p22phox (CYBA, cytochrome B-245 alpha chain) is a membrane-associated protein that plays a crucial role in the activation of NOX1, NOX2, NOX448, and NOX5333. Mutations of CYBA lead to autosomal recessive forms of chronic granulomatous disease334. Germline deletion of CYBA in mice335 or silencing of CYBA in Sprague-Dawley rats does not affect basal blood pressure but ameliorates angiotensin II-induced hypertension125,126. However, smooth muscle-specific overexpression of p22phox in mice increases blood pressure that is normalized in the offspring of dams crossed with Rag1−/− mice25. Polymorphisms in the CYBA promoter in the spontaneously hypertensive rat (SHR) increase the gene expression of CYBA336. Several polymorphisms of CYBA that could affect the production of ROS have also been reported in humans,334,. Some other CYBA gene variants are associated with decreased NOX2-dependent ROS generation but their association with blood pressure has not been studied128. Other CYBA gene variants are associated with increased ROS production and hypertension in several ethnic groups129,130,131,134–136,337. However, although CYBA 242C>T is associated with endothelial dysfunction, it is not associated with hypertension in an Asian-Indian population338. A meta-analysis found no association of CYBA 242C>T with hypertension134. CYBA 242C>T may be protective of coronary artery disease in an Asian population132 but increases the risk of diabetes mellitus133. In an Asian-Indian population, the haplotypes rs8854A/rs9932581G/rs4873C and rs8854G/rs9932581G/rs4873C are positively associated with increased blood pressure and oxidative stress while the haplotype rs8854G/rs9932581A/rs4873T is inversely correlated with blood pressure and oxidative stress339.