title: Association Between Genetic Variation in FOXO3 and Reductions in Inflammation and Disease Activity in Inflammatory Polyarthritis.
abstract: Genetic variation in FOXO3 (tagged by rs12212067) has been associated with a milder course of rheumatoid arthritis (RA) and shown to limit monocyte-driven inflammation through a transforming growth factor β1-dependent pathway. This genetic association, however, has not been consistently observed in other RA cohorts. We sought to clarify the contribution of FOXO3 to prognosis in RA by combining detailed analysis of nonradiographic disease severity measures with an in vivo model of arthritis.
  
  
  
  Collagen-induced arthritis, the most commonly used mouse model of RA, was used to assess how Foxo3 contributes to arthritis severity. Using clinical, serologic, and biochemical methods, the arthritis that developed in mice carrying a loss-of-function mutation in Foxo3 was compared with that which occurred in littermate controls. The association of rs12212067 with nonradiographic measures of RA severity, including the C-reactive protein level, the swollen joint count, the tender joint count, the Disease Activity Score in 28 joints, and the Health Assessment Questionnaire score, were modeled longitudinally in a large prospective cohort of patients with early RA.
  
  
  
  Loss of Foxo3 function resulted in more severe arthritis in vivo (both clinically and histologically) and was associated with higher titers of anticollagen antibodies and interleukin-6 in the blood. Similarly, rs12212067 (a single-nucleotide polymorphism that increases FOXO3 transcription) was associated with reduced inflammation, both biochemically and clinically, and with lower RA activity scores.
  
  
  
  Consistent with its known role in restraining inflammatory responses, FOXO3 limits the severity of in vivo arthritis and, through genetic variation that increases its transcription, is associated with reduced inflammation and disease activity in RA patients, effects that result in less radiographic damage.
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Viatte
authors.affiliation: University of Cambridge School of Clinical Medicine, Cambridge, UK.
authors.forename: James C
authors.initials: JC
authors.lastname: Lee
authors.affiliation: University of Manchester, Manchester, UK, and University College London, London, UK.
authors.forename: Bo
authors.initials: B
authors.lastname: Fu
authors.affiliation: UMR 996, Inflammation, Chemokines, and Immunopathology, INSERM, Université Paris-Sud, Université Paris-Saclay, Clamart, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Espéli
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Lunt
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Jack N E
authors.initials: JN
authors.lastname: De Wolf
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Lily
authors.initials: L
authors.lastname: Wheeler
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Reynolds
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Madhura
authors.initials: M
authors.lastname: Castelino
authors.affiliation: NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Deborah P M
authors.initials: DP
authors.lastname: Symmons
authors.affiliation: University of Cambridge School of Clinical Medicine, Cambridge, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lyons
authors.affiliation: NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. Anne.Barton@manchester.ac.uk.
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.affiliation: University of Cambridge School of Clinical Medicine, Cambridge, UK. kgcs2@cam.ac.uk.
authors.forename: Kenneth G C
authors.initials: KG
authors.lastname: Smith
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D002097:C-Reactive Protein / Q000276:immunology; D015331:Cohort Studies; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000235:genetics*; D006801:Humans; D007249:Inflammation; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012720:Severity of Illness Index
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D002097:C-Reactive Protein