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; Miles Parkes; Paul A. Lyons; Kenneth G.C. Smith

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, Miles Parkes, Paul A. Lyons, Kenneth G.C. Smith^*

^*Corresponding author for this work

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

185 Citations (Scopus)

Abstract

Summary 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. PaperClip

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
Externally published	Yes

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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., ... Smith, K. G. C. (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{cba7165a8aee43c1876c541748fcc885,

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

abstract = "Summary 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. PaperClip",

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 Miles Parkes and Lyons, {Paul A.} and Smith, {Kenneth G.C.}",

year = "2013",

month = sep,

day = "26",

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

language = "English",

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journal = "Cell",

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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, Parkes, M, Lyons, PA & Smith, KGC 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 - Parkes, Miles

AU - Lyons, Paul A.

AU - Smith, Kenneth G.C.

PY - 2013/9/26

Y1 - 2013/9/26

N2 - Summary 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. PaperClip

AB - Summary 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. PaperClip

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U2 - 10.1016/j.cell.2013.08.034

DO - 10.1016/j.cell.2013.08.034

M3 - Article

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

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