Preliminary characterisation of the promoter of the human p22^phox gene: identification of a new polymorphism associated with hypertension

Abstract

The p22phox subunit is an essential protein in the activation of NAD(P)H oxidase. Here we report the preliminary characterisation of the human p22 phox gene promoter. The p22 phox promoter contains TATA and CCAC boxes and Sp1, Q Q-interferon and nuclear factor U UB sites. We screened for mutations in the p22 phox promoter and identi¢ed a new polymorphism, localised at position 3 3930 from the ATG codon, which was associated with hypertension. Mutagenesis experiments showed that the G allele had higher promoter activity than the A allele. These results suggest that the 3 3930 A=G polymorphism in the p22 phox promoter may be a novel genetic marker associated with hypertension.

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

“…We analysed five polymorphisms, three variants which have recently been associated with anthracyclineinduced cardiotoxicity 23 and, in addition, the other two NAD(P)H oxidase variants frequently discussed in relation to several clinical phenotypes. 17,18,22 The most extensively studied NAD(P)H oxidase polymorphism is the 242C4T variant of CYBA causing His4Tyr substitution at position 72. We could not demonstrate a consistent impact of this variant on enzyme activity.…”

“…The À930A4G variant in the promoter region of CYBA has been previously proposed to be a risk factor for hypertension 17 and might be a determinant of NAD(P)H oxidase expression and activity in hypertensive patients. 18 In granulocytes of healthy subjects, we did not see any influence on gene expression or activity in accordance to published data.…”

“…The À930A4G polymorphism in the 5 0 region of CYBA was reported to be associated with hypertension and higher promoter activity 17 as well as with an increased p22phox expression in hypertensive individuals. 18 The first study addressing the functionality of the His72Tyr amino acid substitution (242C4T) in p22phox revealed a reduced superoxide production both basal and stimulated in human blood vessel cells carrying the 242T allele.…”

The effect of p22phox −930A/G, A640G and C242T polymorphisms of NADPH oxidase on peripheral and central pressures in healthy, normotensive individuals

“…The À930A/G, A640G and C242T CYBA gene polymorphisms were analyzed in all subjects using restriction fragment length polymorphism as previously described. 6,14 Genotypes were determined according to the pattern of the bands on electrophoresis by two independent investigators.…”

“…4,5 The CYBA gene encodes the essential p22 phox subunit of NADPH oxidase; substitution of adenosine (A) for guanosine (G) in position À930 or 640, as well as cytidine (C) for thymidine (T) in position 242 have been reported to be more frequent among hypertensives, suggesting a possible role for these SNPs in the development of essential hypertension. 3,6 However, a putative contribution of these polymorphisms to the regulation of blood pressure in a non-hypertensive setting has not yet been addressed. Furthermore, correlations with central blood pressures have not been investigated.…”