Tuesday, July 18, 2017

New IFITM3 Genetic Marker May Help Identify High Risk Flu Patients


One of the great inequities of life is that some people are at a higher risk of experiencing severe flu infections than others.  Sometimes that has to do with their age, immune system, or comorbidities . . . . and sometimes it boils down to their genetics. 
Being able to identify those patients who's genetic traits put them a greater risk of severe illness or death from influenza would be huge advantage in prioritizing treatment - particularly during a pandemic. 
Over the past decade we've followed a number research projects into several genetic markers, including the Interferon-induced transmembrane protein 3  (IFITM3) protein, whose levels are controlled by the IFITM3 gene.

  • In late 2009, in The Best Defense, we looked at research from Harvard Medical School and the Howard Hughes Medical Institute, that identified the IFITM3 protein as capable of inhibiting the replication of influenza, and other viruses, such as West Nile and Dengue.
  • We revisited the IFITM3 story again in early 2012, in Luck Of The Draw, when we looked at research from the Wellcome Trust Sanger Institute, that found that people who carried a particular variant of the IFITM3 gene - (SNP rs12252-C) -  were more likely to be hospitalized with severe influenza. 
  • And again in 2013, in PNAS, we saw reseach that found IFITM3 CC gene variant (aka C/C Genotype) is linked to hypercytokinemia (aka a `Cytokine Storm’), and a severe outcome, in H7N9 infections.    
  • And in 2015, in A Genetic Predisposition To Severe Flu Infection, we looked at a  study published in Science Express that identified yet another (rare) genetic marker -  a mutation of the IRF7 gene -  linked to a lack of interferon production which can lead to a more severe influenza infection.
Today the Journal Nature has published a new study on the role played by a mutation in the IFITM3 gene on influenza severity.  As I write this, the link doesn't appear to be working, but it will hopefully go live soon.
Research | 17 July 2017
SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans
E Kaitlynn Allen, Adrienne G Randolph, Tushar Bhangale, Pranay Dogra, Maikke Ohlson, Christine M Oshansky, Anthony E Zamora, John P Shannon, David Finkelstein, Amy Dressen, John DeVincenzo, Miguela Caniza, Ben Youngblood, Carrie M Rosenberger & Paul G Thomas
In the meantime, we do have the abstract from PubMed, and a press release from St. Jude Children's Research Hospital  in Memphis.  
Nat Med. 2017 Jul 17. doi: 10.1038/nm.4370. [Epub ahead of print]

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

Allen EK1, Randolph AG2, Bhangale T3, Dogra P1, Ohlson M4, Oshansky CM1, Zamora AE1, Shannon JP1, Finkelstein D5, Dressen A3, DeVincenzo J6,7, Caniza M8, Youngblood B1, Rosenberger CM4, Thomas PG1.


Previous studies have reported associations of IFITM3 SNP rs12252 with severe influenza, but evidence of association and the mechanism by which risk is conferred remain controversial. We prioritized SNPs in IFITM3 on the basis of putative biological function and identified rs34481144 in the 5' UTR. We found evidence of a new association of rs34481144 with severe influenza in three influenza-infected cohorts characterized by different levels of influenza illness severity.
We determined a role for rs34481144 as an expression quantitative trait locus (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 IFITM3-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 numbers of CD8+ T cells in their airways during natural influenza infection, consistent with IFITM3 promoting accumulation of CD8+ T cells in airways and 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.

A considerably less technical summation can be found on the St. Jude Children's Research Hospital website, portions of which I've excerpted below. Follow the link to read it in its entirety.
Newly identified genetic marker may help detect high-risk flu patients

Researchers led by St. Jude Children's Research Hospital have identified a genetic variation associated with influenza severity and the supply of killer T cells that help patients fight the infection

Memphis, Tennessee, July 17, 2017

Researchers have discovered an inherited genetic variation that may help identify patients at elevated risk for severe, potentially fatal influenza infections. The scientists have also linked the gene variant to a mechanism that explains the elevated risk and offers clues about the broader anti-viral immune response.

St. Jude Children's Research Hospital led the research, which appears as an advance, online publication today in the scientific journal Nature Medicine.

Researchers screened 393 flu patients ranging from infants to 70 years old. Patients with a particular inherited variation in the gene IFITM3 were more than twice as likely to develop severe, life-threatening flu symptoms as those who carried the protective version of the gene.

Working at the molecular level, the investigators showed how expression of the IFITM3 protein was reduced in killer T cells of patients with the high-risk variant compared to other patients. Researchers also found more killer T cells—which help patients fight the infection—in the upper airways of flu patients with the protective variant compared to other patients.

(Continue . . . )

In addition to the previously discussed IFITM3 (rs12252) and mutations of the IRF7 gene, last year Chinese researchers (see Nature: Mulitple Gene Mutations Identified In Patients With A/H7N9) reported finding 21 genes that showed a high rate of mutation among infected patients when compared to the general population, including the IFITM3 gene.

While we are a long way from knowing all of the genetic risk factors for severe influenza (and likely other viral infections), researchers continue to expand their watch list, and more importantly, their understanding of how these mutations work.

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