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Abstract Background: Coronavirus disease 2019 (COVID-19) is a pandemic respiratory disease with a high mortality rate, caused by infection with severe acute respiratory syndrome coronavirus 2. Variants of the gene encoding the interferon-induced membrane protein IFITM3 have been linked to severe viral illnesses. We investigated whether the COVID-19 clinical outcomes caused by SARS-CoV-2 infection in a cohort of COVID-19 Egyptian patients were inconsistent and could have been caused by the IFITM3-SNP rs12252 polymorphism. Aim of the Work: The purpose of this study is to determine the frequency of the IFITM3 rs12252 SNP in a cohort of COVID-19 Egyptian patients, and its impact on illness severity and outcome, as well as its influence on IL-6 serum levels. Patients and Methods: This cross-sectional study included 100 patients diagnosed as positive for COVID-19. They were enrolled in AL-Obour Quarantine Hospital. They were categorized into three groups, mild cases, who attended AL-Obour outpatient clinic, moderate and severe cases who were admitted to the hospital ward and ICU, respectively. All subjects of this study were subjected to full medical history, clinical evaluation, laboratory investigations, serum IL-6 levels by ELISA and IFITM3 gene polymorphism by real-time PCR. Results: The results of the current study demonstrated a significant difference between mortality and the minor G allele of rs12252 within IFITM3 in COVID-19 patients (OR = 4.5 [95% CI; 1.4–14.30], P = 0.006). IL-6 showed no association either to disease severity or IFITM3 rs12252 genotype frequency. Conclusion: The present study has shown a significant association between G allele variant of IFITM3 rs12252 and COVID-19 mortality. However, results failed to demonstrate any significant association between rs12252 polymorphism and disease severity, ICU admission or serum IL-6 levels. Therefore, understanding the interaction between SARS-CoV-2 and the IFITM3-rs12252 allele could help identify novel therapeutic targets, leading to precise biological and immune therapy for SARS-CoV-2 infection |