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Genetic polymorphisms of NAD(P)H oxidase: variation in subunit expression and enzyme activity

Abstract

Genetic polymorphisms in superoxide-producing NAD(P)H oxidase have been linked to cardiovascular diseases including anthracycline-induced cardiotoxicity. We quantified NAD(P)H oxidase activity in granulocytes of 81 healthy Caucasian volunteers (in addition, 51 in an independent confirmatory study) by chemiluminescence using the luminol analogue L-012. Expression of CYBA, NCF4 and RAC2 coding for NAD(P)H oxidase subunits was measured in whole blood cells in 59 study participants by real-time PCR. Of the five variants investigated (−930A>G, 242C>T, 640A>G in CYBA and the recently reported −368G>A in NCF4 and 7508T>A in RAC2), only CYBA 640A>G was consistently associated with superoxide production (640GG carriers 28% less than AA individuals, P=0.05 in each cohort, P=0.005 in combined analysis). RAC2 7508T>A was related to higher expression of RAC2 (P=0.02) and NCF4 (P=0.04). In summary, CYBA 640A>G rather than 242C>T was associated with reduced activity. The quantitatively moderate effect and the high intra-individual variability should be considered for further study design.

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Acknowledgements

This work was supported by Grants 01GS0107, 01GS0157, 01GR0462 and 01GS0421 of the National Genome Research Network, Federal Ministry of Education and Research, Bonn, Germany; by the Deutsche Forschungsgemeinschaft (Graduiertenkolleg 1034), Bonn, Germany; and by the local research promotion programme of Göttingen University, Germany. We gratefully acknowledge the support of Daniel Sehrt, MD, and Stefan V Vormfelde, MD, concerning volunteer recruitment. And the authors acknowledge the technical assistance of Karoline Jobst and the skillful contributions of the medical students Daniela Bolte, Susanne Pahl, Julia P Kaup, Irmani B Ismadi and Adda Boekhoff. We are thankful to the kind support of the Department of Transfusion Medicine at Göttingen University Hospital.

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Correspondence to M Schirmer.

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Schirmer, M., Hoffmann, M., Kaya, E. et al. Genetic polymorphisms of NAD(P)H oxidase: variation in subunit expression and enzyme activity. Pharmacogenomics J 8, 297–304 (2008). https://doi.org/10.1038/sj.tpj.6500467

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