Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B transcription factors

Hum Mol Genet. 2002 May 15;11(11):1281-9. doi: 10.1093/hmg/11.11.1281.

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 types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • NF-kappa B
  • Organic Cation Transporter 1
  • Tumor Necrosis Factor-alpha