**3. Candidate gene variations in endothelial dysfunction**

A candidate gene in context of gene polymorphisms is one which is presumed to be associated with a particular disease or a phenotypic trait and whose biological functions are derived directly or indirectly from other studies. The role of nitric oxide (NO) and ET-1 in maintaining endothelial homeostasis is well established, and they are the obvious candidate genes of choice for studying endothelial dysfunction. Low levels of NO are associated with impaired endothelial function, and polymorphisms in genes of molecules, factors, and pathways regulating synthesis of nitric oxide in vascular endothelium have been implicated in endothelial dysfunction, the rationale being the impaired bioavailability of endogenous nitric oxide (NO) that underlies vascular disease [2]. They include polymorphisms in the endothelial nitric oxide synthase gene (eNOS gene), NOS3, asymmetric dimethyl arginine gene (*ADMA*), tetrahydrobiopterin gene *BH4*, and the gene encoding the p22phox subunit of NADPH oxidase *(CYB A).* NO in vascular endothelium is synthesized by the enzyme NOS which requires BH4 as a co-factor. NOS is inhibited by ADMA, a naturally occurring product of metabolism found in human circulation and an analog of L-arginine. NO synthesis is inhibited by raised levels of ADMA, and this results in impaired endothelial function. Increased levels of ADMA are found in people with hypercholesterolemia, atherosclerosis, hypertension, chronic heart failure, diabetes mellitus, and chronic renal failure. Reactive oxygen species (ROS) such as superoxide (O2 <sup>−</sup>) lead to increased inactivation of NO with the generation of ONOO<sup>−</sup> which can lead to protein and DNA damage and subsequently loss of atheroprotective functions of NO. A variant of p22phox subunit of NADPH oxidase, an enzyme responsible for generation of O2 <sup>−</sup> in vasculature involved in the production of ROS in vessel wall, has been shown

to be associated with progression of atherosclerosis [9]. Results of polymorphisms studied in other genes whose products have been implicated in endothelial dysfunction have been inconclusive.
