected under the hypothesis.(B) Benjamini-Hochberg false-discovery rates (FDRs) for the 60 analyzed genes. The strongest signal was detected for the POR gene (FDR adjusted p-value = 0.15).

Mentions: Another limitation of the Manhattan plot is that the graphic downplays the gene size, as well as the differences in the number of SNPs between genes. Therefore, we applied a multi-SNP based approach in which each of the 60 genes was tested for association with drop in LVEF using a global test of its SNPs and their linear interactions with dose (Goeman et al., 2006). This test statistic adjusts for gene size, number of SNPs, and LD between the SNPs. The unadjusted p-values for the 60 genes are shown in the quantile-quantile plot (Figure 2A), in which observed p-values are plotted against p-values expected under the hypothesis (no genetic association). The FDR-adjusted p-values for the 60 genes are displayed in Figure 2B, with the strongest signal detected for the POR gene (FDR adjusted p-value = 0.15). After accounting for the effects of anthracycline dose and ethnicity, the proportion of variability in the LVEF drop attributable to POR is estimated to be 11.6% in post-hoc analyses.


A discovery study of daunorubicin induced cardiotoxicity in a sample of acute myeloid leukemia patients prioritizes P450 oxidoreductase polymorphisms as a potential risk factor.

Lubieniecka JM, Graham J, Heffner D, Mottus R, Reid R, Hogge D, Grigliatti TA, Riggs WK - Front Genet (2013)

Results of gene-based tests of association with drop in LVEF. (A) Quantile-quantile plot of nominal p-values for the 60 genes included in analysis—the observed p-values are plotted against p-values expected under the  hypothesis.(B) Benjamini-Hochberg false-discovery rates (FDRs) for the 60 analyzed genes. The strongest signal was detected for the POR gene (FDR adjusted p-value = 0.15).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3822292&req=5

Figure 2: Results of gene-based tests of association with drop in LVEF. (A) Quantile-quantile plot of nominal p-values for the 60 genes included in analysis—the observed p-values are plotted against p-values expected under the hypothesis.(B) Benjamini-Hochberg false-discovery rates (FDRs) for the 60 analyzed genes. The strongest signal was detected for the POR gene (FDR adjusted p-value = 0.15).
Mentions: Another limitation of the Manhattan plot is that the graphic downplays the gene size, as well as the differences in the number of SNPs between genes. Therefore, we applied a multi-SNP based approach in which each of the 60 genes was tested for association with drop in LVEF using a global test of its SNPs and their linear interactions with dose (Goeman et al., 2006). This test statistic adjusts for gene size, number of SNPs, and LD between the SNPs. The unadjusted p-values for the 60 genes are shown in the quantile-quantile plot (Figure 2A), in which observed p-values are plotted against p-values expected under the hypothesis (no genetic association). The FDR-adjusted p-values for the 60 genes are displayed in Figure 2B, with the strongest signal detected for the POR gene (FDR adjusted p-value = 0.15). After accounting for the effects of anthracycline dose and ethnicity, the proportion of variability in the LVEF drop attributable to POR is estimated to be 11.6% in post-hoc analyses.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus