Examining Genetic Factors & Predispositions

An emerging theme in the literature of more recent interest is the role that genetic factors may play in susceptibility to severe influenza infection. Factors such as age and pre-existing health conditions have been known to increase susceptibility for some time,1 but the idea that there may be other genetic factors implicated in susceptibility is relatively new. Mutations identified thus far typically interfere with the canonical host response.1 This area is currently poorly understood, but I suspect that it will be of interesting focus in the biochemical and genetic literature on influenza moving forward.

Transmission electron microscopy of influenza viruses (Image Source).

A polymorphism of the IFITM3 gene is associated with increased susceptibility to influenza infection, but this effect is not entirely understood. In one study, polymorphisms, including the rs-12252 SNP identified in the Nature paper exploring its correlation with severe H1N1 infection, were generated and shown to lead to decreased viral restriction in vitro.2 However, a different study  has suggested that the link between the two may not be perfectly direct. In vitro studies with the Δ21 IFITM3 mutant (the protein product produced by this polymorphism) strongly restricted viral entry to the cell and sufficiently restricted viral production.3 The authors argue that this may speak a more complex correlation, perhaps relying on other factors as well, between this polymorphism and the observed clinical outcomes.3 There does not appear to be a more recent revisiting of this question. 

A polymorphism in IRF7, a component of the innate immune TLR pathway (Host Immunity & Preserving the Healthy State), has also recently been implicated in susceptibility to influenza.1 Much more study into these polymorphisms and their possible implications for clinical treatments and outcomes is warranted moving forward.

Summary of Major Scientific Innovations:

  • 2010s – Identification of IFITM3 and IRF7, innate immune components, mutations as implicated in susceptibility to severe influenza infection1,4

Note: This is not one of my core theme pages.

Works Cited

  1. Krammer, F.; Smith, G. J. D.; Fouchier, R. A. M.; Peiris, M.; Kedzierska, K.; Doherty, P. C.; Palese, P.; Shaw, M. L.; Treanor, J.; Webster, R. G.; et al. Influenza. Nat. Rev. Dis. Primer 2018, 4 (1), 1–21. https://doi.org/10.1038/s41572-018-0002-y.
  2. John, S.P.; Chin, C.R.; Perreira, J.M. et al. The CD225 Domain of IFITM3 Is Required for both IFITM Protein Association and Inhibition of Influenza A Virus and Dengue Virus Replication. J. Virol. 2013, 87(14); 7837-7852. https://dx.doi.org/10.1128%2FJVI.00481-13 
  3. Williams, D.E.; Wu, W.L.; Grotefend, C.R.; Radic, V.; Chung, C.; Chung, Y.H.; Farzan, M.; and Huang, I.C. IFITM3 polymorphism rs12252-C restricts influenza A viruses. PLoS One. 2014, 9(10):e110096. https://dx.doi.org/10.1371%2Fjournal.pone.0110096  
  4. Everitt, A.R.; Clare, S.; Pertel, T.; John, S.P.; Wash, R.S., Smith, S.E.; Chin, C.R.; Feeley, E.M.; Sims, J.S.; Adams, D.J.; Wise, H.M.; Kane, L.; Goulding, D.; Digard, P.; Anttila, V.; Baillie, J.K.; Walsh, T.S.; Hume, D.A.; Palotie, A.; Xue, Y.; Colonna, V.; Tyler-Smith, C.;  Dunning, J.; Gordon, S.B.; The GenISIS Investigators, The MOSAIC Investigators, Smyth, R.L.; Openshaw, P.J.; Dougan, G.; Brass, A.L.; Kellam, P. IFITM3 restricts the morbidity and mortality associated with influenza. Nature. 2012, 484, 519-523. https://doi.org/10.1038/nature10921

For more information and resources, see Annotated Bibliography.

2 Replies to “Examining Genetic Factors & Predispositions”

  1. I think it is super interesting that they have linked a polymorphism in the IFITM3 gene to increased susceptibility to the H1N1 virus. I was wondering if they have done any haplotype analysis on individuals who have the polymorphism. Also, did the researchers look at how the individuals with the polymorphism are affecting by some of the other flu strains?

    1. Hi Lindsay!

      Thanks for your comment, and interesting question! While it was not something that came up directly in my research, it does appear that some haplotype analysis has been done with regards to this polymorphism. Interestingly, some studies suggest that the haplotypes of the IFITM3 polymorphism is associated with rheumatoid arthritis and ulcerative colitis.

      With regards to other influenza strains – the association has certainly been most notable with regards to the H1N1 flu, possibly because of the abundance of data available during the pandemic. I have not seen much about deliberate investigation into IFITM3 polymorphisms in other subtypes, though some studies suggest that this could affect all influenza A virus infections which, given the proposed mechanism of IFITM3, does not seem unreasonable.

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