Cell
Volume 155, Issue 1, 26 September 2013, Pages 57-69
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Article
Human SNP Links Differential Outcomes in Inflammatory and Infectious Disease to a FOXO3-Regulated Pathway

https://doi.org/10.1016/j.cell.2013.08.034Get rights and content
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open access

Highlights

  • Reanalysis of GWAS data identifies a SNP associated with outcome in Crohn’s disease

  • This SNP modulates inflammatory responses in monocytes via a FOXO3-driven pathway

  • The mild disease-associated allele reduces TNFα and increases IL-10 production

  • Prognosis in RA and malaria (also TNFα-related diseases) is also linked to this SNP

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.

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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.

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A full list of The UK IBD Genetics Consortium contributors may be found in the Supplemental Information