Abstract
(1) Background: Combating viral disease outbreaks has doubtlessly been one of the major public health challenges for the 21st century. (2) Methods: The host entry machinery required for COVID-19 (SARS-CoV-2) infection was examined for the gene expression profiles and polymorphism. (3) Results: Lung, kidney, small intestine, and salivary glands were among the tissues which expressed the entry machinery coding genes Ace2, Tmprss2, CtsB, and CtsL. The genes had no significant expression changes between males and females. The four human population groups of Europeans, Africans, Asians, and Americans had specific and also a common pool of rare variants for the X-linked locus of ACE2 receptor. Several specific and common ACE2 variants including S19P, I21T/V, E23K, A25T, K26R, T27A, E35D/K, E37K, Y50F, N51D/S, M62V, N64K, K68E, F72V, E75G, M82I, T92I, Q102P, G220S, H239Q, G326E, E329G, G352V, D355N, H378R, Q388L, P389H, E467K, H505R, R514G/*, and Y515C were of the utmost importance to the viral entry and infection. The variants of S19P, I21T, K26R, T27A, E37K, N51D, N64K, K68E, F72V, M82I, G326E, H378R, Q388L, and P389H also had significant differences in frequencies among the population groups. Most interestingly, the analyses revealed that more than half of the variants can exist in males, i.e., as hemizygous. (4) Conclusions: The rare variants of human ACE2 seem to be one of the determinant factors associated with fitness in the battle against SARS viruses. The hemizygous viral-entry booster variants of ACE2 describe the higher SARS-CoV-2 mortality rate in males. This is also supported by the lack of gender bias for the gene expression profiles of entry machinery. A personalized medicine strategy is conceived for isolating high-risk individuals in epidemic circumstances.