Projects per year
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.
- Arthritis, Rheumatoid
- Cell Nucleus
- Crohn Disease
- Extracellular Matrix Proteins
- Forkhead Transcription Factors
- Genetic Variation
- Malaria, Falciparum
- Polymorphism, Single Nucleotide
- Transcription, Genetic
- Transforming Growth Factor beta
Wilson, D. & Satsangi, J.
1/01/09 → 31/03/14
Evaluating the importance of Autophagy/Xenophagy in protecting the intestinal epithelium in Crohn's Disease
Satsangi, J., Aldhous, M., Hupp, T., Nimmo, E. & Stevens, C.
1/09/08 → 31/01/12