2. A novel FOXO3-driven pathway determines prognosis in Crohn's disease, rheumatoid arthritis and malaria
J. Lee1, M. Espeli1, C. Anderson2, M. Linterman1, J. Pocock1, R. Roberts3, S. Viatte4, N. Peshu5, T.T. Hien6, N.H. Phu6, E. Wesley7, C. Edwards8, T. Ahmad7, J. Mansfield9, R. Gearry3, S. Dunstan10, T. Williams5, A. Barton4, M. Parkes1, P. Lyons1, K. Smith1, 1University of Cambridge, Department of Medicine, Cambridge, 2Wellcome Trust Sanger Institute, Cambridge, United Kingdom, 3University of Otago, Department of Medicine, Christchurch, New Zealand, 4University of Manchester, United Kingdom, 5Kenya Medical Research Institute, Kenya, 6The Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam, 7Royal Devon and Exeter Hospital, United Kingdom, 8Torbay Hospital, United Kingdom, 9Newcastle University, United Kingdom, 10University of Oxford, United Kingdom
The clinical course of Crohn's disease (CD) varies enormously between patients, and has a major bearing on the lives of affected individuals. Indeed, for most patients, their well-being is more dependent on the course their disease takes after diagnosis, than on the actual diagnosis itself. Despite this, genetic studies have largely focused on factors determining susceptibility to the development of disease, rather than on those governing its subsequent course.
To identify mechanisms that determine clinical outcome in CD, which may be of therapeutic interest and assist the delivery of “personalised medicine”, we performed a prognosis-based re-analysis of existing GWAS data. By directly comparing the genetic profiles of patients with contrasting courses of CD, we identify a non-coding SNP that associates with prognosis. Using a series of functional experiments in human samples obtained from a genotype-selectable bioresource, we elucidate the function of this genetic mutation, and show that this single variant can control the magnitude of specific inflammatory responses that directly relate to the biology of CD.
We show that although this genetic variant is not coding (i.e. does not alter protein structure) it does regulate the expression of FOXO3 (a transcription factor) during inflammatory responses. By exploring the effects of the resulting differences, we identify a novel TGFβ1-dependent pathway that controls the production of inflammatory cytokines by stimulated monocytes. In the presence of the indolent disease-associated allele, less pro-inflammatory cytokines, including TNFα (a key therapeutic target in CD) and more anti-inflammatory cytokines, including IL-10, are produced. We delineate the mechanism by which this regulation occurs, and further demonstrate that the outcome of other diseases that involve these cytokines – including rheumatoid arthritis and malaria – are also directly associated with allelic variation at this single genetic variant.
We demonstrate that clinically-relevant insights can be revealed through structured re-analysis of existing GWAS data, and identify a novel FOXO3-driven pathway which modulates the production of inflammatory cytokines by monocytes, and associates with prognosis in at least three distinct diseases, including CD.