Does IFITM3 link inflammation to tumorigenesis?

Uncontrolled chronic inflammation, in most cases due to excessive cytokine signaling through their receptors, is known to contribute to the development of tumorigenesis. Recently, it has been reported that the antiviral membrane protein interferon-induced transmembrane protein 3 (IFITM3), induced by interferon signaling as part of the inflammatory response after viral infection, contributes to the development of B-cell malignancy. The unexpected oncogenic signaling of IFITM3 upon malignant B cell activation elucidated the mechanism by which the uncontrolled expression of inflammatory proteins contributes to leukemogenesis. In this review, the potential effects of inflammatory cytokines on upregulation of IFITM3 and its contribution to tumorigenesis are discussed.

Genetic polymorphism between the Sorani and Hawrami kurdish populations and COVID-19 outcome.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) is a global pandemic, and mortality and clinical consequences vary across countries. One of the factors influencing COVID-19 outcomes is genetic polymorphism. Two Kurdish populations, Sorani and Hawrami, live in the Sulaimani province of the Kurdistan Region of Iraq. It seems Hawrami had a milder COVID-19 outcome. According to previous research conducted on various ethnic groups across the globe, single nucleotide polymorphisms (SNPs) in the interferon-induced transmembrane protein 3 (IFITM3) and interluken-6 (IL6) genes were associated with the severity of COVID-19 in those populations. METHODS AND RESULTS: We hypothesized that Hawrami may have protective SNPs. So, in this study, we used DNA sequencing to genotype three IFITM3 SNPs and nine IL6 SNPs by DNA sequencing to investigate the association of Sorani and Hawrami population polymorphisms. Genotype AA for the rs12252 SNP in IFITM3 was insignificantly more common in the Sorani group (54% vs. 44%). The Hawrami population showed a higher percentage of the CC genotype of the rs34481144 SNP in the IFITM3 gene (62% vs. 44.3%) and a higher proportion of the non-risky GG genotype of the rs1800795 SNP in the IL6 gene (53.4 vs. 43.3); however, the SNPs were insignificantly associated between the two populations. CONCLUSIONS: IFITM3 and IL6 SNPs have no statistically significant association between the two Kurdish populations. The decreased proportion of non-risk alleles at rs34481144 and rs1800795 in the Hawrami population may partially support the research hypothesis. However, contrary to our hypothesis, the Sorani group had an insignificantly higher protective variant of the rs12252 SNP.

FYN, SARS-CoV-2, and IFITM3 in the neurobiology of Alzheimer's disease

Introduction: (IFITM3) is an innate immune protein that has been identified as a novel gamma-secretase (gammas) modulator. FYN is a kinase that stabilizes IFITM3 on the membrane, primes APP for amyloidogenic gammas processing and mediates tau oligomerization. The purpose of this study is to explore the role of FYN and IFITM3 in AD and COVID-19, expanding on previous research from our group. Method(s): A 520 gene signature containing FYN and IFITM3 (termed Ia) was extracted from a previously published meta-analysis of Alzheimer's disease (AD) bulk- and single nuclei sequencing data. Exploratory analyses involved meta-analysis of bulk and single cell RNA data for IFITM3 and FYN differential expression per CNS site and cellular type. Confirmatory analyses, gene set enrichment analysis (GSEA) on Ia was performed to detect overlapping enriched biological networks between COVID-19 with AD. Result(s): Bulk RNA data analysis revealed that IFITM3 and FYN were overexpressed in two CNS regions in AD vs. Controls: the temporal cortex Wilcoxon p-value=1.3e-6) and the parahippocampal cortex Wilcoxon p-value=0.012). Correspondingly, single cell RNA analysis of IFITM3 and FYN revealed that it was differentially expressed in neurons, glial and endothelial cells donated b AD patients, when compared to controls. Discussion(s): IFITM3 and FYN were found as interactors within biological networks overlapping between AD and SARS-CoV-2 infection. Within the context of SARS-CoV-2 induced tau aggregation and interactions between tau and Ab1-42, the FYN - IFITM3 regulome may outline an important innate immunity element responsive to viral infection and IFN-I signaling in both AD and COVID-19.Copyright © 2021 The Authors

Interferon-induced transmembrane protein 3 (IFITM3) limits lethality of SARS-CoV-2 in mice.

Interferon-induced transmembrane protein 3 (IFITM3) is an antiviral protein that alters cell membranes to block fusion of viruses. Conflicting reports identified opposing effects of IFITM3 on SARS-CoV-2 infection of cells, and its impact on viral pathogenesis in vivo remains unclear. Here, we show that IFITM3 knockout (KO) mice infected with SARS-CoV-2 experience extreme weight loss and lethality compared to mild infection in wild-type (WT) mice. KO mice have higher lung viral titers and increases in inflammatory cytokine levels, immune cell infiltration, and histopathology. Mechanistically, we observe disseminated viral antigen staining throughout the lung and pulmonary vasculature in KO mice, as well as increased heart infection, indicating that IFITM3 constrains dissemination of SARS-CoV-2. Global transcriptomic analysis of infected lungs shows upregulation of gene signatures associated with interferons, inflammation, and angiogenesis in KO versus WT animals, highlighting changes in lung gene expression programs that precede severe lung pathology and fatality. Our results establish IFITM3 KO mice as a new animal model for studying severe SARS-CoV-2 infection and overall demonstrate that IFITM3 is protective in SARS-CoV-2 infections in vivo.

Differential Leukocyte Expression of IFITM1 and IFITM3 in Patients with Severe Pandemic Influenza A(H1N1) and COVID-19.

Interferon-induced transmembrane (IFITM) proteins mediate protection against enveloped viruses by blocking membrane fusion at endosomes. IFITM1 and IFITM3 are crucial for protection against influenza, and various single nucleotide polymorphisms altering their function have been linked to disease susceptibility. However, bulk IFITM1 and IFITM3 mRNA expression dynamics and their correlation with clinical outcomes have not been extensively addressed in patients with respiratory infections. In this study, we evaluated the expression of IFITM1 and IFITM3 in peripheral leukocytes from healthy controls and individuals with severe pandemic influenza A(H1N1) or coronavirus disease 2019 (COVID-19). Comparisons between participants grouped according to their clinical characteristics, underlying disease, and outcomes showed that the downregulation of IFITM1 was a distinctive characteristic of severe pandemic influenza A(H1N1) that correlated with outcomes, including mortality. Conversely, increased IFITM3 expression was a common feature of severe pandemic influenza A(H1N1) and COVID-19. Using a high-dose murine model of infection, we confirmed not only the downregulation of IFITM1 but also of IFITM3 in the lungs of mice with severe influenza, as opposed to humans. Analyses in the comparative cohort also indicate the possible participation of IFITM3 in COVID-19. Our results add to the evidence supporting a protective function of IFITM proteins against viral respiratory infections in humans.

ACE2 Affects the Expression and Function of IFITM3 During SARS-CoV-2 Pseudovirus Infection in Vero E6 Cells.

COVID-19 is a globally infectious viral epidemic of great public health concern caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) plays its role as the receptor for SARS-CoV-2 through binding with S protein and the binding results in ACE2 expression decrease. The change of ACE2 is supposed to elicit a series of cellular and molecular events. Other than as the receptor, ACE2's roles on infection by regulating other molecules need to be further studied during SARS-CoV-2 infection. In the present study, we established the ACE2 knockdown model using Vero E6 cells to study how ACE2 influenced the downstream signaling molecules. Analysis of transcriptome sequencing discovered that ACE2 alteration per se caused the alteration of immune factors, including some related to the viral infection-related signaling pathways. We found that ACE2 silencing induced the reduced interferon-induced transmembrane protein 3 (IFITM3) expression. Overexpression of IFITM3 promoted the SARS-CoV-2 pseudovirus infection of Vero E6 cells lacking the ACE2. It indicates that ACE2 can affect IFITM3 expression and function to affect the SARS-CoV-2 infection. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and contribute to explaining the rapid spread and pathogenesis especially in the case of ACE2 low expression.

Evaluation The Polymorphism of IFITM3 Gene and Its Role in Covid 19 Infection Outcome and Disease Severity in Babylon Province

By preventing viral membrane hemifusion between the host and viral cell cytoplasm, the interferon-induced transmembrane protein 3 (IFITM3) contributes significantly to the adaptive and innate immune response. Incidence and severity of influenza or other viral infections have been linked to single nucleotide polymorphisms (SNPs) in the gene IFITM3. Our goal was to examine how SNPs in the gene IFITM3 affected SARS-CoV-2 infection. The study's sampling took place on Covid-19, a subject patient in Babylon Governorate, between October 24, 2021 and November 1, 2022. There were Four single-nucleotide polymorphisms (SNPs) were genotyped in the 305 base-pair PCR results of the IFITM3 center advertiser locale around record start site (rs6598045), (rs7478728), (rs71452596), (rs7479267). Every one of these SNPs were in Hardy-Weinberg harmony (P.0.05) both in the Covid -19 and control gatherings. was found among three SNPs, rs7478728, rs71452596 and rs7479267. © 2022, ResearchTrentz Academy Publishing Education Services. All rights reserved.

IFITM3 Inhibits SARS-CoV-2 Infection and Is Associated with COVID-19 Susceptibility.

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.

Association of interferon gamma inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1 alpha, interleukin-6, and rs12252 single nucleotide polymorphism of interferon-induced transmembrane protein-3 gene with the severity of COVID-19 infection.

Background: Evaluating the serum levels of IP-10, MCP-1, MIP-1α, and IL-6 and genotyping of rs12252 SNP of IFITM3 gene among different categories of COVID-19 patients might aid in understanding the pathogenesis of COVID-19 and contribute to developing disease-specific biomarkers and therapeutic strategies. Methods: This is a cross-sectional study involving a total of 84 COVID-19 patients confirmed by positive RT-PCR and 28 healthy controls. COVID-19 patients were recruited from the intensive care unit (ICU) and COVID unit of Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka. COVID-19 patients were categorized into moderate, severe, and critically ill groups according to the World Health Organization classification. The serum IP-10, MCP-1, and MIP-1α levels were measured by cytometric bead array assay by flow cytometry, and serum IL-6 level was detected by the chemiluminescence method. rs12252 SNP of the IFITM3 gene was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP). Results: The serum IP-10, MCP-1, MIP-1α, and IL-6 levels among critically ill COVID-19 patients were significantly higher than that in patients with moderate disease and healthy controls (p < 0.001). Genotype distribution for rs12252 (42 T/C) SNP of the IFITM3 gene between the different groups of COVID-19 patients and healthy controls showed that CC genotype was statistically associated with disease severity (p < 0.001). Conclusions: IP-10 and MCP-1, MIP-α, IL-6, and CC genotype of rs12252 (42 T/C) SNP of IFITM3 gene are associated with COVID-19 severity.

The association of ACE1, ACE2, TMPRSS2, IFITM3 and VDR polymorphisms with COVID-19 severity: A systematic review and meta-analysis.

Genes involved in the regulation of viral recognition and its entry into a host cell have been identified as candidates for genetic association studies on COVID-19 severity. Published findings on the effects of polymorphisms within ACE1, ACE2, TMPRSS2, IFITM3 and VDR genes remained inconclusive, so we conducted a systematic review and meta-analysis in order to elucidate their potential involvement in the genetic basis underlying the severity of COVID-19 and/or an outcome of SARS-CoV-2 infection. Identification of potentially eligible studies was based on PubMed, Scopus and Web of Science database search. Relevant studies (n=29) with a total number of 8247 SARS-CoV-2-positive participants were included in qualitative synthesis, while results of 21 studies involving 5939 were pooled in meta-analysis. Minor allele I of rs1799752 located within ACE1 was identified as a protective variant against severe COVID-19, while its effect on mortality rate was opposite. Similarly, minor allele A of ACE2 polymorphism, rs2285666, was found to associate with a decreased risk of severe COVID-19 (P = 0.003, OR = 0.512, 95 % CI = 0.331-0.793). Statistical significance was also seen for the association between COVID-19 severity and rs12329760 located within TMPRSS2. Our results did not support the supposed association of rs12252 in IFITM3 and polymorphisms within VDR with disease severity. We conclude that genetic variants within ACE1, ACE2 and TMPRSS2 may be potential biomarkers of COVID-19 severity, which needs to be further confirmed in a larger set of studies.

Interferon-induced transmembrane protein 3 gene polymorphisms are associated with COVID-19 susceptibility and severity: A meta-analysis.

BACKGROUND: Recent evidence has linked the interferon-induced transmembrane protein 3 gene (IFITM3) to coronavirus disease 2019 (COVID-19) outcomes, but the results are inconsistent. The purpose of this meta-analysis was to evaluate the association of IFITM3 gene polymorphisms with COVID-19 susceptibility and severity. METHOD: A systematic search was performed with PubMed, Web of Science, Cochrane Library, and Embase from the date of inception to 20 December 2021. The results were analyzed with pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). The robustness was performed using the method of sequential removal for each trial. RESULTS: Four studies involving 1989 subjects were included, from which 1114 patients were positive for COVID-19. For IFITM3 rs12252, the pooled OR showed that there was a significant association between the genotype frequencies and infection with COVID-19 in any of the gene models, i.e., the allelic model (OR = 1.91, 95% CI, 1.36-2.68), the dominant model (OR = 1.80, 95% CI, 1.27-2.56), the recessive model (OR = 5.67, 95% CI, 1.01-31.77), the heterozygous model (OR = 1.65, 95% CI, 1.16-2.36) and the homozygous model (OR = 5.88, 95% CI, 1.05-32.98). The results stratified by severity showed that there was a significant correlation only between the allelic (OR = 0.69, 95% CI, 0.49-0.97) and recessive (OR = 0.43, 95% CI, 0.20-0.93) models. Our results did not support the associations between the IFITM3 rs34481144 gene polymorphism and COVID-19 susceptibility or severity in any of the gene models. CONCLUSIONS: The findings indicated that IFITM3 rs12252 gene polymorphisms were associated with COVID-19 susceptibility and that the rs12252-C variant was particularly critical for severity. Genetic factors should be considered in future vaccine development.

Progress on Exosome During Flaviviridae and Coronaviridae Infection

Exosome is one of the extracellular vesicles, which plays an important role in intercellular communication and material transportation. Its content includes proteins, lipids, RNAs and other substances from host cells, and has an important influence on the physiological state of recipient cells. Flaviviridae including hepatitis C virus and Coronaviridae including SARS-CoV-2 are pathogens causing a variety of human infectious diseases. Understanding the interaction between virus and host is of great significance for screening therapeutic cellular targets and developing exosome-based vaccines. Accumulating studies have shown that exosomal protein and RNA play inhibitory roles for viruses. Moreover, Flaviviridae and Coronaviridae could hijack exosomemediated cellular communication to harm the hosts and promote virus spread. In current review, we summarized the recent progress on the interaction between Flaviviridae/Coronaviridae and exosome, shedding the mechanistic insights into Flaviviridae/Coronaviridae induced exosome.

Association between the interferon-induced transmembrane protein 3 gene (IFITM3) rs34481144 / rs12252 haplotypes and COVID-19.

The interferon induced transmembrane-protein 3 (IFITM3) plays an important role in the defence against viral infection. IFITM3 gene variants have been linked to differences in expression and associated with the risk of severe influenza by some authors. More recently, these variants have been associated with the risk of COVID-19 after SARS-CoV-2 infection. We determined the effect of two common IFITM3 polymorphisms (rs34481144 â€‹C/T and rs12252 A/G) on the risk of hospitalization due to COVID-19 by comparing 484 patients (152 required support in thr intensive care unit, ICU) and 182 age and sex matched controls (no disease symptoms). We found significantly higher frequencies of rs34481144 â€‹T and rs12252 â€‹G carriers among the patients (OR â€‹= â€‹2.02 and OR â€‹= â€‹1.51, respectively). None of the two variants were associated with ICU-admission or death. We found a significantly higher frequency of rs34481144 CC â€‹+ â€‹rs12252 AA genotype carriers among the controls, suggesting a protective effect (p = 0.001, OR = 0.56, 95%CI = 0.40-0.80). Moreover, haplotype rs34481144 â€‹C - rs12252 A was significantly increased in the controls (p â€‹= â€‹0.008, OR â€‹= â€‹0.71, 95%CI â€‹= â€‹0.55-0.91). Our results showed a significant effect of the IFITM3 variants in the risk for hospitalization after SARS-CoV-2 infection.

A bioorthogonal chemical reporter for fatty acid synthase-dependent protein acylation.

Mammalian cells acquire fatty acids (FAs) from dietary sources or via de novo palmitate production by fatty acid synthase (FASN). Although most cells express FASN at low levels, it is upregulated in cancers of the breast, prostate, and liver, among others, and is required during the replication of many viruses, such as dengue virus, hepatitis C, HIV-1, hepatitis B, and severe acute respiratory syndrome coronavirus 2, among others. The precise role of FASN in disease pathogenesis is poorly understood, and whether de novo FA synthesis contributes to host or viral protein acylation has been traditionally difficult to study. Here, we describe a cell-permeable and click chemistry-compatible alkynyl acetate analog (alkynyl acetic acid or 5-hexynoic acid [Alk-4]) that functions as a reporter of FASN-dependent protein acylation. In an FASN-dependent manner, Alk-4 selectively labels the cellular protein interferon-induced transmembrane protein 3 at its known palmitoylation sites, a process that is essential for the antiviral activity of the protein, and the HIV-1 matrix protein at its known myristoylation site, a process that is required for membrane targeting and particle assembly. Alk-4 metabolic labeling also enabled biotin-based purification and identification of more than 200 FASN-dependent acylated cellular proteins. Thus, Alk-4 is a useful bioorthogonal tool to selectively probe FASN-mediated protein acylation in normal and diseased states.

Opposing activities of IFITM proteins in SARS-CoV-2 infection.

Interferon-induced transmembrane proteins (IFITMs) restrict infections by many viruses, but a subset of IFITMs enhance infections by specific coronaviruses through currently unknown mechanisms. We show that SARS-CoV-2 Spike-pseudotyped virus and genuine SARS-CoV-2 infections are generally restricted by human and mouse IFITM1, IFITM2, and IFITM3, using gain- and loss-of-function approaches. Mechanistically, SARS-CoV-2 restriction occurred independently of IFITM3 S-palmitoylation, indicating a restrictive capacity distinct from reported inhibition of other viruses. In contrast, the IFITM3 amphipathic helix and its amphipathic properties were required for virus restriction. Mutation of residues within the IFITM3 endocytosis-promoting YxxФ motif converted human IFITM3 into an enhancer of SARS-CoV-2 infection, and cell-to-cell fusion assays confirmed the ability of endocytic mutants to enhance Spike-mediated fusion with the plasma membrane. Overexpression of TMPRSS2, which increases plasma membrane fusion versus endosome fusion of SARS-CoV-2, attenuated IFITM3 restriction and converted amphipathic helix mutants into infection enhancers. In sum, we uncover new pro- and anti-viral mechanisms of IFITM3, with clear distinctions drawn between enhancement of viral infection at the plasma membrane and amphipathicity-based mechanisms used for endosomal SARS-CoV-2 restriction.

Evaluating MERS-CoV Entry Pathways.

Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging zoonotic pathogen with a broad host range. The extent of MERS-CoV in nature can be traced to its adaptable cell entry steps. The virus can bind host-cell carbohydrates as well as proteinaceous receptors. Following receptor interaction, the virus can utilize diverse host proteases for cleavage activation of virus-host cell membrane fusion and subsequent genome delivery. The fusion and genome delivery steps can be completed at variable times and places, either at or near cell surfaces or deep within endosomes. Investigators focusing on the CoVs have developed several methodologies that effectively distinguish these different cell entry pathways. Here we describe these methods, highlighting virus-cell entry factors, entry inhibitors, and viral determinants that specify the cell entry routes. While the specific methods described herein were utilized to reveal MERS-CoV entry pathways, they are equally suited for other CoVs, as well as other protease-dependent viral species.

Outside-in induction of the IFITM3 trafficking system by infections, including SARS-CoV-2, in the pathobiology of Alzheimer's disease.

BACKGROUND: IFITM3 is a viral restriction protein that enables sequestration of viral particles and subsequent trafficking to lysosomes. Recently, IFITM3 upregulation was found to induce gamma - secretase activity and the production of amyloid beta. The purpose of this study was to determine whether dysregulation of IFITM3-dependent pathways was present in neurons and peripheral immune cells donated by AD patients. As a secondary aim, we sought to determine whether these perturbations could be induced by viruses, including SARS-CoV-2. METHODS: Gene set enrichment analyses (GSEA) previously performed on publicly available transcriptomic data from tissues donated by AD patients were screened for enriched pathways containing IFITM3. Subsequently, signature containing IFITM3, derived from entorhinal cortex (EC) neurons containing neurofibrillary tangles (NFT) was screened for overlap with curated, publicly available, viral infection-induced gene signatures (including SARS-CoV-2). RESULTS: GSEA determined that IFITM3 gene networks are significantly enriched both in CNS sites (entorhinal and hippocampal cortices) and in peripheral blood mononuclear cells (PBMCs) donated by AD patients. Overlap screening revealed that IFITM3 signatures are induced by several viruses, including SARS-CoV, MERS-CoV, SARS-CoV-2 and HIV-1 (adjusted p-value <0.001; Enrichr Database). DISCUSSION: A data-driven analysis of AD tissues revealed IFITM3 gene signatures both in the CNS and in peripheral immune cells. GSEA revealed that an IFITM3 derived gene signature extracted from EC/NFT neurons overlapped with those extracted from publicly available viral infection datasets, including SARS-CoV-2. Our results are in line with currently emerging evidence on IFITM3's role in AD, and SARS-CoV-2's potential contribution in the setting of an expanded antimicrobial protection hypothesis.

The influence of IFITM3 polymorphisms on susceptibility to SARS-CoV-2 infection and severity of COVID-19.

BACKGROUND AND AIMS: The interferon-induced transmembrane protein 3 (IFITM3) plays an important role in the adaptive and innate immune response by inhibiting viral membrane hemifusion between the host and viral cell cytoplasm. Single nucleotide polymorphisms (SNPs) in the gene IFITM3 have been associated with susceptibility and severity of influenza or other viral infections. We aimed to analyze the role of SNPs in the gene IFITM3 in SARS-CoV-2 infection. METHODS: We performed genotyping of the SNPs rs12252 and rs34481144 in the gene IFITM3 in 239 SARS-CoV-2-positive and 253 SARS-CoV-2-negative patients. We analyzed the association of the SNPs with susceptibility to SARS-CoV-2 infection and severity of COVID-19. RESULTS: SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding demographics. Neither IFITM3 rs12252 nor rs34481144 polymorphisms were related to SARS-CoV-2 infection risk or severity of COVID-19. Interestingly, we observed the putative deleterious rs12252 CC genotype only in SARS-CoV-2-positive patients (N = 2). Also, we found a non-significant higher frequency of rs34481144 A-allele carriers in the patients with 'serious' COVID-19. CONCLUSIONS: In summary, we could not confirm the recently reported influence of polymorphisms in the gene IFITM3 on SARS-CoV-2 infection risk or severity of COVID-19 in a German cohort. Additional studies are needed to clarify the influence of the rs12252 CC genotype on SARS-CoV-2 infection risk and the rs34481144 A-allele on course of COVID-19.

Strong Correlation between the Case Fatality Rate of COVID-19 and the rs6598045 Single Nucleotide Polymorphism (SNP) of the Interferon-Induced Transmembrane Protein 3 (IFITM3) Gene at the Population-Level.

Coronavirus disease 2019 (COVID-19) is a fatal pandemic disease that is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of 13 December, 2020, over 70,000,000 cases and 1,500,000 deaths have been reported over a period of several months; however, the mechanism underlying the pathogenesis of COVID-19 has not been elucidated. To identify the novel risk genetic biomarker for COVID-19, we evaluated the correlation between the case fatality rate of COVID-19 and the genetic polymorphisms of several potential COVID-19-related genes, including interferon-induced transmembrane protein 3 (IFITM3), the angiotensin I converting enzyme 2 (ACE2) gene, transmembrane protease, serine 2 (TMPRSS2), interleukin 6 (IL6), leucine zipper transcription factor-like protein 1 (LZTFL1), and the ABO genes, in various ethnic groups. We obtained the number of COVID-19 cases and deaths from the World Health Organization (WHO) COVID-19 dashboard and calculated the case fatality rate of each ethnic group. In addition, we obtained the allele distribution of the polymorphisms of the IFITM3, ACE2, TMPRSS2, IL6, LZTFL1, and ABO genes from the 1000 Genomes Project and performed Log-linear regression analysis using SAS version 9.4. We found different COVID-19 case fatality rates in each ethnic group. Notably, we identified a strong correlation between the case fatality rate of COVID-19 and the allele frequency of the rs6598045 single nucleotide polymorphism (SNP) of the IFITM3 gene. To the best of our knowledge, this report is the first to describe a strong correlation between the COVID-19 case fatality rate and the rs6598045 SNP of the IFITM3 gene at the population-level.