title: Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis.
abstract: Nuclear Factor-kappaB (NF-kappaB) 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-kappaB 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.
authors: Johns Hopkins University School of Medicine, 1503 E. Jefferson Street, Room B136, Baltimore, MD 21231, USA.
authors: Amir S
authors: AS
authors: Karban
authors: Toshihiko
authors: T
authors: Okazaki
authors: Carolien I M
authors: CI
authors: Panhuysen
authors: Thomas
authors: T
authors: Gallegos
authors: James J
authors: JJ
authors: Potter
authors: Joan E
authors: JE
authors: Bailey-Wilson
authors: Mark S
authors: MS
authors: Silverberg
authors: Richard H
authors: RH
authors: Duerr
authors: Judy H
authors: JH
authors: Cho
authors: Peter K
authors: PK
authors: Gregersen
authors: Yuqiong
authors: Y
authors: Wu
authors: Jean-Paul
authors: JP
authors: Achkar
authors: Themistocles
authors: T
authors: Dassopoulos
authors: Esteban
authors: E
authors: Mezey
authors: Theodore M
authors: TM
authors: Bayless
authors: Franklin J
authors: FJ
authors: Nouvet
authors: Steven R
authors: SR
authors: Brant
mesh_terms: D001483:Base Sequence; D016022:Case-Control Studies; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005787:Gene Frequency; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008969:Molecular Sequence Data; D052002:NF-kappa B p50 Subunit; D009841:Oligonucleotides / Q000378:metabolism; D010375:Pedigree; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D009841:Oligonucleotides; D014157:Transcription Factors; D008156:Luciferases