Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway

James C Lee; Marion Espéli; Carl A Anderson; Michelle A Linterman; Joanna M Pocock; Naomi J Williams; Rebecca Roberts; Sebastien Viatte; Bo Fu; Norbert Peshu; Tran Tinh Hien; Nguyen Hoan Phu; Emma Wesley; Cathryn Edwards; Tariq Ahmad; John C Mansfield; Richard Gearry; Sarah Dunstan; Thomas N Williams; Anne Barton; Carola G Vinuesa; UK IBD Genetics Consortium; Hazel Drummond; Nick Kennedy; Charlie Lees; Jack Satsangi; Miles Parkes; Paul A Lyons; Kenneth G C Smith; Paul Henderson

doi:10.1016/j.cell.2013.08.034

Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway

James C Lee, Marion Espéli, Carl A Anderson, Michelle A Linterman, Joanna M Pocock, Naomi J Williams, Rebecca Roberts, Sebastien Viatte, Bo Fu, Norbert Peshu, Tran Tinh Hien, Nguyen Hoan Phu, Emma Wesley, Cathryn Edwards, Tariq Ahmad, John C Mansfield, Richard Gearry, Sarah Dunstan, Thomas N Williams, Anne BartonCarola G Vinuesa, UK IBD Genetics Consortium, Hazel Drummond (Member of Consortium), Nick Kennedy (Member of Consortium), Charlie Lees (Member of Consortium), Jack Satsangi (Member of Consortium), Miles Parkes, Paul A Lyons, Kenneth G C Smith, Paul Henderson (Member of Consortium)

Research output: Contribution to journal › Article › peer-review

Abstract

The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals. This variability critically determines the impact a disease has on a patient's life but is very poorly understood. Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn's disease and rheumatoid arthritis and with increased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFβ1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10. Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses.

Original language	English
Pages (from-to)	57-69
Number of pages	13
Journal	Cell
Volume	155
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2013.08.034
Publication status	Published - 26 Sept 2013

Keywords / Materials (for Non-textual outputs)

Animals
Arthritis, Rheumatoid
Cell Nucleus
Crohn Disease
Extracellular Matrix Proteins
Forkhead Transcription Factors
Genetic Variation
Humans
Inflammation
Malaria, Falciparum
Mice
Monocytes
Polymorphism, Single Nucleotide
Transcription, Genetic
Transforming Growth Factor beta

Access to Document

10.1016/j.cell.2013.08.034

Human SNP Links Differential Outcomes in Inflammatory and Infectious Disease to a FOXO3-Regulated Pathway
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
Final published version, 1.71 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

http://www.sciencedirect.com/science/article/pii/S0092867413010283#

The Paediatric-onset inflammatory bowel disease cohort and treatment study (PICTS)
Wilson, D. (Principal Investigator) & Satsangi, J. (Co-investigator)
MRC
1/01/09 → 31/03/14
Project: Research
Evaluating the importance of Autophagy/Xenophagy in protecting the intestinal epithelium in Crohn's Disease
Satsangi, J. (Principal Investigator), Aldhous, M. (Co-investigator), Hupp, T. (Co-investigator), Nimmo, E. (Co-investigator) & Stevens, C. (Co-investigator)
MRC
1/09/08 → 31/01/12
Project: Research

Cite this

Lee, J. C., Espéli, M., Anderson, C. A., Linterman, M. A., Pocock, J. M., Williams, N. J., Roberts, R., Viatte, S., Fu, B., Peshu, N., Hien, T. T., Phu, N. H., Wesley, E., Edwards, C., Ahmad, T., Mansfield, J. C., Gearry, R., Dunstan, S., Williams, T. N., ... Henderson, P. (2013). Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway. Cell, 155(1), 57-69. https://doi.org/10.1016/j.cell.2013.08.034

@article{a63e15cfcffc4e1f8c3c949144e18248,

title = "Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway",

abstract = "The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals. This variability critically determines the impact a disease has on a patient's life but is very poorly understood. Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn's disease and rheumatoid arthritis and with increased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFβ1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10. Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses.",

keywords = "Animals, Arthritis, Rheumatoid, Cell Nucleus, Crohn Disease, Extracellular Matrix Proteins, Forkhead Transcription Factors, Genetic Variation, Humans, Inflammation, Malaria, Falciparum, Mice, Monocytes, Polymorphism, Single Nucleotide, Transcription, Genetic, Transforming Growth Factor beta",

author = "Lee, {James C} and Marion Esp{\'e}li and Anderson, {Carl A} and Linterman, {Michelle A} and Pocock, {Joanna M} and Williams, {Naomi J} and Rebecca Roberts and Sebastien Viatte and Bo Fu and Norbert Peshu and Hien, {Tran Tinh} and Phu, {Nguyen Hoan} and Emma Wesley and Cathryn Edwards and Tariq Ahmad and Mansfield, {John C} and Richard Gearry and Sarah Dunstan and Williams, {Thomas N} and Anne Barton and Vinuesa, {Carola G} and {UK IBD Genetics Consortium} and Hazel Drummond and Nick Kennedy and Charlie Lees and Jack Satsangi and Miles Parkes and Lyons, {Paul A} and Smith, {Kenneth G C} and Paul Henderson",

year = "2013",

month = sep,

day = "26",

doi = "10.1016/j.cell.2013.08.034",

language = "English",

volume = "155",

pages = "57--69",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

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Lee, JC, Espéli, M, Anderson, CA, Linterman, MA, Pocock, JM, Williams, NJ, Roberts, R, Viatte, S, Fu, B, Peshu, N, Hien, TT, Phu, NH, Wesley, E, Edwards, C, Ahmad, T, Mansfield, JC, Gearry, R, Dunstan, S, Williams, TN, Barton, A, Vinuesa, CG, UK IBD Genetics Consortium, Drummond, H, Kennedy, N, Lees, C, Satsangi, J, Parkes, M, Lyons, PA, Smith, KGC & Henderson, P 2013, 'Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway', Cell, vol. 155, no. 1, pp. 57-69. https://doi.org/10.1016/j.cell.2013.08.034

TY - JOUR

T1 - Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway

AU - Lee, James C

AU - Espéli, Marion

AU - Anderson, Carl A

AU - Linterman, Michelle A

AU - Pocock, Joanna M

AU - Williams, Naomi J

AU - Roberts, Rebecca

AU - Viatte, Sebastien

AU - Fu, Bo

AU - Peshu, Norbert

AU - Hien, Tran Tinh

AU - Phu, Nguyen Hoan

AU - Wesley, Emma

AU - Edwards, Cathryn

AU - Ahmad, Tariq

AU - Mansfield, John C

AU - Gearry, Richard

AU - Dunstan, Sarah

AU - Williams, Thomas N

AU - Barton, Anne

AU - Vinuesa, Carola G

AU - UK IBD Genetics Consortium

AU - Parkes, Miles

AU - Lyons, Paul A

AU - Smith, Kenneth G C

A2 - Drummond, Hazel

A2 - Kennedy, Nick

A2 - Lees, Charlie

A2 - Satsangi, Jack

A2 - Henderson, Paul

PY - 2013/9/26

Y1 - 2013/9/26

N2 - The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals. This variability critically determines the impact a disease has on a patient's life but is very poorly understood. Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn's disease and rheumatoid arthritis and with increased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFβ1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10. Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses.

AB - The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals. This variability critically determines the impact a disease has on a patient's life but is very poorly understood. Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn's disease and rheumatoid arthritis and with increased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFβ1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10. Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses.

KW - Animals

KW - Arthritis, Rheumatoid

KW - Cell Nucleus

KW - Crohn Disease

KW - Extracellular Matrix Proteins

KW - Forkhead Transcription Factors

KW - Genetic Variation

KW - Humans

KW - Inflammation

KW - Malaria, Falciparum

KW - Mice

KW - Monocytes

KW - Polymorphism, Single Nucleotide

KW - Transcription, Genetic

KW - Transforming Growth Factor beta

U2 - 10.1016/j.cell.2013.08.034

DO - 10.1016/j.cell.2013.08.034

M3 - Article

C2 - 24035192

SN - 0092-8674

VL - 155

SP - 57

EP - 69

JO - Cell

JF - Cell

IS - 1

ER -

Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

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Projects

The Paediatric-onset inflammatory bowel disease cohort and treatment study (PICTS)

Evaluating the importance of Autophagy/Xenophagy in protecting the intestinal epithelium in Crohn's Disease

Cite this