Functional effect of the C242T polymorphism in the NAD(P)H oxidase p22phoxgene on vascular superoxide production in atherosclerosis

Background-Increased superoxide anion production increases oxidative stress and reduces nitric oxide bioactivity in vascular disease states. NAD(P)H o xidase is an important source of superoxide in human blood vessels, and som e studies suggest a possible association between polymorphisms in the NAD(P )H oxidase CYBA gene and atherosclerosis; however, no functional data addre ss this hypothesis. We examined the relationships between the CYBA C242T po lymorphism and direct measurements of superoxide production in human blood vessels. Methods and Results-Vascular NAD(P)H oxidase activity was determined ill hu man saphenous veins obtained from 110 patients with coronary artery disease and identified risk factors. Immunoblotting, reverse-transcription polymer ase chain reaction, and DNA sequencing showed that p22phox protein, mRNA, a nd 242C/T allelic variants are expressed in human blood vessels. Vascular s uperoxide production, both basal and NADH-stimulated, was highly variable b etween patients, but the presence of the CYBA 242T allele was associated wi th significantly reduced vascular NAD(P)H oxidase activity, independent of other clinical risk factors for atherosclerosis. Conclusions-Association of the CYBA 242T allele with reduced NAD(P)H oxidas e activity in human blood vessels suggests that genetic variation in NAD(P) H oxidase components may play a significant role in modulating superoxide p roduction in human atherosclerosis.