Functional annotation of a novel NFKB1 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, Steven R. Brant

Research output: Contribution to journalReview articlepeer-review

316 Scopus citations


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 call 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.

Original languageEnglish
Pages (from-to)35-45
Number of pages11
JournalHuman Molecular Genetics
Issue number1
StatePublished - 1 Jan 2004
Externally publishedYes


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