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

Tumour necrosis factor-α (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-κB 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.