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SARS-CoV-2 has become a global threat to public health. Infected individuals can be asymptomatic or develop mild to severe symptoms, including pneumonia, respiratory distress, and death. This wide spectrum of clinical presentations of SARS-CoV-2 infection is believed in part due to the polymorphisms of key genetic factors in the population. In this study, we report that the interferon-induced antiviral factor IFITM3 inhibits SARS-CoV-2 infection by preventing SARS-CoV-2 spike-protein-mediated virus entry and cell-to-cell fusion. Analysis of a Chinese COVID-19 patient cohort demonstrates that the rs12252 CC genotype of IFITM3 is associated with SARS-CoV-2 infection risk in the studied cohort. These data suggest that individuals carrying the rs12252 C allele in the IFITM3 gene may be vulnerable to SARS-CoV-2 infection and thus may benefit from early medical intervention.

Background and aims: Interferon-induced transmembrane protein 3 (IFITM3) plays an important antiviral role in the adaptive and innate immune response, it prevents hemifusion of the viral membrane and host cellular membrane in a broad spectrum of enveloped viruses, e.g. influenza A, ebola, marburg or SARS-CoV. This study aimed to evaluate correlation of IFITM3 gene polymorphisms (rs12252) and infection susceptibility, severity and mortality rate of COVID-19 patients. Patients and methods: The IFITM3 SNP (rs12252) polymorphism was genotyped by (RT-PCR) in 100 SARSCoV-2-negative controls and 100 SARS-CoV-2-positive, who admitted to Chest, Assiut University and other quarantine Hospitals respectively in Assiut city, Egypt. Results: The minor allele frequency (rs12252 (G)) were significantly more frequent in the patients compared to controls after age and sex matching (p-value = 0.011, OR (95% CI) =2.44 (1.20-4.97). This allele (G) was significantly more common among patients who ICU admitted than non-ICU admitted (p -value = 0.001, OR (95% CI) =3.78 (1.64-8.75)). Also, was significantly more frequent in dead patients than cured patients (p -value = 0.005, OR (95% CI) =3.33 (1.37-8.10)). Conclusion: The present study has shown significant association between G (the mutant type) allele variant of IFITM3 rs12252 and COVID-19 infection susceptibility and disease severity and mortality. [ABSTRACT FROM AUTHOR]

Interferon-induced transmembrane protein 3 (IFITM3) plays a substantial role in the immune system by repressing viral entry into host cells and restricting virus replication. Recent research suggests that specific polymorphisms of the IFITM3 gene, rs34481144 and rs12252, contribute to susceptibility to viral infections across populations dependent on their population frequencies, which needs further clarification. This population-based study determined the prevalence of two regulator SNPs in the Turkish population and evaluated genotype and allele frequencies in individuals stratified into groups based on a pilot survey conducted during the COVID-19 pandemic. Tetra-Primer Arms PCR assays and Sanger sequencing methods were used to genotype rs34481144 and rs12252; all participants (n = 200) answered a questionnaire on individual experiences (e.g., disease severity, vaccine side effects) during the COVID-19 pandemic. Distributions of genotype frequencies and pairwise linkage disequilibrium correlations were calculated and compared to publicly available data from worldwide populations. The minor allele frequencies for rs12252-G and rs34481144-T were 0.128 and 0.324, respectively, in the total sample. Our preliminary survey data gave no concrete evidence of a correlation between the analyzed SNPs and COVID-19 severity or vaccine side effects yet pinpointed a trend for an association between rs12252-G and symptom burdens, which merits further investigation. Overall, our results present genotype and allele distributions of two IFITM3 polymorphisms in the Turkish population and provide preliminary data on previously suggested correlations of genotype with COVID-19 in our population. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 has become a global threat to public health. Infected individuals can be asymptomatic or develop mild to severe symptoms, including pneumonia, respiratory distress, and death. This wide spectrum of clinical presentations of SARS-CoV-2 infection is believed in part due to the polymorphisms of key genetic factors in the population. In this study, we report that the interferon-induced antiviral factor IFITM3 inhibits SARS-CoV-2 infection by preventing SARS-CoV-2 spike-protein-mediated virus entry and cell-to-cell fusion. Analysis of a Chinese COVID-19 patient cohort demonstrates that the rs12252 CC genotype of IFITM3 is associated with SARS-CoV-2 infection risk in the studied cohort. These data suggest that individuals carrying the rs12252 C allele in the IFITM3 gene may be vulnerable to SARS-CoV-2 infection and thus may benefit from early medical intervention.

Evidence was brought forward in England and the USA that Black, Asian, Latino and Minority Ethnic people exhibit higher mortality risk from COVID-19 than White people. While socioeconomic factors were suggested to contribute to this trend, they arguably do not explain the range of the differences observed, allowing for possible genetic implications. Almost concurrently, the analysis of a cohort in Chinese COVID-19 patients proposed an association between the severity of the disease and the presence of the minor allele of rs12252 of the Interferon-induced transmembrane protein 3 (IFITM3) gene. This SNP, together with rs34481144, are the two most studied polymorphisms of IFITM3 and have been associated in the past with increased severity in Influenza, Dengue, Ebola, and HIV viruses. IFITM3 is an immune effector protein that is pivotal for the restriction of viral replication, but also for the regulation of cytokine production. Following up on these two developments in the ongoing SARS-CoV-2 pandemic, the present study investigates a possible association between the differences in mortality of ethnic groups in England and the combined haplotypes of rs12252 and rs34481144. The respective allele frequencies were collected for 26 populations from the 1000 Genomes Project and subgroups were pooled wherever possible to create correspondences with ethnic groups in England. A significant correlation (r = 0.9687, p = 0.0003) and a striking agreement was observed between the reported Standardized Mortality Ratios and the frequency of the combined haplotype of both reference alleles, suggesting that the combination of the reference alleles of the specific SNPs may be implicated in more severe outcomes of COVID-19. This study calls for further focus on the role of IFITM3 variants in the mechanism of cellular invasion of SARS-CoV-2, their impact in COVID-19 severity and their possible implications in vaccination efficacy.

Evidence was brought forward in England and the USA that Black, Asian, Latino and Minority Ethnic people exhibit higher mortality risk from COVID-19 than White people. While socioeconomic factors were suggested to contribute to this trend, they arguably do not explain the range of the differences observed, allowing for possible genetic implications. Almost concurrently, the analysis of a cohort in Chinese COVID-19 patients proposed an association between the severity of the disease and the presence of the minor allele of rs12252 of the Interferon-induced transmembrane protein 3 (IFITM3) gene. This SNP, together with rs34481144, are the two most studied polymorphisms of IFITM3 and have been associated in the past with increased severity in Influenza, Dengue, Ebola, and HIV viruses. IFITM3 is an immune effector protein that is pivotal for the restriction of viral replication, but also for the regulation of cytokine production. Following up on these two developments in the ongoing SARS-CoV-2 pandemic, the present study investigates a possible association between the differences in mortality of ethnic groups in England and the combined haplotypes of rs12252 and rs34481144. The respective allele frequencies were collected for 26 populations from the 1000 Genomes Project and subgroups were pooled wherever possible to create correspondences with ethnic groups in England. A significant correlation (r = 0.9687, p = 0.0003) and a striking agreement was observed between the reported Standardized Mortality Ratios and the frequency of the combined haplotype of both reference alleles, suggesting that the combination of the reference alleles of the specific SNPs may be implicated in more severe outcomes of COVID-19. This study calls for further focus on the role of IFITM3 variants in the mechanism of cellular invasion of SARS-CoV-2, their impact in COVID-19 severity and their possible implications in vaccination efficacy. [ABSTRACT FROM AUTHOR]

A major unanswered question in the current global coronavirus disease 2019 (COVID-19) outbreak is why severe disease develops in a small minority of infected individuals. In the current article, we report that homozygosity for the C allele of rs12252 in the interferon-induced transmembrane protein 3 (IFITM3) gene is associated with more severe disease in an age-dependent manner. This supports a role for IFITM3 in disease pathogenesis and the opportunity for early targeted intervention in at-risk individuals. [ABSTRACT FROM AUTHOR]