Human Molecular Genetics, 2002, Vol. 11, No. 11 1281-1289
© 2002 Oxford University Press
Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF-
B transcription factors
1Wellcome Trust Centre for Human Genetics, 2Gastroenterology Unit and 3Department of Paediatrics, University of Oxford, UK, 4Tohoku University Graduate School of Medicine, Sendai, Japan and 5Oxagen Ltd, Abingdon, UK
Received January 17, 2002; Accepted March 13, 2002
Tumour necrosis factor-
(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-
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.
* To whom correspondence should be addressed at: Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. Tel: +44 1865 287651/287623; Fax: +44 1865 287533; Email: david.vanheel{at}well.ox.ac.uk
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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