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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 publication

DOI

10.1016/j.cell.2013.08.034

Type

Journal article

Journal

Cell

Publication Date

26/09/2013

Volume

155

Pages

57 - 69

Keywords

Animals, Arthritis, Rheumatoid, Cell Nucleus, Crohn Disease, Extracellular Matrix Proteins, Forkhead Box Protein O3, Forkhead Transcription Factors, Genetic Variation, Humans, Inflammation, Malaria, Falciparum, Mice, Monocytes, Polymorphism, Single Nucleotide, Transcription, Genetic, Transforming Growth Factor beta