**1. Introduction**

Endothelial dysfunction (ED) is a hallmark of many human vascular diseases [1] like peripheral arterial disease, cardiovascular diseases including atherosclerosis and hypertension, stroke, diabetes, chronic kidney failure, tumor growth, and metastasis. Endothelial dysfunction, like many other multifactorial diseases, is caused by a combination of multiple genetic and environmental factors, a large proportion of which remain unexplained. Individual differences in endothelial function and hence susceptibility to diseases might relate not only to different levels of exposure

to risk factors but also to differences in the presence of different risk alleles of genes expressed in vascular endothelium, in different individuals [2]. Genetic regulation of variation in vascular function in different individuals is poorly understood and is largely mystifying. The genetic factors are one of the key determinants in the approach to prevent or treat diseases as envisaged by the Precision Medicine Initiative (PMI) [3] launched in 2015. Single-nucleotide polymorphisms (SNPs) are the most common genetic variation between human beings and key enablers of the concept of personalized medicine. An SNP is a single base substitution occurring at a specific site in the DNA sequence and in at least 1% or more of the population.

The healthy endothelium acts a gatekeeper of cardiovascular health regulating an exchange of fluids, nutrients, and metabolites critical to homeostasis and vascular health. Endothelial dysfunction leads to (i) loss of vascular integrity, (ii) increased expression of adhesion molecules, (iii) pro-thrombotic phenotype, (iv) production of cytokines, and (v) upregulation of human leukocyte antigen molecules [4].

Endothelial cells modulate the underlying vascular smooth muscle compartment by secreting several vasoactive substances [5] that control vascular relaxation and contraction as well as enzymes that control blood clotting, immune function, and platelet adhesion. Two major endothelium-derived factors are nitric oxide (NO) and endothelin-1 (ET-1) that have opposing effects on the function and structure of the vessel wall. Nitric oxide (NO) is a vasodilator, and endothelin (EDN-1) is a potent vasoconstrictor. Both molecules are critical regulators of vascular function. Decrease in NO production and the consequent impaired vasodilation is a hallmark of endothelial dysfunction. Failure of the complex balance between vasodilation brought about by NO and vasoconstriction brought about by ET- 1, because of genetic or acquired disturbances between these two molecules, results in changes in vascular tone and ED, triggering the pathological process of vascular diseases at their primary stage [6].
