Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Wojnowski, L; Kulle, B; Schirmer, M; Schlüter, G; Schmidt, A; Rosenberger, A; Vonhof, S; Bickeböller, H; Toliat, MR; Suk, EK; Tzvetkov, M; Kruger, A; Seifert, S; Kloess, M; Hahn, H; Loeffler, M; Nürnberg, P; Pfreundschuh, M; Trümper, L; Brockmöller, J; Hasenfuss, G.
NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity.
Circulation. 2005; 112(24): 3754-3762.
Doi: 10.1161/CIRCULATIONAHA.105.576850
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- Co-Autor*innen der Med Uni Graz
- Schmidt Albrecht
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- Abstract:
- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Adolescent -
- Adult -
- Aged -
- Animals -
- Anthracyclines - metabolism Anthracyclines - toxicity
- Biological Transport - genetics
- Case-Control Studies -
- Doxorubicin - metabolism Doxorubicin - toxicity
- Drug Toxicity - genetics
- Female -
- Free Radicals - metabolism
- Heart Diseases - chemically induced
- Humans -
- Male -
- Membrane Glycoproteins - genetics
- Mice -
- Mice, Knockout -
- Middle Aged -
- NADPH Oxidase - genetics
- P-Glycoprotein - genetics
- Pharmacogenetics - methods
- Polymorphism, Genetic -
- Ventricular Function, Left - drug effects
- Find related publications in this database (Keywords)
- drugs
- genes
- genetics
- heart failure