Journal Article

Inflammatory bowel disease is associated with a <i>TNF</i> polymorphism that affects an interaction between the OCT1 and NF-κB transcription factors

David A. van Heel, Irina A. Udalova, Arjuna P. De Silva, Dermot P. McGovern, Yoshitaka Kinouchi, Jeremy Hull, Nicholas J. Lench, Lon R. Cardon, Alisoun H. Carey, Derek P. Jewell and Dominic Kwiatkowski

in Human Molecular Genetics

Volume 11, issue 11, pages 1281-1289
Published in print May 2002 | ISSN: 0964-6906
Published online May 2002 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/11.11.1281
Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF-κB transcription factors

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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.

Journal Article.  6933 words.  Illustrated.

Subjects: Genetics and Genomics

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