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

BACKGROUND:
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 TGFβ1-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 non-radiographic 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, serological 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 non-radiographic measures of RA severity, including CRP, Swollen Joint Count, Tender Joint Count, DAS28 and the HAQ score were modelled longitudinally in a large prospective cohort of early RA patients.
RESULTS:
Loss of Foxo3 function resulted in more severe arthritis in vivo (both clinically and histologically) and was associated with higher titres of anti-collagen antibodies and IL-6 in blood. Similarly, rs12212067 (a SNP that increases FOXO3 transcription) was associated with reduced inflammation - both biochemically and clinically - and with lower RA activity scores.
CONCLUSIONS:
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 would lead to lesser radiographic damage