Human Molecular Genetics Advance Access published online on November 12, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddh008
© 2003 by Oxford University Press
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1 Meyerhoff IBD Center, Gastroenterology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
* To whom correspondence should be addressed. E-mail: sbrant{at}jhmi.edu.
Nuclear Factor-
Article
Functional Annotation of a Novel NFKB1 Promoter Polymorphism that Increases Risk for Ulcerative Colitis
2 Boston University School of Medicine, Boston, Massachusetts
3 National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland
4 Departments of Medicine and Surgery, University of Toronto and Mount Sinai Hospital, Toronto, Canada
5 Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
6 The Martin Boyer Laboratories, Section of Gastroenterology, Department of Medicine, The University of Chicago Hospitals, Chicago, Illinois
7 Center for Genomics and Human Genetics, North Shore Long Island Jewish Research Institute, Manhasset, New York
8 Department of Gastroenterology, The Cleveland Clinic Foundation, Cleveland, Ohio
9 Meyerhoff IBD Center, Gastroenterology Division, Department of Medicine, 1503 E. Jefferson Street, Room B136, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA; Dept. of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
Abstract 
B (NF-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-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.
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