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

Journal article

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.

Authors: van Heel, D; Udalova, I; De Silva, A; McGovern, D; Kinouchi, Y

• Publication status: Published
• Journal: Human molecular genetics
• Volume: 11
• Issue: 11
• Pages: 1281-1289
• Publication date: 2002-05-01
• DOI: 10.1093/hmg/11.11.1281
• EISSN: 1460-2083
• ISSN: 0964-6906
• Language: English
• Keywords: Inflammatory Bowel Diseases; NF-kappa B; Tumor Necrosis Factor-alpha; Humans; Genes, Reporter; Promoter Regions, Genetic; Protein Structure, Tertiary; Homozygote; Cercopithecus aethiops; Organic Cation Transporter 1; Animals; Polymorphism, Genetic; Case-Control Studies; COS Cells