Dec. 22, 2003 Researchers at Johns Hopkins have linked versions of two different genes with the inflammatory bowel diseases known as Crohn's disease and ulcerative colitis. The discoveries are a crucial step in developing new treatments and prevention strategies for these disabling conditions that together afflict one million Americans, the scientists say.
The first discovery demonstrates that a version of the NFKB1 gene was an important risk factor for ulcerative colitis. NFKB1 is the gene that contains the DNA sequence for nuclear factor kappa B (NF-Kappa B) protein, which is one of the foremost regulators of the immune system and programmed cell death. The results are reported in the January 1, 2004 issue of the journal Human Molecular Genetics.
"Our greatest hope is that by identifying the gene abnormalities associated with inflammatory bowel disease (IBD), we'll be able to figure out how they contribute to causing disease and then interfere with that process to stop the disease in its tracks," says Steven Brant, M.D., associate professor of medicine at Johns Hopkins, director of the Meyerhoff Inflammatory Bowel Disease Genetics Laboratory, whose research team discovered the NFKB1 link.
Evidence from twin studies and the tendency for IBD to run in families strongly suggested a genetic component to the disease, says Brant. Relatives of Crohn's disease patients have a 10-fold risk of developing Crohn's disease, while relatives of ulcerative colitis patients have an eightfold risk of developing ulcerative colitis. In addition, the two diseases appear to be genetically related to each other, as relatives of patients with just one of the diseases have an increased risk of developing either Crohn's or ulcerative colitis.
For these reasons, Brant and colleagues have been searching for genes that might contribute to the development of IBD and, in 2001, they participated in the discovery of the first gene, called NOD2, that was clearly associated with Crohn's disease. These NOD2 Crohn's disease predisposing gene variants occur in 30 percent to 40 percent of patients with the disease.
In the current study, Brant's team focused on the NFKB1 gene, which in addition to IBD, may have a role in a variety of diseases including cancer, AIDS, asthma, arthritis, shock, lung disease, diabetes, atherosclerosis and stroke. A major clue that NFKB1 may be involved in IBD was uncovered when it was shown that NFKB1 seems to be responsible for mice genetically predisposed to developing colitis, says Brant.
The team searched the DNA of 235 families with IBD (from Johns Hopkins, the University of Chicago and the University of Pittsburgh) in which 131 had offspring with ulcerative colitis for evidence of a link between the disease and the NFKB1 gene. They found six variants of the gene, and showed that one variant - involving a small deletion of the NFKB1 gene sequence - influences the amount of NFKB1 gene product made. Closely examining the pedigrees with several genetic techniques revealed that this NFKB1 deletion variant was significantly increased in the 131 ulcerative colitis offspring, and thus strongly suggested a link between the gene variant and ulcerative colitis. They then replicated this finding in a second, independent set of patients (including those from University of Toronto) with ulcerative colitis. The researchers suggested that this NFKB1 deletion may potentially be important in the some of the many other diseases where NFKB1 has been shown to play a role.
In the second study, appearing in the December 2003 issue of the American Journal of Human Genetics and led jointly by Brant and Judy Cho, M.D., of the University of Chicago, they found that a version of another gene, called MDR1, is strongly associated with Crohn's disease and possibly ulcerative colitis as well.
The DNA of 1,118 individuals, including 558 patients with IBD and 329 families in which at least one person had the disease, was examined using several genetic techniques. They found a clear association between IBD and the MDR1 gene. Like NFKB1, mouse genetic studies similarly suggested that the MDR1 gene was important in colitis, alerting researchers to the potential importance of MDR1 to human IBD.
"Taken together, these new discoveries combine with the original NOD2 gene discovery and will hopefully lead to ways to intervene and possibly prevent IBD from occurring," says Brant. In addition to their association with IBD, Brant hopes the new discoveries will prove useful to researchers working on different diseases.
Crohn's disease and ulcerative colitis primarily affect the intestines, resulting in pain, severe diarrhea, intestinal bleeding, weight loss and fever. Symptoms vary in severity and duration; some patients suffer from frequent prolonged attacks, and others have fewer recurrences. The disease usually starts in the adolescent or young adult years. In ulcerative colitis, the inner lining of the colon is inflamed. People with Crohn's disease have similar inflammation, but it extends deeper into the intestinal wall and can also involve the small and large intestines.
Researchers from Johns Hopkins University, University of Chicago, University of Pittsburgh and the Cleveland Clinic participated in both studies, and researchers from University of Toronto and New York University participated in the NFKB1 study. These studies were funded by the National Institutes of Health, the Crohn's and Colitis Foundation of America, the Meyerhoff IBD Center, the Stewart W. Bainum family, the Reva and David Logan Foundation, the Scaife Family Foundation, the Israeli Society of Gastroenterology, Toyobo Biotechnology Foundation, the Crohn's and Colitis Foundation of Canada, the Canadian Association of Gastroenterology, the Canadian Institutes of Health Research, , and the Gastrointestinal Research Foundation.
Functional Annotation of a Novel NFKB1 Promoter Polymorhpism that Increases Risk for Ulcerative Colitis. Amir Karban, Toshihiko Okazaki, Carolien I. Panhuysen, Thomas Gallegos, James J. Potter, Joan E. Bailey-Wilson, Mark S. Silverberg, Richard H. Duerr, Judy Cho, Peter K. Gregersen, Yuqiong Wu, Jean-Paul Achkar, Themistocles Dassopoulos, Esteban Mezey, Theodore M. Bayless, Franklin J. Nouvet, Steven R. Brant. Human Molecular Genetics. January 1, 2004.
MDR1 Ala893 Polymorphism is Associated with Inflammatory Bowel Disease. Steven R. Brant, Carolien I. M. Panhuysen, Dan Nicolae, Deepthi M. Reddy, Denise K. Bonen, Reda Karaliukas, Leilei Zhang, Eric Swanson, Lisa W. Datta, Thomas Moran, Geoffrey Ravenhill, Richard H. Duerr, Jean-Paul Achkar, Amir S. Karban, Judy H. Cho. American Journal of Human Genetics. December 2003.
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