**4. Implication of human polymorphism of ACE2 in disease susceptibility**

A lot of ACE2 variants have been recognized in different databases [60, 61]. over the last decades, much focus has been assigned on some of ACE2 polymorphisms, due to their effects on the development of cardiovascular disease (CVD) and, more specifically, their association with hypertension (HT). ACE2 restricts the negative profibrotic and vasoconstrictor influences of AngII, as the breakdown of AngII to Ang (1-7) decreases the AngII oxidative stress of the cerebral arteries endothelium [62]. Ang (1-7) has been stated to have antifibrotic and vasodilation [63, 64]. Low cardiac expression of ACE2 levels has been notified in hypertension and diabetes heart failure [65, 66]. ACE2 gene polymorphisms were first detected in the Chinese people with different ACE2 variants (rs4830542, rs4240157, and rs4646155) linked to hypertension (HT) [67–70]. Also, ACE2 SNP rs21068809 (C > T) was found to be linked to the clinical features of HT [71]. In India, a study of 246 patients with HT and 274 normal subjects showed a connection of ACE2 rs21068809 SNP with HT [72]. in Brazilian cohorts, a study of genetic association of the combination of ACE2 G8790A and ACE I/D polymorphisms reveal susceptibility to HT [73]. ACE polymorphism has been described in African- Americans with HT [74].
