¹Department of Clinical Pharmacology, Georg-August-University Göttingen, Göttingen, Germany

Correspondence: Dr M Schirmer, Department of Clinical Pharmacology, Georg-August-University Göttingen, Robert-Koch-Str. 40, Göttingen D-37075, Germany. E-mail: mschirmer@med.uni-goettingen.de

²These two authors contributed equally to this work.

Received 5 October 2006; Revised 26 June 2007; Accepted 28 June 2007; Published online 7 August 2007.

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.