A consortium of American and Canadian researchers report in Science Express, a rapid online publication by the journal Science, the discovery of a new genetic link to Crohn's disease. Mutations of a gene, which codes for a receptor in a major inflammatory pathway, are strongly associated with Crohn's disease, the researchers found. Surprisingly, one type of mutation appears to confer significant protection, prioritizing a crucial target for drugs that might better manage Crohn's disease and ulcerative colitis.
More than 1 million Americans have Crohn's or colitis, known collectively as inflammatory bowel disease (IBD).
The study's authors represent the IBD Genetics Consortium, which is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH). The Consortium's member institutions include Cedars-Sinai Medical Center in Los Angeles, the University of Chicago, Johns Hopkins University, Université de Montréal, the University of Pittsburgh, Mount Sinai Hospital in Toronto and the University of Toronto, and Yale University.
According to senior author Judy H.Cho, M.D., associate professor in the departments of medicine and genetics at Yale School of Medicine, the findings highlight a major inflammatory pathway and change in thinking about disease-associated genetic variation. "This pathway is particularly intriguing because we appear to have identified a gene variant that protects against development of IBD, a finding that may lead us to think about the genetics of health as much as about the genetics of disease," said Dr. Cho, who also is director of the Inflammatory Bowel Disease Center at Yale.
Because IBD tends to run in families and is more frequent in certain ethnic populations, especially Ashkenazi Jews, scientists have long suspected a significant genetic component. Although previous genetic studies found a link between Crohn's disease and mutations in a gene known as CARD15, those mutations alone are not considered to account for all of the genetic components of the disease.
To identify additional genes that are associated with IBD, the international team of researchers scanned the genome--all 22,000 or so genes--by testing more than 300,000 single nucleotide polymorphisms, or SNPs, in people with Crohn's disease. They looked for the presence of these SNPs in a similar number of people without IBD for comparison.
Out of the hundreds of thousands of SNPs, the genome-wide scan found three that were most strongly associated with Crohn's disease. Of those, two were in the CARD15 gene. However, the third SNP was in a different gene on a different chromosome.
When the researchers looked at the specific gene where the third SNP resided, they found that it coded for a protein that is part of the immune cell receptor for interleukin-23 (IL-23), an important mediator of inflammation in the body. However, when they began looking for all of the polymorphisms in the IL-23 receptor gene of affected individuals to determine which ones were the most detrimental, they made an unexpected discovery.
Although several polymorphisms were associated with a significantly increased risk of developing IBD, one appeared to confer a very strong protection against IBD.
"Of all the SNPs we studied in people with and without IBD, this protective SNP was the most statistically significant finding in our study. So, it took us a bit by surprise," said first author, Richard H. Duerr, M.D., associate professor of medicine and human genetics at the University of Pittsburgh. "What it means in terms of improving treatments for IBD patients, we are not sure yet. But, we speculate that it may be possible to mimic the conditions within the IL-23 inflammatory pathway that result from the chain of events initiated by this particular genetic variant."
Members of the consortium are attempting to tease out the specific downstream effects of this protective polymorphism. Yet, because IL-23 plays an important role in activating inflammation, including in the organs of the digestive tract, it could be an extremely important target for improving the management of Crohn's disease and other IBDs.
"We identified multiple genetic signals in the IL-23 receptor gene that were strongly associated with Crohn's disease. In fact, the statistical significance for some IL-23 receptor SNPs was two orders of magnitude greater than that of other SNPs in other genes. So, we believe that blocking the activity of IL-23 or manipulating its pathway will be an effective way to manage IBD," said Dr. Duerr, who also is head of the Inflammatory Bowel Disease Genetics Program at the University of Pittsburgh School of Medicine and co-director of the Inflammatory Bowel Disease Center at the University of Pittsburgh Medical Center.
In a previous study by other investigators, an early stage clinical trial showed that IBD patients exhibit improvement when given a monoclonal antibody that blocks IL-23 and a related inflammatory mediator. Furthermore, recent studies in mice in which the gene for IL-23 is deleted demonstrated that IL-23 is essential for the development and maintenance of chronic intestinal inflammation. Such evidence, combined with the current discovery, suggests therapies that target the IL-23 pathway may lead to more individualized, better-directed therapies for IBDs, the authors say.
"This important discovery not only offers new hope for better therapies for patients with Crohn's disease, it also highlights the promise of the human genome project and subsequent investments by the NIH in large scale, collaborative research projects to unravel the causes of, and hopefully better treatments for complex, enigmatic diseases," said Stephen P. James, M.D., director of the Division of Digestive Diseases and Nutrition at the National Institutes of Health's NIDDK.
Dr. Cho offers a cautionary note, however. "The IL-23 pathway may serve a very useful purpose in protecting us from other diseases, so when seeking to block or manipulate its activity with drugs or other means, we need to take this balancing act into consideration," she said.
In addition to Drs. Duerr and Cho, other authors include: Kent D. Taylor, Ph.D., Huiying Yang, Ph.D., Stephan Targan, M.D., and Jerome I. Rotter, M.D., Cedars-Sinai Medical Center Medical Genetics Institute and IBD Center in Los Angeles; Steven R. Brant, M.D., Themistocles Dassopoulos, M.D., and Lisa Wu Datta, M.S., Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center and the Johns Hopkins University Bloomberg School of Public Health, Baltimore; John D. Rioux, Ph.D., Université de Montréal and the Montreal Heart Institute, Montreal; Mark S. Silverberg, M.D., Ph.D., and A. Hillary Steinhart, M.D., Mount Sinai Hospital IBD Centre, University of Toronto; Mark J. Daly, Ph.D., Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston; Clara Abraham, M.D., Emily O. Kistner, Ph.D., L. Philip Schumm, M.A., and Dan L. Nicolae, Ph.D., University of Chicago; Miguel Regueiro, M.D., University of Pittsburgh School of Medicine; Anne Griffiths, M.D., Department of Pediatrics, The Hospital for Sick Children, Toronto; Alain Bitton, M.D., Royal Victoria Hospital, McGill University Health Centre, Montreal; Annette Lee, Ph.D., and Peter K. Gregersen, M.D., Feinstein Institute for Medical Research, Manhasset, N.Y.; and M. Michael Barmada, Ph.D., University of Pittsburgh Graduate School of Public Health.
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