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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.

Pubmed ID: 12019209


  • van Heel DA
  • Udalova IA
  • De Silva AP
  • McGovern DP
  • Kinouchi Y
  • Hull J
  • Lench NJ
  • Cardon LR
  • Carey AH
  • Jewell DP
  • Kwiatkowski D


Human molecular genetics

Publication Data

May 15, 2002

Associated Grants

  • Agency: NEI NIH HHS, Id: EY15652

Mesh Terms

  • Animals
  • COS Cells
  • Case-Control Studies
  • Cercopithecus aethiops
  • Genes, Reporter
  • Homozygote
  • Humans
  • Inflammatory Bowel Diseases
  • NF-kappa B
  • Organic Cation Transporter 1
  • Polymorphism, Genetic
  • Promoter Regions, Genetic
  • Protein Structure, Tertiary
  • Tumor Necrosis Factor-alpha