Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway

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 -