title: NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity.
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.
  
  
  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.
authors.affiliation: Department of Pharmacology, University Mainz, D-55101 Mainz, Germany. Wojnowski@uni-mainz.de
authors.forename: Leszek
authors.initials: L
authors.lastname: Wojnowski
authors.forename: Bettina
authors.initials: B
authors.lastname: Kulle
authors.forename: Markus
authors.initials: M
authors.lastname: Schirmer
authors.forename: Gregor
authors.initials: G
authors.lastname: Schlüter
authors.forename: Albrecht
authors.initials: A
authors.lastname: Schmidt
authors.forename: Albert
authors.initials: A
authors.lastname: Rosenberger
authors.forename: Stefan
authors.initials: S
authors.lastname: Vonhof
authors.forename: Heike
authors.initials: H
authors.lastname: Bickeböller
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Toliat
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Suk
authors.forename: Mladen
authors.initials: M
authors.lastname: Tzvetkov
authors.forename: Anke
authors.initials: A
authors.lastname: Kruger
authors.forename: Silvia
authors.initials: S
authors.lastname: Seifert
authors.forename: Marita
authors.initials: M
authors.lastname: Kloess
authors.forename: Heidi
authors.initials: H
authors.lastname: Hahn
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Michael
authors.initials: M
authors.lastname: Pfreundschuh
authors.forename: Lorenz
authors.initials: L
authors.lastname: Trümper
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brockmöller
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D018943:Anthracyclines / Q000378:metabolism / Q000633:toxicity; D001692:Biological Transport / Q000235:genetics; D016022:Case-Control Studies; D004317:Doxorubicin / Q000378:metabolism / Q000633:toxicity*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D006331:Heart Diseases / Q000139:chemically induced*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018943:Anthracyclines; D005609:Free Radicals; D008562:Membrane Glycoproteins; D004317:Doxorubicin; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases