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

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)975-983
Number of pages9
JournalNature Medicine
Volume23
Issue number8
DOIs
StatePublished - Aug 1 2017

Fingerprint

Human Influenza
Single Nucleotide Polymorphism
T-cells
Alleles
T-Lymphocytes
Association reactions
Methylation
5' Untranslated Regions
Quantitative Trait Loci
T-Lymphocyte Subsets
Set theory
Assays
Genes
Messenger RNA
Infection

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Allen, E. K., Randolph, A. G., Bhangale, T., Dogra, P., Ohlson, M., Oshansky, C. M., ... Thomas, P. G. (2017). SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans. Nature Medicine, 23(8), 975-983. https://doi.org/10.1038/nm.4370

SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans. / Allen, E. Kaitlynn; Randolph, Adrienne G.; Bhangale, Tushar; Dogra, Pranay; Ohlson, Maikke; Oshansky, Christine M.; Zamora, Anthony E.; Shannon, John P.; Finkelstein, David; Dressen, Amy; Devincenzo, John; Caniza, Miguela; Youngblood, Ben; Rosenberger, Carrie M.; Thomas, Paul G.

In: Nature Medicine, Vol. 23, No. 8, 01.08.2017, p. 975-983.

Research output: Contribution to journalArticle

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, PG 2017, 'SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans', Nature Medicine, vol. 23, no. 8, pp. 975-983. https://doi.org/10.1038/nm.4370
Allen, E. Kaitlynn ; Randolph, Adrienne G. ; Bhangale, Tushar ; Dogra, Pranay ; Ohlson, Maikke ; Oshansky, Christine M. ; Zamora, Anthony E. ; Shannon, John P. ; Finkelstein, David ; Dressen, Amy ; Devincenzo, John ; Caniza, Miguela ; Youngblood, Ben ; Rosenberger, Carrie M. ; Thomas, Paul G. / SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans. In: Nature Medicine. 2017 ; Vol. 23, No. 8. pp. 975-983.
@article{d9654dfe933e432eb2798338fe8082f2,
title = "SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans",
abstract = "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 = "Allen, {E. Kaitlynn} and Randolph, {Adrienne G.} and Tushar Bhangale and Pranay Dogra and Maikke Ohlson and Oshansky, {Christine M.} and Zamora, {Anthony E.} and Shannon, {John P.} and David Finkelstein and Amy Dressen and John Devincenzo and Miguela Caniza and Ben Youngblood and Rosenberger, {Carrie M.} and Thomas, {Paul G.}",
year = "2017",
month = "8",
day = "1",
doi = "10.1038/nm.4370",
language = "English (US)",
volume = "23",
pages = "975--983",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans

AU - Allen, E. Kaitlynn

AU - Randolph, Adrienne G.

AU - Bhangale, Tushar

AU - Dogra, Pranay

AU - Ohlson, Maikke

AU - Oshansky, Christine M.

AU - Zamora, Anthony E.

AU - Shannon, John P.

AU - Finkelstein, David

AU - Dressen, Amy

AU - Devincenzo, John

AU - Caniza, Miguela

AU - Youngblood, Ben

AU - Rosenberger, Carrie M.

AU - Thomas, Paul G.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85029295000&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029295000&partnerID=8YFLogxK

U2 - 10.1038/nm.4370

DO - 10.1038/nm.4370

M3 - Article

VL - 23

SP - 975

EP - 983

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 8

ER -