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Title: | Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B transcription factors |
Authors: | van Heel, D.A. Udalova, I.A. de Silva, A.P. McGovern, D.P. Kinouchi, Y. Hull, J. Lench, N.J. Cardon, L.R. Carey, A.H. Jewell, D.P. Kwiatkowski, D. |
Keywords: | Inflammatory Bowel Diseases-genetics Organic Cation Transporter 1-metabolism Polymorphism, Genetic Tumor Necrosis Factor-alpha-genetics NF-kappa B-metabolism Case-Control Studies Organic Cation Transporter 1-metabolism Polymorphism, Genetic Tumor Necrosis Factor-alpha-genetics NF-kappa B-metabolism Case-Control Studies |
Issue Date: | 2002 |
Publisher: | Oxford University Press |
Citation: | Human Molecular Genetics. 2002; 11(11): pp.1281-9. |
Abstract: | 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-inflammatoryNF(-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. |
Description: | Indexed in MEDLINE |
URI: | http://repository.kln.ac.lk/handle/123456789/1545 |
ISSN: | 0964-6906 (Print) 1460-2083 (Electronic) |
Appears in Collections: | Journal/Magazine Articles |
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