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Nat Med. 2017 Aug;23(8):975-983. doi: 10.1038/nm.4370. Epub 2017 Jul 17.

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

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Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, and Departments of Anesthesia and Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
Human Genetics, Genentech, Inc., South San Francisco, California, USA.
Biomarker Discovery, Genentech, Inc., South San Francisco, California, USA.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Departments of Pediatrics and of Microbiology, Immunology and Molecular Biology, University of Tennessee School of Medicine, Memphis, Tennessee, USA.
Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.


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.

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