Journal Article

Functional annotation of a novel <i>NFKB1</i> promoter polymorphism that increases risk for ulcerative colitis

Amir S. Karban, Toshihiko Okazaki, Carolien I.M. Panhuysen, Thomas Gallegos, James J. Potter, Joan E. Bailey-Wilson, Mark S. Silverberg, Richard H. Duerr, Judy H. Cho, Peter K. Gregersen, Yuqiong Wu, Jean-Paul Achkar, Themistocles Dassopoulos, Esteban Mezey, Theodore M. Bayless, Franklin J. Nouvet and Steven R. Brant

in Human Molecular Genetics

Volume 13, issue 1, pages 35-45
Published in print January 2004 | ISSN: 0964-6906
Published online January 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddh008
Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis

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Nuclear Factor-κB (NF-κB) is a major transcription regulator of immune response, apoptosis and cell-growth control genes, and is upregulated in inflammatory bowel disease (IBD), both ulcerative colitis (UC) and Crohn's disease. The NFKB1 gene encodes the NF-κB p105/p50 isoforms. Genome-wide screens in IBD families show evidence for linkage on chromosome 4q where NFKB1 maps. We sequenced the NFKB1 promoter, exon 1 and all coding exons in 10 IBD probands and two controls, and identified six nucleotide variants, including a common insertion/deletion promoter polymorphism (−94ins/delATTG). Using pedigree-based transmission disequilibrium tests, we observed modest evidence for linkage disequilibrium (LD), independent of linkage, between the −94delATTG allele and UC in 131 out of 235 IBD pedigrees with UC offspring (P=0.047–0.052). This allele was also more frequent in the 156 non-Jewish UC probands from the 235 IBD pedigrees than in 149 non-Jewish controls (P=0.015). The −94delATTG association with UC was replicated in a second set of 258 unrelated, non-Jewish UC cases and 653 new, non-Jewish controls (P=0.021). Nuclear proteins from normal human colon tissue and colonic cell lines, but not ileal tissue, showed significant binding to −94insATTG but not to −94delATTG containing oligonucleotides. NFKB1 promoter/exon 1 luciferase reporter plasmid constructs containing the −94delATTG allele and transfected into either HeLa or HT-29 cell lines showed less promoter activity than comparable constructs containing the −94insATTG allele. Therefore, we have identified the first potentially functional polymorphism of NFKB1 and demonstrated its genetic association with a common human disease, ulcerative colitis.

Journal Article.  9357 words.  Illustrated.

Subjects: Genetics and Genomics

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