Evaluation of IFITM3 rs12252 Association With Severe Pediatric Influenza Infection

Randolph, Adrienne G.; Yip, Wai‐Ki; Allen, E. Kaitlynn; Rosenberger, Carrie M.; Agan, Anna A.; Ash, Stephanie; Zhang, Yu; Bhangale, Tushar; Finkelstein, David; Cvijanovich, Natalie Z.; Mourani, Peter M.; Hall, Mark W.; Su, Helen C.; Thomas, Paul G.; Kong, Michele; Sewell, Kate; Sanders, Ronald C.; Hefley, Glenda; Téllez, David; Bliss, Courtney; Labell, Aimee; Liss, Danielle; Ortiz, Ashely L.; Typpo, Katri; Deschenes, Jen; Markovitz, Barry P.; Terry, J.E.; Morzov, Rica Sharon P.; Graciano, Ana Lía; Baldwin, Melita; Flori, Heidi R.; Brumfield, Becky; Simon, Julie; Anas, Nick; Schwarz, Adam; Onwunyi, Chisom; Osborne, Stephanie; Patterson, Tiffany; Vargas-Shiraishi, Ofelia; Sapru, Anil; Convery, Maureen; Lo, Victoria; Czaja, Angela S.; Aymami, Valeri Batara; Burr, Susanna; Brocato, Megan; Huston, Stephanie; Jewett, Emily; Lindahl, Sandra B.; Loyola, Danielle; Sierra, Yamila; Carroll, Christopher L.; Sala, Kathleen; Thornton-Thompson, Sherell; Giuliano, John S.; Tala, Joana; McLaughlin, Gwenn E.; Paden, Matthew L.; Manghram, Chee-Chee; Meisner, Stephanie; Stone, Cheryl; Toney, Rich; Coates, Bria M.; Shukla, Avani; Wardenburg, Juliane Bubeck; DeDent, Andrea C.; Montgomery, Vicki; Evans, Tracy; Richardson, Kara; Smith, Ellen M. Lavoie; Sullivan, Ryan M.; Yoon, Grace; Kiers, Michael; Keisling, Shannon M.; Bembea, Melania M.; White, Elizabeth; Kurachek, Stephen C.; Doucette, Angela A.; Zielinski, Erin E.; Doctor, Allan; Hartman, Mary E.; Jacobs, Rachel H.; Shetty, Shivan; Truemper, Edward J.; Dawson, Machelle; Levin, Daniel L.; Jarvis, Janet; Katyal, Chhavi; Ackerman, Kate G.; Daugherty, L. Eugene; Baglia, Laurel A.; Nofziger, Ryan A; Anthony, Healther; Shein, S v; Adams, Rebecca; Bergant, Susan; Lemon, Eloise; Petersen, Lisa; Greathouse, Kristin; Steele, Lisa; Thomas, Neal J.; Raymond, Jill; Spear, Debra; Fitzgerald, Julie C; Helfaer, Mark A.; Weiss, Scott L.; Bush, Jenny; DiLiberto, Mary Ann; Egan, Jillian; Park, Brooke B.; Sisko, Martha; Carell, Monroe; Barr, Frederick E.; Arnold, Judi; Higgerson, Renee A.; Christie, LeeAnn M.; Thompson, Marita; Loftis, Laura; Jaimon, Nancy; Kyle, Ursula G.; Willson, Douglas F.; Traul, Christine; Kelly, Robin L.; Gedeit, Rainer; Horn, Briana E.; Luther, Kate; Murkowski, Kathy; Jouvet, Philippe; Fontaine, Anne-Marie; Dugas, Marc-André

doi:10.1093/infdis/jix242

Cited by 57 publications

(58 citation statements)

References 25 publications

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“…If host genetics have a significant impact on risk of influenza-related hospitalization, it would most likely be observed in children who have a more limited lifetime exposure to influenza and fewer comorbid conditions. Notably, a recent study in a pediatric population observed no association between IFITM3 rs12252 and severe influenza infection, 35 similar to this study’s findings for adults. Another limitation was the inability to distinguish whether hospital admission within 14 days after illness onset was a direct consequence of the primary viral infection or was due to a secondary bacterial infection.…”

Section: Discussionsupporting

confidence: 91%

“…31, 32 Mutation or deletion of Y20 resulted in similar effects. 30, 31, 33, 34 Lymphoblastoid cells and peripheral blood mononuclear cells from individuals with the rs12252 minor CC genotype did not express the Δ1-21 variant protein; 3, 35 therefore, the relevance of the Δ1-21 variant protein to the level of severity of influenza infection in humans is unclear. At present, it is unknown whether the predicted splice site is used for splicing in vivo , and experimental studies of splice site usage are needed to determine whether the rs12252 minor C allele has a functional effect that impedes the ability of IFITM3 to restrict influenza virus infection.…”

Section: Discussionmentioning

confidence: 99%

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Pilot screening study of targeted genetic polymorphisms for association with seasonal influenza hospital admission

Carter

Hebbring

Liu

et al. 2017

Journal of Medical Virology

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Host response to influenza is highly variable, suggesting a potential role of host genetic variation. To investigate the host genetics of severe influenza in a targeted fashion, 32 single nucleotide polymorphisms (SNPs) within viral immune response genes were evaluated for association with seasonal influenza hospitalization in an adult study population with European ancestry. SNP allele and genotype frequencies were compared between hospitalized influenza patients (cases) and population controls in a case-control study that included a discovery group (26 cases and 993 controls) and two independent, validation groups (1 with 84 cases and 4076 controls; the other with 128 cases and 9187 controls). Cases and controls had similar allele frequencies for variant rs12252 in interferon-inducible transmembrane protein 3 (IFITM3) (P > 0.05), and the study did not replicate the previously reported association of rs12252 with hospitalized influenza. In the discovery group, the preliminary finding of an association with a nonsense polymorphism (rs8072510) within the schlafen family member 13 (SFLN13) gene (P = 0.0099) was not confirmed in either validation group. Neither rs12252 nor rs8072510 showed an association according to the presence of clinical risk factors for influenza complications (P > 0.05), suggesting that these factors did not modify associations between the SNPs and hospitalized influenza. No other SNPs showed a statistically significant association with hospitalized influenza. Further research is needed to identify genetic factors involved in host response to seasonal influenza infection and to assess whether rs12252, a low-frequency variant in Europeans, contributes to influenza severity in populations with European ancestry.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Pilot screening study of targeted genetic polymorphisms for association with seasonal influenza hospital admission

Carter

Hebbring

Liu

et al. 2017

Journal of Medical Virology

View full text Add to dashboard Cite

show abstract

“…SNP genotypes were identified by inspection of sequencing chromatogram files using Sequencher (Gene Codes Corp) and CLC Main Workbench 7.5 (CLC Bio). The second genotyping method was used for samples from the PICFlu cohort has been previously published 13 . Genotype concordance was measured at 100% between the two genotyping methods used in this study.…”

Section: Methodsmentioning

confidence: 99%

“…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. While its role in human disease may be ambiguous, IFITM3 remains a strong candidate for a protein influencing influenza severity based on the increased susceptibility of IFITM3-deficient mice to influenza disease and its characterized activity as a viral restriction factor.…”

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

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168

213

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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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“…They were also found to progress faster towards AIDS [37]. These findings, although not undisputed (see [38][39][40][41][42][43] for examples), indicates that polymorphisms in huIFITM3 can impact the course of viral infections. This notion has recently been reinforced by the finding that a polymorphism in the huI-FITM3 promoter that reduces IFITM3 expression increases the risk for severe influenza [44,45].…”

Section: Discussionmentioning

confidence: 95%

Role of rhesus macaque IFITM3(2) in simian immunodeficiency virus infection of macaques

et al. 2019

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The experimental infection of rhesus macaques (rh) with simian immunodeficiency virus (SIV) is an important model for human immunodeficiency virus (HIV) infection of humans. The interferon-induced transmembrane protein 3 (IFITM3) inhibits HIV and SIV infection at the stage of host cell entry. However, it is still unclear to what extent the antiviral activity of IFITM3 observed in cell culture translates into inhibition of HIV/SIV spread in the infected host. We have shown previously that although rhIFITM3 inhibits SIV entry into cultured cells, polymorphisms in the rhIFITM3 gene are not strongly associated with viral load or disease progression in SIV infected macaques. Here, we examined whether rhIFITM3(2), which is closely related to rhIFITM3 at the sequence level, exerts antiviral activity and whether polymorphisms in the rhIFITM3(2) gene impact the course of SIV infection. We show that expression of rhIFITM3(2) is interferon-inducible and inhibits SIV entry into cells, although with reduced efficiency as compared to rhIFITM3. We further report the identification of 19 polymorphisms in the rhIFITM3(2) gene. However, analysis of a well characterized cohort of SIV infected macaques revealed that none of the polymorphisms had a significant impact upon the course of SIV infection. These results and our previous work suggest that polymorphisms in the rhIFITM3 and rhIFITM3(2) genes do not strongly modulate the course of SIV infection in macaques.

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Evaluation of IFITM3 rs12252 Association With Severe Pediatric Influenza Infection

Abstract: 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.

Cited by 57 publications

References 25 publications

Pilot screening study of targeted genetic polymorphisms for association with seasonal influenza hospital admission

Pilot screening study of targeted genetic polymorphisms for association with seasonal influenza hospital admission

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

Role of rhesus macaque IFITM3(2) in simian immunodeficiency virus infection of macaques

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