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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.

The interferon-inducible transmembrane 3 (IFITM3) protein is an effector of the host innate immune system that shows defensive activity against a wide range of viruses, including the influenza A virus. Previous studies have reported that three transcription-related regulatory single nucleotide polymorphisms (SNPs), rs12252, rs34481144, and rs6598045, showed potent associations with the severity of pandemic influenza A 2009 infection and susceptibility to this virus, respectively. However, the distribution of the risk genotypes of these three SNPs according to ethnic background has remained elusive. In this study, we compared the genotype and allele frequencies of the IFITM3 polymorphisms among several ethnic groups including American, African, European, South Asian, and East Asian using chi-square test. In addition, we analyzed the worldwide distribution of risk genotypes for pandemic influenza A 2009 virus infection. We found that the genotype and allele distributions of the rs12252, rs34481144, and rs6598045 SNPs were significantly different among several ethnic groups. In addition, the risk genotypes of the IFITM3 polymorphisms were also significantly different worldwide. To the best of our knowledge, this was the first simultaneous estimation of the risk genotypes of the IFITM3 gene with respect to pandemic influenza A 2009 virus infection.

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., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Intrinsic host susceptibility to viral infections plays a major role in determining infection severity in different individuals. In human influenza virus infections, multiple genetic association studies have identified specific human gene variants that might contribute to enhanced susceptibility or resistance to influenza. Recent studies suggested, the rs12252 T > C polymorphism in the interferon-inducible transmembrane protein 3 (IFITM3) gene might be associated with susceptibility to severe influenza. However, the studies reported conflicting and inconclusive results. To resolve the controversy, we conducted a systematic meta-analysis to evaluate the role of the IFITM3 rs12252 polymorphism in influenza susceptibility and severity, including twelve studies published before February 19, 2018 with a total 16,263 subjects (1836 influenza cases and 14,427 controls). Odds ratios (OR) and 95% confidence intervals were used to assess the strength of the association. Our results indicated increased risk of both severe and mild influenza in subjects carrying the IFITM3 rs12252 polymorphism in the allele contrast C vs. T: OR (severe) = 1.69, 95% CI = 1.23-2.33, P = 0.001, and OR (mild) = 1.46, 95% CI = 1.13-1.87, P = 0.004. Similar results were obtained in the homozygote comparison and dominant model. Stratified analyses by ethnicity revealed increased risk of severe influenza in both the White and East Asian populations, but significant association with mild influenza was found only in the White population. Overall, our meta-analysis suggests a significant association between the IFITM3 rs12252 polymorphism and the risk of influenza in both the White and East Asian populations., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Interferon-induced transmembrane 3 (IFITM3) is known to restrict the entry of a range of enveloped viruses. The single nucleotide polymorphism rs12252-C within IFITM3 has been shown to be associated with severe influenza A virus infection. It has been suggested that rs12252-C results in expression of a truncated IFITM3 protein lacking the first 21 amino acids. By performing high-throughput RNA sequencing on primary dendritic cells and peripheral blood mononuclear cells isolated from pandemic H1N1 influenza and human immunodeficiency virus-1 (HIV-1) infected patients we show that full-length IFITM3 mRNA is dominantly expressed (>99%) across all rs12252 genotypes. Full-length IFITM3 protein can be detected in all genotypes., (© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)