Display options
Cite
Lubieniecka JM, Graham J, Heffner D, et al. A discovery study of daunorubicin induced cardiotoxicity in a sample of acute myeloid leukemia patients prioritizes P450 oxidoreductase polymorphisms as a potential risk factor. Front Genet. 2013;4:231doi: 10.3389/fgene.2013.00231.
Lubieniecka, J. M., Graham, J., Heffner, D., Mottus, R., Reid, R., Hogge, D., Grigliatti, T. A., & Riggs, W. K. (2013). A discovery study of daunorubicin induced cardiotoxicity in a sample of acute myeloid leukemia patients prioritizes P450 oxidoreductase polymorphisms as a potential risk factor. Frontiers in genetics, 4231. https://doi.org/10.3389/fgene.2013.00231
Lubieniecka, Joanna M, et al. "A discovery study of daunorubicin induced cardiotoxicity in a sample of acute myeloid leukemia patients prioritizes P450 oxidoreductase polymorphisms as a potential risk factor." Frontiers in genetics vol. 4 (2013): 231. doi: https://doi.org/10.3389/fgene.2013.00231
Lubieniecka JM, Graham J, Heffner D, Mottus R, Reid R, Hogge D, Grigliatti TA, Riggs WK. A discovery study of daunorubicin induced cardiotoxicity in a sample of acute myeloid leukemia patients prioritizes P450 oxidoreductase polymorphisms as a potential risk factor. Front Genet. 2013 Nov 11;4:231. doi: 10.3389/fgene.2013.00231. eCollection 2013. PMID: 24273552; PMCID: PMC3822292.
Copy Download .nbib Format: NLM
Share it on

Front Genet. 2013 Nov 11;4:231. doi: 10.3389/fgene.2013.00231. eCollection 2013.

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

Frontiers in genetics

Joanna M Lubieniecka, Jinko Graham, Daniel Heffner, Randy Mottus, Ronald Reid, Donna Hogge, Tom A Grigliatti, Wayne K Riggs

Affiliations

  1. 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.

PMID: 24273552 PMCID: PMC3822292 DOI: 10.3389/fgene.2013.00231

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.

Keywords: P450 oxidoreductase variants; acute myeloid leukemia; adverse drug reactions; anthracycline induced cardiotoxicity; complex trait; daunorubicin; global test

References

  1. Trends Genet. 2012 Nov;28(11):538-43 - PubMed
  2. Prog Cardiovasc Dis. 2010 Sep-Oct;53(2):105-13 - PubMed
  3. Drug Metab Dispos. 2011 Aug;39(8):1433-9 - PubMed
  4. Br J Cancer. 2005 Jul 11;93(1):89-97 - PubMed
  5. Leuk Lymphoma. 2009 Oct;50(10):1693-8 - PubMed
  6. Biochem Soc Trans. 2009 Aug;37(Pt 4):843-8 - PubMed
  7. Nat Rev Genet. 2013 Jan;14(1):23-34 - PubMed
  8. Am J Hum Genet. 2007 Sep;81(3):559-75 - PubMed
  9. Pediatr Blood Cancer. 2011 Oct;57(4):612-9 - PubMed
  10. Nat Genet. 2010 Jul;42(7):565-9 - PubMed
  11. Oncology (Williston Park). 2009 Mar;23(3):234-5, 239 - PubMed
  12. Nature. 2010 Oct 28;467(7319):1061-73 - PubMed
  13. Cytometry B Clin Cytom. 2012 Sep;82(5):283-94 - PubMed
  14. J Clin Oncol. 2012 May 1;30(13):1415-21 - PubMed
  15. Expert Opin Drug Saf. 2012 May;11 Suppl 1:S21-36 - PubMed
  16. Toxicol Appl Pharmacol. 2010 Jan 1;242(1):38-46 - PubMed
  17. Cancer Res. 2007 Jun 1;67(11):5425-33 - PubMed
  18. Epidemiology. 2008 Sep;19(5):640-8 - PubMed
  19. Mol Cell Endocrinol. 2011 Apr 10;336(1-2):174-9 - PubMed
  20. Trends Genet. 2011 Mar;27(3):107-15 - PubMed
  21. Cancer. 2008 Jun 15;112(12):2789-95 - PubMed
  22. Nat Rev Genet. 2010 Dec;11(12):880-6 - PubMed
  23. Stat Appl Genet Mol Biol. 2012 Jan 21;11(1):Article 11 - PubMed
  24. Genet Epidemiol. 2009 Sep;33(6):497-507 - PubMed
  25. Eur J Epidemiol. 2009;24(10):585-7 - PubMed
  26. Cancer Inform. 2010 Dec 07;9:281-92 - PubMed
  27. Biochem Soc Trans. 2009 Dec;37(Pt 6):1311-5 - PubMed
  28. Pharmacogenomics. 2011 Oct;12(10):1407-15 - PubMed
  29. Pharmacogenomics. 2009 Apr;10(4):579-99 - PubMed
  30. PLoS One. 2013 Apr 16;8(4):e60164 - PubMed
  31. Circulation. 2010 Jan 19;121(2):276-92 - PubMed
  32. Circulation. 2005 Dec 13;112(24):3754-62 - PubMed
  33. Am J Hum Genet. 2009 Feb;84(2):210-23 - PubMed
  34. J Clin Oncol. 2012 May 1;30(13):1422-8 - PubMed
  35. Nat Genet. 2012 Nov;44(11):1191-8 - PubMed
  36. Am J Hematol. 2012 Jan;87(1):89-99 - PubMed
  37. PLoS One. 2011;6(11):e27964 - PubMed
  38. Cold Spring Harb Protoc. 2009 Oct;2009(10):pdb.ip71 - PubMed
  39. Nat Genet. 2005 Nov;37(11):1217-23 - PubMed
  40. Nature. 2009 Aug 6;460(7256):748-52 - PubMed
  41. J Clin Oncol. 2009 Dec 10;27(35):5972-8 - PubMed
  42. N Engl J Med. 2009 Apr 23;360(17):1701-3 - PubMed
  43. Nat Genet. 2006 Aug;38(8):904-9 - PubMed
  44. Science. 2013 Mar 29;339(6127):1563-6 - PubMed
  45. J Am Coll Cardiol. 2009 Jun 16;53(24):2231-47 - PubMed
  46. Lancet. 2005 Oct 8;366(9493):1315-23 - PubMed
  47. Free Radic Biol Med. 1997;23(5):775-82 - PubMed
  48. Proc Natl Acad Sci U S A. 1979 Feb;76(2):954-7 - PubMed

Publication Types