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Human Molecular Genetics Advance Access originally published online on November 12, 2003
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Human Molecular Genetics, 2004, Vol. 13, No. 1 35-45
DOI: 10.1093/hmg/ddh008
© 2004 Oxford University Press

Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis

Amir S. Karban1,{dagger}, Toshihiko Okazaki1,{dagger}, Carolien I.M. Panhuysen2, Thomas Gallegos1, James J. Potter1, Joan E. Bailey-Wilson3, Mark S. Silverberg4, Richard H. Duerr5, Judy H. Cho6, Peter K. Gregersen7, Yuqiong Wu1, Jean-Paul Achkar8, Themistocles Dassopoulos1, Esteban Mezey1, Theodore M. Bayless1, Franklin J. Nouvet1 and Steven R. Brant1,9,*

1The Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Gastroenterology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2Boston University School of Medicine, Boston, MA, USA, 3National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA, 4Departments of Medicine and Surgery, University of Toronto and Mount Sinai Hospital, Toronto, Canada, 5Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA, 6The Martin Boyer Laboratories, Section of Gastroenterology, Department of Medicine, The University of Chicago Hospitals, Chicago, IL, USA, 7Center for Genomics and Human Genetics, North Shore Long Island Jewish Research Institute, Manhasset, NY, USA, 8Department of Gastroenterology, The Cleveland Clinic Foundation, Cleveland, OH, USA and 9Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

Received July 18, 2003; Revised October 20, 2003; Accepted October 29, 2003

Nuclear Factor-{kappa}B (NF-{kappa}B) 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-{kappa}B 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.

* To whom correspondence should be addressed at: 1503 E. Jefferson Street, Room B136, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Tel: +14109559679; Fax: +14105029913; Email: sbrant{at}jhmi.edu

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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