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Although older patients with preexisting chronic illnesses are more prone to develop severe complications, younger, healthy individuals might also exhibit serious manifestations. Previous studies directed to detect genetic susceptibility factors for earlier epidemics have provided evidence of certain protective variations. Following SARS-CoV-2 exposure, viral entry into cells followed by recognition and response by the innate immunity are key determinants of COVID-19 development. In the present review our aim was to conduct a thorough review of the literature on the role of single nucleotide polymorphisms (SNPs) as key agents affecting the viral entry of SARS-CoV-2 and innate immunity. Several SNPs within the scope of our approach were found to alter susceptibility to various bacterial and viral infections. Additionally, a multitude of studies confirmed genetic associations between the analyzed genes and autoimmune diseases, underlining the versatile immune consequences of these variants. Based on confirmed associations it is highly plausible that the SNPs affecting viral entry and innate immunity might confer altered susceptibility to SARS-CoV-2 infection and its complex clinical consequences. Anticipating several COVID-19 genomic susceptibility loci based on the ongoing genome wide association studies, our review also proposes that a well-established polygenic risk score would be able to clinically leverage the acquired knowledge.<\/jats:p>","DOI":"10.3389\/fimmu.2021.653489","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T04:55:48Z","timestamp":1615179348000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Germline Genetic Variants of Viral Entry and Innate Immunity May Influence Susceptibility to SARS-CoV-2 Infection: Toward a Polygenic Risk Score for Risk Stratification"],"prefix":"10.3389","volume":"12","author":[{"given":"Vince 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