SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans. Nat Med 2017 Aug;23(8):975-983
Date
07/18/2017Pubmed ID
28714988Pubmed Central ID
PMC5702558DOI
10.1038/nm.4370Scopus ID
2-s2.0-85029295000 (requires institutional sign-in at Scopus site) 134 CitationsAbstract
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.
Author List
Allen EK, Randolph AG, Bhangale T, Dogra P, Ohlson M, Oshansky CM, Zamora AE, Shannon JP, Finkelstein D, Dressen A, DeVincenzo J, Caniza M, Youngblood B, Rosenberger CM, Thomas PGAuthor
Anthony E. Zamora PhD Assistant Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AllelesBlotting, Western
CCCTC-Binding Factor
CD8-Positive T-Lymphocytes
DNA Methylation
Genetic Predisposition to Disease
Genotype
Humans
Influenza, Human
Interferon Regulatory Factor-3
Membrane Proteins
Nasal Lavage Fluid
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Quantitative Trait Loci
RNA-Binding Proteins
Repressor Proteins
Severity of Illness Index