Human SNP Links Differential Outcomes in Inflammatory and Infectious Disease to a FOXO3-Regulated Pathway

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. [Display omitted] [Display omitted] •Reanalysis of GWAS data identifies a SNP associated with outcome in Crohn’s disease•This SNP modulates inflammatory responses in monocytes via a FOXO3-driven pathway•The mild disease-associated allele reduces TNFα and increases IL-10 production•Prognosis in RA and malaria (also TNFα-related diseases) is also linked to this SNP An analysis of GWAS data of patients with Crohn’s disease distinguishes SNPs associated with disease risk from those associated with outcome. Functional studies indicate that a noncoding SNP associated with FOXO3A influences a cytokine inflammatory pathway that impacts outcome, not only in Crohn’s but also other diseases such as rheumatoid arthritis and malaria.