Published online before print April 12, 2004, doi: 10.1161/01.HYP.0000126579.50711.62
(Hypertension. 2004;43:1246.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
C242T CYBA Polymorphism of the NADPH Oxidase Is Associated With Reduced Respiratory Burst in Human Neutrophils
From the Department of Medicine (K.E.W., S.S.W., K.K.G., S.I.D., S.R., B.F., D.G.H., A.M.Z.), Division of Cardiology, Emory University, Atlanta, Ga; Atlanta Veterans Affairs Medical Center (S.S.W., S.R., D.G.H., A.M.Z.), Decatur, Ga; and Rollins School of Public Health (H.A.), Department of Epidemiology, Emory University, Atlanta, Ga.
Correspondence to Dr A. Maziar Zafari, Emory University School of Medicine, Division of Cardiology, 1639 Pierce Drive, 319 WMB, Atlanta, GA 30322. E-mail azafari{at}emory.edu
Oxidative stress contributes to the pathogenesis of atherosclerosis. p22phox-based NAD(P)H oxidases exist in the vessel wall, acting as important superoxide-generating systems in the vasculature. Some studies have identified reduced atherosclerosis in the presence of the C242T CYBA polymorphism, whereas others have not. Because vascular p22phox is identical to neutrophil p22phox, we studied the association between the C242T, A640G, and –930A/G CYBA polymorphisms and the quantity of superoxide produced from neutrophils isolated from healthy adults to determine if these polymorphisms had any functional impact on NADPH oxidase function. Neutrophils were isolated from 90 subjects by Percoll density gradient centrifugation. Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping, as well as real-time PCR. The oxidative burst was stimulated with phorbol 12-myristate 13-acetate. Superoxide was quantified using the superoxide dismutase inhibitable oxidation of the spin probe hydroxylamine 1-hydroxy-3-carboxy-pyrrolidine, detected by electron paramagnetic resonance. Superoxide production was significantly affected by the C242T polymorphism, being 8.7±0.7, 7.9±0.6, and 5.9±1.2 µmol/L per minute per 106 neutrophils for the C242T CC, CT, and TT genotypes, respectively (P<0.05). In contrast, the A640G and the –930A/G polymorphisms did not alter the neutrophil respiratory burst. Phagocytic respiratory burst activity in homozygous individuals with the T allele of the C242T CYBA polymorphism is significantly lower than of wild-type carriers and heterozygous individuals. Because p22phox exists in both the neutrophil and vessel wall, vascular oxidative stress is likely diminished in individuals with this polymorphism.
Key Words: atherosclerosis • neutrophils • oxidative stress • polymorphism • risk factors
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