Official websites use .gov
A
.gov
website belongs to an official government organization in the
United States.
Secure .gov websites use HTTPS
A
lock
(
) or
https://
means you’ve safely connected to the .gov website. Share sensitive
information only on official, secure websites.
PubMed ID:
14613970
Public Release Type:
Journal
Publication Year: 2004
Affiliation: Johns Hopkins University School of Medicine, 1503 E. Jefferson Street, Room B136, Baltimore, MD 21231, USA.
DOI:
https://doi.org/10.1093/hmg/ddh008
Authors:
Okazaki T,
Brant SR,
Nouvet FJ,
Bayless TM,
Mezey E,
Dassopoulos T,
Achkar JP,
Wu Y,
Gregersen PK,
Cho JH,
Duerr RH,
Silverberg MS,
Bailey-Wilson JE,
Potter JJ,
Gallegos T,
Panhuysen CI,
Karban AS
Studies:
Inflammatory Bowel Disease Genetics
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.
