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, Nick Kennedy, Charlie Lees, Jack Satsangi, Miles Parkes, Paul A Lyons, Kenneth G C Smith, Paul Henderson

Research output: Contribution to journalArticlepeer-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 languageEnglish
Pages (from-to)57-69
Number of pages13
JournalCell
Volume155
Issue number1
DOIs
Publication statusPublished - 26 Sep 2013

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

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