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AU - Lee JC
AU - Espéli M
AU - Anderson CA
AU - Linterman MA
AU - Pocock JM
AU - Williams NJ
AU - Roberts R
AU - Viatte S
AU - Fu B
AU - Peshu N
AU - Hien TT
AU - Phu NH
AU - Wesley E
AU - Edwards C
AU - Ahmad T
AU - Mansfield JC
AU - Gearry R
AU - Dunstan S
AU - Williams TN
AU - Barton A
AU - Vinuesa CG
AU - Parkes M
AU - Lyons PA
AU - Smith KG
T1 - Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway.
JO - Cell
VL - 155
IS - 1
DP -
ID - 24035192
LA - en
SP - 57
EP - 69
DA - 2013/09PY - 2013
KW - Artrite Reumatoide/genética
KW - Doença de Crohn/genética
KW - Fatores de Transcrição Forkhead/genética
KW - Malária Falciparum/genética
KW - Polimorfismo de Nucleotídeo Único
KW - Animais
KW - Artrite Reumatoide/fisiopatologia
KW - Núcleo Celular/metabolismo
KW - Doença de Crohn/fisiopatologia
KW - Proteínas da Matriz Extracelular/imunologia
KW - Fatores de Transcrição Forkhead/metabolismo
KW - Variação Genética
KW - Humanos
KW - Inflamação/genética
KW - Malária Falciparum/fisiopatologia
KW - Camundongos
KW - Monócitos/imunologia
KW - Transcrição Genética
KW - Fator de Crescimento Transformador beta/imunologia
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 TGFß1 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.
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