Association Between Genetic Variation in FOXO3 and Reductions in Inflammation and Disease Activity in Inflammatory Polyarthritis

Abstract

ObjectiveGenetic 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.MethodsCollagen‐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.ResultsLoss 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.ConclusionConsistent 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.

FOXO3 is involved in the tumor necrosis factor-driven inflammatory response in fibroblast-like synoviocytes

“…Perturbations in the expression or activity of FOXO3 are increasingly linked to chronic inflammatory diseases, such as colitis and arthritis [14,15,33,34]. Research into the mechanism of the FOXO3-regulated inflammatory response has mainly concentrated on leukocytes.…”

“…A single-nucleotide polymorphism (SNP) in FOXO3 (rs12212067; T > G) was associated with lower RA activity scores and less radiographic progression [14,15]. Correspondingly, collagen-induced arthritis (CIA) was pronounced in mice with loss-of-FOXO3 function [14]. By contrast, FOXO3 deficiency ameliorated symptoms in the K/BxN serum transfer arthritis model.…”

Beyond disease susceptibility—Leveraging genome‐wide association studies for new insights into complex disease biology

“…Intriguingly, however, we did find additional evidence that the genetic contribution to prognosis may be shared between distinct diseases. For example, the FOXO3 haplotype that was associated with a milder course of Crohn's disease, and reduced TNFα production, has also been associated with a milder course of rheumatoid arthritis and with more severe courses of malaria and tuberculosis . Similarly, the IGFBP1 / IGFBP3 locus that was associated with more aggressive Crohn's disease was previously shown to associate with anti‐citrullinated peptide antibodies in rheumatoid arthritis …”

A polymorphism in the cachexia-associated gene INHBA predicts efficacy of regorafenib in patients with refractory metastatic colorectal cancer

“…This finding may result from etiological differences between Japanese and Italian populations. Several studies have shown that FOXO3 rs12212067 is associated with the clinical course of inflammatory diseases such as Crohn's disease or rheumatoid arthritis [44,45]. FOXO3 has also been linked to the regulation of immune responses using systems biology [46] and knockout mouse models [47].…”