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.

Original publication




Journal article


Human molecular genetics

Publication Date





1281 - 1289


Wellcome Trust Centre for Human Genetics, University of Oxford, UK. david.vanheel@well.ox.ac.uk


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