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- Title
Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B transcription factors.
- Authors
van Heel, David A; Udalova, Irina A; De Silva, Arjuna P; McGovern, Dermot P; Kinouchi, Yoshitaka; Hull, Jeremy; Lench, Nicholas J; Cardon, Lon R; Carey, Alisoun H; Jewell, Derek P; Kwiatkowski, Dominic
- Abstract
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.
- Publication
Human molecular genetics, 2002, Vol 11, Issue 11, p1281
- ISSN
0964-6906
- Publication type
Journal Article
- DOI
10.1093/hmg/11.11.1281