Association between genetic variation in FOXO3 and reductions in inflammation and disease activity in inflammatory polyarthritis

Sebastien Viatte, James C. Lee, Bo Fu, Marion Espéli, Mark Lunt, Jack N.E. De Wolf, Lily Wheeler, John A. Reynolds, Madhura Castelino, Deborah P. M. Symmons, Paul A. Lyons, Anne Barton*, Kenneth G. C. Smith

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)
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Abstract

Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)2629-2636
Number of pages8
JournalArthritis and Rheumatology
Volume68
Issue number11
Early online date23 May 2016
DOIs
Publication statusPublished - 1 Nov 2016

Bibliographical note

Viatte, S. , Lee, J. C., Fu, B. , Espéli, M. , Lunt, M. , De Wolf, J. N., Wheeler, L. , Reynolds, J. A., Castelino, M. , Symmons, D. P., Lyons, P. A., Barton, A. and Smith, K. G. (2016), Association Between Genetic Variation in FOXO3 and Reductions in Inflammation and Disease Activity in Inflammatory Polyarthritis. Arthritis & Rheumatology, 68: 2629-2636. doi:10.1002/art.39760

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

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