The genetic variations among individuals are one of the notable factors determining disease severity and drug response. Nowadays, COVID-19 pandemic has been adversely affecting many aspects of human life. We used the Tehran Cardio-Metabolic Genetic Study (TCGS) data that is an ongoing genetic study including the whole-genome sequencing of 1200 individuals and chip genotyping of more than 15,000 participants. Here, the effect of ACE2 variations by focusing on the receptor-binding site of SARS-CoV-2 and ACE2 cleavage by TMPRSS2 protease were investigated through simulations study. After analyzing TCGS data, 570 genetic variations on the ACE2 gene, including single nucleotide polymorphisms (SNP) and insertion/deletion (INDEL) were detected. Interestingly, two observed missense variants, K26R and S331F, which only the first one was previously reported, can reduce the receptor affinity for the viral Spike protein. Moreover, our bioinformatics simulation of 3D structures and docking of proteins explains important details of ACE2-Spike and ACE2-TMPRSS2 interactions, especially the critical role of Arg652 of ACE2 for protease function of TMPRSS2 was uncovered. As our results show that the genetic variation of ACE2 can at least influence the affinity of this receptor to its partners, we need to consider the genetic variations on ACE2 as well as other genes in the pathways that contribute to the pathogenesis of COVID-19 for designing efficient drugs and vaccines.

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