title: Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway.
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.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: James C
authors.initials: JC
authors.lastname: Lee
authors.forename: Marion
authors.initials: M
authors.lastname: Espéli
authors.forename: Carl A
authors.initials: CA
authors.lastname: Anderson
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Linterman
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Pocock
authors.forename: Naomi J
authors.initials: NJ
authors.lastname: Williams
authors.forename: Rebecca
authors.initials: R
authors.lastname: Roberts
authors.forename: Sebastien
authors.initials: S
authors.lastname: Viatte
authors.forename: Bo
authors.initials: B
authors.lastname: Fu
authors.forename: Norbert
authors.initials: N
authors.lastname: Peshu
authors.forename: Tran Tinh
authors.initials: TT
authors.lastname: Hien
authors.forename: Nguyen Hoan
authors.initials: NH
authors.lastname: Phu
authors.forename: Emma
authors.initials: E
authors.lastname: Wesley
authors.forename: Cathryn
authors.initials: C
authors.lastname: Edwards
authors.forename: Tariq
authors.initials: T
authors.lastname: Ahmad
authors.forename: John C
authors.initials: JC
authors.lastname: Mansfield
authors.forename: Richard
authors.initials: R
authors.lastname: Gearry
authors.forename: Sarah
authors.initials: S
authors.lastname: Dunstan
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Williams
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.forename: Carola G
authors.initials: CG
authors.lastname: Vinuesa
authors.forename: Miles
authors.initials: M
authors.lastname: Parkes
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lyons
authors.forename: Kenneth G C
authors.initials: KG
authors.lastname: Smith
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000503:physiopathology; D002467:Cell Nucleus / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics* / Q000503:physiopathology; D016326:Extracellular Matrix Proteins / Q000276:immunology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D007249:Inflammation / Q000235:genetics; D016778:Malaria, Falciparum / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D009000:Monocytes / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000276:immunology; D000099222:betaIG-H3 Protein
chemical_list: D016326:Extracellular Matrix Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein; C499517:FOXO3 protein, human
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