Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B transcription factors.
Tumour necrosis factor-alpha (TNF) expression is increased in inflammatory bowel disease (IBD), and TNF maps to the IBD3 susceptibility locus. Transmission disequilibrium and case-control analyses, in two independent Caucasian cohorts, showed a novel association of the TNF(-857C) promoter polymorphism with IBD (overall P=0.001 in 587 IBD families). Further genetic associations of TNF(-857C) with IBD sub-phenotypes were seen for ulcerative colitis and for Crohn's disease, but only in patients not carrying common NOD2 mutations. The genetic data suggest a recessive model of inheritance, and we observed ex vivo lipopolysaccharide-stimulated whole-blood TNF production to be higher in healthy TNF(-857C) homozygotes. We show the transcription factor OCT1 binds TNF(-857T) but not TNF(-857C), and interacts in vitro and in vivo with the pro-inflammatory NF(-kappa)B transcription factor p65 subunit at an adjacent binding site. Detailed functional analyses of these interactions in gut macrophages, in addition to further genetic mapping of this gene-dense region, will be critical to understand the significance of the observed association of TNF(-857C) with IBD.
van Heel
David A
DA
Wellcome Trust Centre for Human Genetics, University of Oxford, UK. david.vanheel@well.ox.ac.uk
Udalova
Irina A
IA
De Silva
Arjuna P
AP
McGovern
Dermot P
DP
Kinouchi
Yoshitaka
Y
Hull
Jeremy
J
Lench
Nicholas J
NJ
Cardon
Lon R
LR
Carey
Alisoun H
AH
Jewell
Derek P
DP
Kwiatkowski
Dominic
D
D000818:Animals; D019556:COS Cells; D016022:Case-Control Studies; D002522:Chlorocebus aethiops; D017930:Genes, Reporter; D006720:Homozygote; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D016328:NF-kappa B; D027702:Organic Cation Transporter 1; D014409:Tumor Necrosis Factor-alpha