Published online before print December 5, 2005, doi: 10.1161/CIRCULATIONAHA.105.576850
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(Circulation. 2005;112:3754-3762.)
© 2005 American Heart Association, Inc.
Heart Failure |
NAD(P)H Oxidase and Multidrug Resistance Protein Genetic Polymorphisms Are Associated With Doxorubicin-Induced Cardiotoxicity
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.).
Correspondence to Dr Leszek Wojnowski, Department of Pharmacology, University Mainz, Obere Zahlbacher Strasse 67, D-55101 Mainz, Germany. E-mail Wojnowski{at}uni-mainz.de
Received March 18, 2005; de novo received July 19, 2005; revision received September 8, 2005; accepted September 27, 2005.
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 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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