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Recent studies emphasize the significant impact of the renin-angiotensin aldosterone system (RAAS) as a risk factor associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, according to the literature, the effect of rs4646994 and rs2285666 polymorphisms on susceptibility and progression to severe clinical outcomes is still controversial. Our aim was to investigate the effect of polymorphisms such as rs4646994 and rs2285666 on susceptibility to coronavirus disease-2019 (COVID-19). We conducted a comprehensive literature search using databases such as ISI Web of Science, PubMed, Scopus, and Google Scholar to retrieve studies on the effect of two polymorphisms (rs4646994 and rs2285666) of the angiotensin-converting enzyme (ACE) gene on COVID-19. Finally, the effect of each polymorphism on SARS-CoV-2 infection was measured based on the odds ratio with 95% confidence intervals. Analysis of the rs4646994 polymorphism showed that the frequency of the D allele in patients infected with COVID-19 was higher than that the I allele. Moreover, the authors found that the DD genotype increased the risk of severe disease by 1.7-fold in Asian population, whereas, this was not the case in the Western population. However, the rs4646994 II genotype plays a protective role against COVID-19 in Western countries. In the case of the rs2285666 polymorphism based on patient ethnicity, the C allele had the highest frequency. Interestingly, in people harboring the GG and TT genotypes, the risk of progression to severe disease significantly increased, while people with genotypes such as GA, AA and CC seem to be more resistant to severe Covid-19. Based on geographical region, the rs4646994 DD genotype may be considered as a predictive biomarker to identify the susceptibility of human to SARS-CoV-2 infection and severe COVID-19 outcomes. We also concluded that individuals with GG and TT genotypes are significantly more susceptible to severe outcomes of disease, while conversely, individuals with GA, AA, and CC genotypes are less susceptible to severe COVID-19. • The rs4646994 DD genotype increases the risk of susceptibility to COVID-19 by approximately 1.7-fold in Asian populations. • The rs4646994 II genotype plays a protective role against COVID-19 in Western countries. • The rs2285666 GG genotype can increase the risk of ARDS in Western patients. • The rs2285666 GA genotype plays a protective role against ARDS. [ABSTRACT FROM AUTHOR]