Interferon-Inducible Transmembrane Protein 3 Genetic Variant rs12252 and Influenza Susceptibility and Severity: A Meta-Analysis

Yang, Xiaoling; Tan, Bin; Zhou, Xipeng; Xue, Jian; Zhang, Xian; Wang, Peng; Chuang, Shao Yuan; Li, Yingli; Li, Chaorui; Xia, Huiming; Qiu, Jingfu

doi:10.1371/journal.pone.0124985

Cited by 39 publications

(42 citation statements)

References 32 publications

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“…Individuals homozyogous for the IFITM3 allele, rs12252-C, are at increased risk of severe influenza (Everitt et al, 2012;Yang et al, 2015;Zhang et al, 2013). While rare in individuals of European ancestry, the rs12252-C allele is more prevalent in Asia and Micronesia.…”

Section: Discussionmentioning

confidence: 99%

The IFITMs Inhibit Zika Virus Replication

et al. 2016

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Zika virus has emerged as a severe health threat with a rapidly expanding range. The IFITM family of restriction factors inhibits the replication of a broad range of viruses, including the closely related flaviruses West Nile virus and dengue virus. Here, we show that IFITM1 and IFITM3 inhibit Zika virus infection early in the viral life cycle. Moreover, IFITM3 can prevent Zika-virus-induced cell death. These results suggest that strategies to boost the actions and/or levels of the IFITMs might be useful for inhibiting a broad range of emerging viruses.

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Section: Discussionmentioning

confidence: 99%

The IFITMs Inhibit Zika Virus Replication

et al. 2016

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“…Given the importance of IFITM3 in animal studies and in vitro models 5,6 , several groups investigated polymorphisms in IFITM3 for associations with disease outcome. The C/C genotype of rs12252 in IFITM3 was linked to severe illness in adults during the 2009 IAV pandemic 7–9 , but the mechanism for this risk allele remains unresolved. The rs12252 C allele correlation with influenza severity has been validated in two cohorts of Han Chinese, where the majority carry at least one C allele 7,10 , but not in cohorts of European ancestry 11–13 , suggesting that the effects of this allele may vary across ancestral populations.…”

mentioning

confidence: 99%

SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans

Allen

Randolph

Bhangale³

et al. 2017

Nat Med

176

220

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Previous studies reported associations of IFITM3 SNP rs12252 with severe influenza, but evidence of association and the mechanism of risk remains controversial. We prioritized SNPs in IFITM3 based on putative biological function and identified rs34481144 in the 5′ UTR. We found evidence of a novel association of rs34481144 with severe influenza in three influenza-infected cohorts characterized by different levels of influenza illness severity. We determined the role of rs34481144 as an expression quantitative trait loci (eQTL) for IFITM3, with the risk allele associated with lower mRNA expression. The risk allele was found to have decreased IRF3 binding and increased CTCF binding in promoter-binding assays, and risk allele carriage diminished transcriptional correlations among neighboring genes, indicative of CTCF boundary activity. Furthermore, the risk allele disrupts a CpG site that undergoes differential methylation in CD8 T-cell subsets. Carriers of the risk allele had reduced CD8 T-cells in their airways during natural influenza infection, consistent with IFITM3 promoting airway CD8 T-cell accumulation, indicating that a critical function for IFITM3 may be to promote immune cell persistence at mucosal sites. Our study identifies a new regulator of IFITM3 expression that associates with CD8 T-cell levels in the airways and a spectrum of clinical outcomes.

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“…Moreover, the CC genotype was found in 25% of Chinese patients showing mild disease after pH1N1 virus infection compared to 69% in patients developing a severe pH1N1 virus infection. In addition, the CC genotype was estimated to confer a six-fold increased risk for severe infection than the CT and TT genotypes [120], reinforcing the idea that IFITM3 is a factor affecting human IAV disease [121]. In another study, over-representation of the IFITM3 CC genotype was detected among fatal cases of Chinese patients infected with IAV pH1N1 and H7N9 viruses [100], and in a more general study, including twelve studies published before February 2018 with more than 16,000 subjects, revealed increased risk of severe influenza in both the East Asian and White populations in the subjects encoding the IFITM3 CC genotype [122].…”

Section: Snps In Host Genes Affecting Iav Diseasementioning

confidence: 75%

Host Single Nucleotide Polymorphisms Modulating Influenza A Virus Disease in Humans

Nogales¹,

DeDiego

2019

Pathogens

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A large number of human genes associated with viral infections contain single nucleotide polymorphisms (SNPs), which represent a genetic variation caused by the change of a single nucleotide in the DNA sequence. SNPs are located in coding or non-coding genomic regions and can affect gene expression or protein function by different mechanisms. Furthermore, they have been linked to multiple human diseases, highlighting their medical relevance. Therefore, the identification and analysis of this kind of polymorphisms in the human genome has gained high importance in the research community, and an increasing number of studies have been published during the last years. As a consequence of this exhaustive exploration, an association between the presence of some specific SNPs and the susceptibility or severity of many infectious diseases in some risk population groups has been found. In this review, we discuss the relevance of SNPs that are important to understand the pathology derived from influenza A virus (IAV) infections in humans and the susceptibility of some individuals to suffer more severe symptoms. We also discuss the importance of SNPs for IAV vaccine effectiveness. multiple mechanisms, although there are some differences between strains. For that genome plasticity, IAV take advantage of multiple strategies, such as alternative splicing, frameshift mechanisms, and overlapping open reading frames (ORFs) [7][8][9]. In addition, the coding capability of the viral genome is extended by encoding multifunctional proteins that act at different steps during virus infection. of synthetized vRNP, ensuring that the vRNPs are available for packaging [24]. Moreover, NEP has also other functions during IAV infection, contributing to viral budding and to regulate viral RNA synthesis. NS1 is a multifunctional protein and a key viral factor that counteracts the host antiviral responses. NS1 has been shown to inhibit the production of interferon (IFN), the activity and expression of multiple interferon-induced genes (ISG) and the processing and nuclear transport of host mRNAs causing cellular shut-off [25,26]. Segment 3 of IAV also encodes two proteins, the polymerase component PA and PA-X. PA is translated directly from the PA mRNA, whereas PA-X is translated using a +1 frameshift mechanism from the same open reading frame (ORF) [9]. Synergistically with NS1, PA-X is also able to block the cellular antiviral responses by inhibiting host protein expression. Moreover, the PA-X protein has been shown to modulate host inflammation, immune responses, apoptosis, and virus pathogenesis [25][26][27][28][29][30].

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Interferon-Inducible Transmembrane Protein 3 Genetic Variant rs12252 and Influenza Susceptibility and Severity: A Meta-Analysis

Cited by 39 publications

References 32 publications

The IFITMs Inhibit Zika Virus Replication

The IFITMs Inhibit Zika Virus Replication

SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans

Host Single Nucleotide Polymorphisms Modulating Influenza A Virus Disease in Humans

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