TY - JOUR
T1 - Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway
AU - Lee, James C.
AU - Espéli, Marion
AU - Anderson, Carl A.
AU - Linterman, Michelle A.
AU - Pocock, Joanna M.
AU - Williams, Naomi J.
AU - Roberts, Rebecca
AU - Viatte, Sebastien
AU - Fu, Bo
AU - Peshu, Norbert
AU - Hien, Tran Tinh
AU - Phu, Nguyen Hoan
AU - Wesley, Emma
AU - Edwards, Cathryn
AU - Ahmad, Tariq
AU - Mansfield, John C.
AU - Gearry, Richard
AU - Dunstan, Sarah
AU - Williams, Thomas N.
AU - Barton, Anne
AU - Vinuesa, Carola G.
AU - UK IBD Genetics Consortium
AU - Parkes, Miles
AU - Lyons, Paul A.
AU - Smith, Kenneth G. C.
A2 - Mowat, Craig
N1 - Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2013/9/26
Y1 - 2013/9/26
N2 - 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.
AB - 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.
KW - Animals
KW - Arthritis, Rheumatoid/genetics
KW - Cell Nucleus/metabolism
KW - Crohn Disease/genetics
KW - Extracellular Matrix Proteins/immunology
KW - Forkhead Box Protein O3
KW - Forkhead Transcription Factors/genetics
KW - Genetic Variation
KW - Humans
KW - Inflammation/genetics
KW - Malaria, Falciparum/genetics
KW - Mice
KW - Monocytes/immunology
KW - Polymorphism, Single Nucleotide
KW - Transcription, Genetic
KW - Transforming Growth Factor beta/immunology
U2 - 10.1016/j.cell.2013.08.034
DO - 10.1016/j.cell.2013.08.034
M3 - Article
C2 - 24035192
SN - 0092-8674
VL - 155
SP - 57
EP - 69
JO - Cell
JF - Cell
IS - 1
ER -
