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- PMID: 24035192
- UKPMCID: 24035192
- DOI: 10.1016/j.cell.2013.08.034
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Human SNP Links Differential Outcomes in Inflammatory and Infectious Disease to a FOXO3-Regulated Pathway.
Lee, James C; Espéli, Marion; Anderson, Carl A; Linterman, Michelle A; Pocock, Joanna M; Williams, Naomi J; Roberts, Rebecca; Viatte, Sebastien; Fu, Bo; Peshu, Norbert; Hien, Tran Tinh; Phu, Nguyen Hoan; Wesley, Emma; Edwards, Cathryn; Ahmad, Tariq; Mansfield, John C; Gearry, Richard; Dunstan, Sarah; Williams, Thomas N; Barton, Anne; Vinuesa, Carola G; ; Parkes, Miles; Lyons, Paul A; Smith, Kenneth G C
Cell. 2013;155(1):57-69.
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Full-text held externally
- PMID: 24035192
- UKPMCID: 24035192
- DOI: 10.1016/j.cell.2013.08.034
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. PAPERCLIP:
Bibliographic metadata
- Lee, James C
- Espéli, Marion
- Anderson, Carl A
- Linterman, Michelle A
- Pocock, Joanna M
- Williams, Naomi J
- Roberts, Rebecca
- Viatte, Sebastien
- Fu, Bo
- Peshu, Norbert
- Hien, Tran Tinh
- Phu, Nguyen Hoan
- Wesley, Emma
- Edwards, Cathryn
- Ahmad, Tariq
- Mansfield, John C
- Gearry, Richard
- Dunstan, Sarah
- Williams, Thomas N
- Barton, Anne
- Vinuesa, Carola G
- Parkes, Miles
- Lyons, Paul A
- Smith, Kenneth G C