Author/Authors :
James C. Lee، نويسنده , , Marion Espéli، نويسنده , , Carl A. Anderson، نويسنده , , Michelle A. Linterman، نويسنده , , Joanna M. Pocock، نويسنده , , Naomi J. Williams، نويسنده , , Rebecca Roberts، نويسنده , , Sebastien Viatte، نويسنده , , Bo Fu، نويسنده , , Norbert Peshu، نويسنده , , Tran Tinh Hien، نويسنده , , Nguyen Hoan Phu، نويسنده , , Emma Wesley، نويسنده , , Cathryn Edwards، نويسنده , , Tariq Ahmad War، نويسنده , , John C. Mansfield، نويسنده , , Richard Gearry، نويسنده , , Sarah Dunstan، نويسنده , , Thomas N. Williams، نويسنده , , Anne Barton، نويسنده , , et al.، نويسنده ,
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.
