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          Institute: MPI für molekulare Genetik     Collection: Department of Vertebrate Genomics     Display Documents



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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
Language:English
Date of Publication (YYYY-MM-DD):2005-12
Title of Journal:Circulation
Volume:112
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.

Conclusions:
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
Identifiers:ISSN:1524-4539
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