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

ABSTRACT: 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 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 T and rs12252 G carriers among the patients (OR = 2.02 and OR = 1.51, respectively). None of the two variants were associated with ICU-admission or death. We found a significantly higher frequency of rs34481144 CC + 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 C - rs12252 A was significantly increased in the controls (p = 0.008, OR = 0.71, 95%CI = 0.55-0.91). Our results showed a significant effect of the IFITM3 variants in the risk for hospitalization after SARS-CoV-2 infection.

SUBMITTER: Cuesta-Llavona E

PROVIDER: S-EPMC8629514 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Interferon-induced transmembrane protein-3 genetic variant rs12252 is associated with COVID-19 mortality.

Project description:Interferon-induced membrane proteins (IFITM) 3 gene variants are known risk factor for severe viral diseases. We examined whether IFITM3 variant may underlie the heterogeneous clinical outcomes of SARS-CoV-2 infection-induced COVID-19 in large Arab population. We genotyped 880 Saudi patients; 93.8% were PCR-confirmed SARS-CoV-2 infection, encompassing most COVID-19 phenotypes. Mortality at 90 days was 9.1%. IFITM3-SNP, rs12252-G allele was associated with hospital admission (OR = 1.65 [95% CI; 1.01-2.70], P = 0.04]) and mortality (OR = 2.2 [95% CI; 1.16-4.20], P = 0.01). Patients less than 60 years old had a lower survival probability if they harbor this allele (log-rank test P = 0.002). Plasma levels of IFNγ were significantly lower in a subset of patients with AG/GG genotypes than patients with AA genotype (P = 0.00016). Early identification of these individuals at higher risk of death may inform precision public health response.

| S-EPMC8025598 | biostudies-literature

Impact of interferon-induced transmembrane protein 3 gene rs12252 polymorphism on COVID-19 mortality.

Project description:Background and aimsInterferon-induced transmembrane protein 3 (IFITM3) plays a critical role in the adaptive and innate immune response by preventing membrane hemifusion between the host and viral cell cytoplasm. This study aimed to evaluate whether IFITM3 rs12252 polymorphism is related to an increased mortality rate of coronavirus disease 2019 (COVID-19).MethodsThe IFITM3 rs12252 polymorphism was genotyped using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in 548 dead and 630 improved patients positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).ResultsIn the present study, the minor allele frequency of IFITM3 rs12252 (C) was significantly more frequent in dead patients than in improved cases. The results of the multivariate logistic regression analysis indicated that the lower lipid profiles, PCR Ct value, 25-hydroxyvitamin D, and uric acid and higher levels of erythrocyte sedimentation rate (ESR), liver enzymes, and creatinine, and IFITM3 rs12252 CC genotypes were related to the COVID-19 infection mortality.ConclusionsIn summary, our findings suggested a possible link between the mortality of COVID-19 infection, the CC genotypes of IFITM3 rs12252, and clinical parameters. Further investigations are required worldwide to prove the link relationship of COVID-19 mortality with host genetic factors.

| S-EPMC9250290 | biostudies-literature

The Interferon-Induced Transmembrane Protein 3 -rs12252 Allele May Predict COVID-19 Severity Among Ethnic Minorities.

Project description: Not available

| S-EPMC8380955 | biostudies-literature

Genetic association between the rs12252 SNP of the interferon-induced transmembrane protein gene and influenza A virus infection in the Korean population.

Project description:BackgroundInterferon-induced transmembrane protein 3 (IFITM3) is a potent host antiviral effector protein that blocks the invasion of various viruses, including the influenza A virus (IAV). The C allele of the rs12252 single nucleotide polymorphism (SNP) shows vulnerability to the pandemic 2009 H1N1 IAV in European and Asian populations.ObjectiveHere, we estimated the disease susceptibility of the rs12252 SNP with the pandemic 2009 H1N1 IAV infection in the Korean population.ResultsWe carried out direct sequencing of the IFITM3 gene and compared the genotype and allele frequencies of the rs12252 SNP of the IFITM3 gene in healthy Koreans and pandemic 2009 H1N1 IAV-infected patients. Notably, we observed that healthy individuals had a similar genotype distribution of the rs12252 SNP (P = 0.140) as patients. The dominant model and recessive model did not find a statistically significant difference in genotype distribution between healthy individuals and patients. In addition, the allele distribution of the rs12252 SNP of in healthy individuals and patients also showed a similar genetic distribution (P = 0.757). However, the genetic distribution of rs12252 SNP in merged patient group (Koreans and Chinese populations) showed significant association with susceptibility of pandemic 2009 IAV (P = 0.0393).ConclusionTo the best of our knowledge, this was the first evaluation of the susceptibility of the pandemic 2009 H1N1 IAV in the Korean population.

| S-EPMC7640581 | biostudies-literature

Evaluation of IFITM3 rs12252 Association With Severe Pediatric Influenza Infection.

Project description:Background:Interferon-induced transmembrane protein 3 (IFITM3) restricts endocytic fusion of influenza virus. IFITM3 rs12252_C, a putative alternate splice site, has been associated with influenza severity in adults. IFITM3 has not been evaluated in pediatric influenza. Methods:The Pediatric Influenza (PICFLU) study enrolled children with suspected influenza infection across 38 pediatric intensive care units during November 2008 to April 2016. IFITM3 was sequenced in patients and parents were genotyped for specific variants for family-based association testing. rs12252 was genotyped in 54 African-American pediatric outpatients with influenza (FLU09), included in the population-based comparisons with 1000 genomes. Splice site analysis of rs12252_C was performed using PICFLU and FLU09 patient RNA. Results:In PICFLU, 358 children had influenza infection. We identified 22 rs12252_C homozygotes in 185 white non-Hispanic children. rs12252_C was not associated with influenza infection in population or family-based analyses. We did not identify the ?21 IFITM3 isoform in RNAseq data. The rs12252 genotype was not associated with IFITM3 expression levels, nor with critical illness severity. No novel rare IFITM3 functional variants were identified. Conclusions:rs12252 was not associated with susceptibility to influenza-related critical illness in children or with critical illness severity. Our data also do not support it being a splice site.

| S-EPMC5853450 | biostudies-literature

Genetic characteristics and polymorphisms in the chicken interferon-induced transmembrane protein (IFITM3) gene.

Project description:The interferon-induced transmembrane protein 3 (IFITM3) gene is classified as a small interferon-stimulated gene and is associated with a broad spectrum of antiviral functions against several fatal enveloped viruses, including influenza A viruses (IAVs). The rs12252 single nucleotide polymorphism (SNP) of the IFITM3 gene in humans was associated with susceptibility to H1N1 influenza in a 2009 pandemic. In addition, overexpression of the IFITM3 protein potently inhibits the highly pathogenic avian influenza H5N1 virus in ducks and chickens. Although chickens are a major host of influenza viruses and the IFITM3 gene participates in the host antiviral system, studies on chicken IFITM3 gene are very rare. To investigate the genetic characteristics of the chicken IFITM3 gene, we performed direct sequencing and alignment in 108 Dekalb White and 72 Ross breeds. We also investigated the genotype and haplotype frequencies and linkage disequilibrium of the IFITM3 gene polymorphisms and evaluated whether the non-synonymous SNPs are deleterious. We found significantly different genotype, allele and haplotypes frequencies between two chicken breeds, Dekalb White and Ross. Furthermore, we compared and analyzed the promoter structure of the chicken IFITM3 gene with that of several species. We found that birds have a long C-terminal domain and inverted topology of the IFITM3 protein compared to mammals. We also identified fourteen genetic polymorphisms in the chicken IFITM3 gene. L100 M and N125H were predicted as 'probably damaging' and L100 M can alter the length of its conserved intracellular loop (CIL). Furthermore, chickens, but not mammals, contain CpG islands (CGIs) in this promoter region.

| S-EPMC7089262 | biostudies-literature

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

Project description: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.

| S-EPMC10074051 | biostudies-literature

The palmitoyltransferase ZDHHC20 enhances interferon-induced transmembrane protein 3 (IFITM3) palmitoylation and antiviral activity.

Project description:Interferon-induced transmembrane protein 3 (IFITM3) is a cellular endosome- and lysosome-localized protein that restricts numerous virus infections. IFITM3 is activated by palmitoylation, a lipid posttranslational modification. Palmitoylation of proteins is primarily mediated by zinc finger DHHC domain-containing palmitoyltransferases (ZDHHCs), but which members of this enzyme family can modify IFITM3 is not known. Here, we screened a library of human cell lines individually lacking ZDHHCs 1-24 and found that IFITM3 palmitoylation and its inhibition of influenza virus infection remained strong in the absence of any single ZDHHC, suggesting functional redundancy of these enzymes in the IFITM3-mediated antiviral response. In an overexpression screen with 23 mammalian ZDHHCs, we unexpectedly observed that more than half of the ZDHHCs were capable of increasing IFITM3 palmitoylation with ZDHHCs 3, 7, 15, and 20 having the greatest effect. Among these four enzymes, ZDHHC20 uniquely increased IFITM3 antiviral activity when both proteins were overexpressed. ZDHHC20 colocalized extensively with IFITM3 at lysosomes unlike ZDHHCs 3, 7, and 15, which showed a defined perinuclear localization pattern, suggesting that the location at which IFITM3 is palmitoylated may influence its activity. Unlike knock-out of individual ZDHHCs, siRNA-mediated knockdown of both ZDHHC3 and ZDHHC7 in ZDHHC20 knock-out cells decreased endogenous IFITM3 palmitoylation. Overall, our results demonstrate that multiple ZDHHCs can palmitoylate IFITM3 to ensure a robust antiviral response and that ZDHHC20 may serve as a particularly useful tool for understanding and enhancing IFITM3 activity.

| S-EPMC5766958 | biostudies-literature

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.

Project description:BackgroundEvaluating 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.MethodsThis 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).ResultsThe 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).ConclusionsIP-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.

| S-EPMC9264736 | biostudies-literature

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.

Project description: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.

| S-EPMC7824003 | biostudies-literature

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