RGD Reference Report - NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. - Rat Genome Database

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NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity.

Authors: Wojnowski, L  Kulle, B  Schirmer, M  Schluter, G  Schmidt, A  Rosenberger, A  Vonhof, S  Bickeboller, H  Toliat, MR  Suk, EK  Tzvetkov, M  Kruger, A  Seifert, S  Kloess, M  Hahn, H  Loeffler, M  Nurnberg, P  Pfreundschuh, M  Trumper, L  Brockmoller, J  Hasenfuss, G 
Citation: Wojnowski L, etal., Circulation. 2005 Dec 13;112(24):3754-62. Epub 2005 Dec 5.
RGD ID: 11041175
Pubmed: PMID:16330681   (View Abstract at PubMed)
DOI: DOI:10.1161/CIRCULATIONAHA.105.576850   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ABCB1HumanAnthracycline-induced Cardiotoxicity susceptibilityIAGP DNA:missense mutation:cds:p.G671V (human)RGD 
Abcb1aRatAnthracycline-induced Cardiotoxicity susceptibilityISOABCB1 (Homo sapiens)DNA:missense mutation:cds:p.G671V (human)RGD 
Abcb1aMouseAnthracycline-induced Cardiotoxicity susceptibilityISOABCB1 (Homo sapiens)DNA:missense mutation:cds:p.G671V (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Abcb1a  (ATP binding cassette subfamily B member 1A)

Genes (Mus musculus)
Abcb1a  (ATP-binding cassette, sub-family B member 1A)

Genes (Homo sapiens)
ABCB1  (ATP binding cassette subfamily B member 1)


Additional Information