Oxidative stress in the vasculature induced by ROS (particularly the superoxide anion) via the NAD(P)H oxidase pathway causes vascular wall remodeling and endothelial dysfunction, consistent with the initial pathogenesis of vascular diseases such as atherosclerosis and CAD.[5] Genetic alterations in the CYBA gene have been reported that interrupt this pathway in the vasculature, including the C242T and A640G polymorphisms.[2]
The C242T polymorphism occurs in exon 4 and results in a histidine to tyrosine amino acid substitution[1] in the p22phox protein. This leads to reduced NAD(P)H oxidase activity in human blood vessels and therefore a decreased production of ROS and vascular oxidative stress.[6] A 2014 meta-analysis indicated a protective role of this polymorphism for CAD in an Asian population due to reduced NAD(P)H oxidase activity.[2] Functional studies have further shown that the C242T variant is associated with lower superoxide production in human blood vessels, independent of established atherosclerosis risk factors.[6] Associations between the p22phox C242T polymorphism and other vascular diseases have also been investigated. Pooled analyses have examined its relationship with ischemic cerebrovascular disease, with results varying by population and disease subtype.[7]
The A640G polymorphism is located in the 3' untranslated region (UTR) of the CYBA gene and does not cause an amino acid substitution, however it has still been shown to have an effect on ROS generation.[8] Although this variation has been less extensively studied, it has also been linked to a decreased risk of CAD,[2] possibly due to decreased translational activity of the CYBA gene.[8] Specific mechanisms of this particular polymorphism are currently under investigation.[2]