NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity.
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.
Wojnowski
Leszek
L
Department of Pharmacology, University Mainz, D-55101 Mainz, Germany. Wojnowski@uni-mainz.de
Kulle
Bettina
B
Schirmer
Markus
M
Schlüter
Gregor
G
Schmidt
Albrecht
A
Rosenberger
Albert
A
Vonhof
Stefan
S
Bickeböller
Heike
H
Toliat
Mohammad Reza
MR
Suk
Eun-Kyung
EK
Tzvetkov
Mladen
M
Kruger
Anke
A
Seifert
Silvia
S
Kloess
Marita
M
Hahn
Heidi
H
Loeffler
Markus
M
Nürnberg
Peter
P
Pfreundschuh
Michael
M
Trümper
Lorenz
L
Brockmöller
Jürgen
J
Hasenfuss
Gerd
G
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
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