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276170.0 [No comment] 12.06.2006 14:13 Released

ID: 276170.0, MPI für molekulare Genetik / Department of Vertebrate Genomics
NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity
Authors:Wojnowski, Leszek; Kulle, Bettina; Schirmer, Markus; Schlüter, Gregor; Schmidt, Albrecht; Rosenberger, Albert; Vonhof, Stefan; Bickeböller, Heike; Toliat, Mohammad Reza; Suk, Eun-Kyung; Tzvetkov, Mladen; Kruger, Anke; Seifert, Silvia; Kloess, Marita; Hahn, Heidi; Loeffler, Markus; Nürnberg, Peter; Pfreundschuh, Michael; Trümper, Lorenz; Brockmöller, Jürgen; Hasenfuss, Gerd
Date of Publication (YYYY-MM-DD):2005-12
Title of Journal:Circulation
Issue / Number:24
Start Page:3754
End Page:3762
Copyright:© 2005 American Heart Association, Inc.
Review Status:not specified
Audience:Experts Only
Abstract / Description: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, -212A->G; 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 7508T->A (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.

Genetic variants in doxorubicin transport and free radical metabolism may modulate the individual risk to develop ACT.
Free Keywords:drugs; genes; genetics; heart failure
External Publication Status:published
Document Type:Article
Communicated by:Hans Lehrach
Affiliations:MPI für molekulare Genetik
External Affiliations:Department of Pharmacology, University Mainz, Mainz, Germany;
Departments of Genetic Epidemiology, Clinical Pharmacology, Human Genetics, Cardiology and Pneumonology and Hematology and Oncology, University Göttingen, Göttingen, Germany;
Gene Mapping Center, Max-Delbrück Center, Berlin, Germany; Cologne Center for Genomics, University of Cologne, Cologne, Germany;
Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig, Germany;
Department of Internal Medicine I, University of Saarland, Homburg, Germany;
Departments of Biostatistics and Mathematics, University of Oslo, Oslo, Norway