Genetic polymorphisms of NAD(P)H oxidase: variation in subunit expression and enzyme activity.
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.
Schirmer
M
M
Department of Clinical Pharmacology, Georg-August-University Göttingen, Göttingen, Germany. mschirmer@med.uni-goettingen.de
Hoffmann
M
M
Kaya
E
E
Tzvetkov
M
M
Brockmöller
J
J
D000293:Adolescent; D000328:Adult; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D014644:Genetic Variation / Q000502:physiology*; D006098:Granulocytes / Q000201:enzymology; D006801:Humans; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000096:biosynthesis* / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000502:physiology*; D021122:Protein Subunits / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
D021122:Protein Subunits; D012333:RNA, Messenger; D019255:NADPH Oxidases