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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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