Published Online
on December 5, 2005

A more recent version of this article appeared on December 13, 2005

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Submitted on March 18, 2005
Revised on September 8, 2005
Accepted on September 27, 2005

NAD(P)H Oxidase and Multidrug Resistance Protein Genetic Polymorphisms Are Associated With Doxorubicin-Induced Cardiotoxicity

Leszek Wojnowski MD^*, Bettina Kulle PhD, Markus Schirmer MD, Gregor Schlüter MD, Albrecht Schmidt MD, Albert Rosenberger PhD, Stefan Vonhof MD, Heike Bickeböller PhD, Mohammad Reza Toliat PhD, Eun-Kyung Suk PhD, Mladen Tzvetkov PhD, Anke Kruger PhD, Silvia Seifert MSc, Marita Kloess PhD, Heidi Hahn MD, Markus Loeffler MD, Peter Nürnberg PhD, Michael Pfreundschuh MD, Lorenz Trümper MD, Jürgen Brockmöller MD, and Gerd Hasenfuss MD

From the Department of Pharmacology, University Mainz, Mainz, Germany (L.W., A.K.); Departments of Genetic Epidemiology (B.K., A.R., H.B.), Clinical Pharmacology (L.W., M.S., M.T., J.B.), Human Genetics, (G.S., S.S., H.H.), Cardiology and Pneumonology (A.S., S.V., G.H.), and Hematology and Oncology (L.T.), University Göttingen, Göttingen, Germany; Gene Mapping Center, Max-Delbrück Center, Berlin, Germany (M.R.T., E.S., P.N.); Cologne Center for Genomics, University of Cologne, Cologne, Germany (M.R.T., P.N.); Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig, Germany (M.K., M.L.); Department of Internal Medicine I, University of Saarland, Homburg, Germany (M.P.); and Departments of Biostatistics and Mathematics, University of Oslo, Oslo, Norway (B.K.).

^* To whom correspondence should be addressed. E-mail: Wojnowski{at}uni-mainz.de.

Background--A significant number of patients treated with anthracyclines develop cardiotoxicity (anthracycline-induced cardiotoxicity [ACT]), mainly presenting as arrhythmias (acute ACT) or congestive heart failure (chronic ACT). There are no data on pharmacogenomic predictors of ACT.

Methods and Results--We genotyped participants of the German non-Hodgkin lymphoma study (NHL-B) who were followed up for the development of heart failure for a median of >3 years. Single-nucleotide polymorphisms (SNPs) were selected from 82 genes with conceivable relevance to ACT. Of 1697 patients, 55 developed acute and 54 developed chronic ACT (cumulative incidence of either form, 3.2%). We detected 5 significant associations with polymorphisms of the NAD(P)H oxidase and doxorubicin efflux transporters. Chronic ACT was associated with a variant of the NAD(P)H oxidase subunit NCF4 (rs1883112, -212AG; symbols with right-pointing arrows, as edited?‘ odds ratio [OR], 2.5; 95% CI, 1.3 to 5.0). Acute ACT was associated with the His72Tyr polymorphism in the p22phox subunit (rs4673; OR, 2.0; 95% CI, 1.0 to 3.9) and with the variant 7508TA (rs13058338; OR, 2.6; 95% CI, 1.3 to 5.1) of the RAC2 subunit of the same enzyme. In agreement with these results, mice deficient in NAD(P)H oxidase activity, unlike wild-type mice, were resistant to chronic doxorubicin treatment. In addition, acute ACT was associated with the Gly671Val variant of the doxorubicin efflux transporter multidrug resistance protein 1 (MRP1) (OR, 3.6; 95% CI, 1.6 to 8.4) and with the Val1188Glu-Cys1515Tyr (rs8187694-rs8187710) haplotype of the functionally similar MRP2 (OR, 2.3; 95% CI, 1.0 to 5.4). Polymorphisms in adrenergic receptors previously demonstrated to be predictive of heart failure were not associated with ACT.

Conclusions--Genetic variants in doxorubicin transport and free radical metabolism may modulate the individual risk to develop ACT.

Key words: drugs • genes • genetics • heart failure

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