Human SNP Links Differential Outcomes in Inflammatory and Infectious Disease to a FOXO3-Regulated Pathway
Graphical Abstract – Audio Interview at Link
- 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
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.