New gene found for Crohn's disease

PITTSBURGH, Oct. 26 -- 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. While most of the mutations in the gene, which codes for a receptor in a major inflammatory pathway, are strongly associated with Crohn's, surprisingly, one type of mutation appears to confer significant protection. The finding, say the researchers, points to 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).

"Crohn's and colitis are chronic conditions that profoundly impact the day-to-day lives of affected individuals. Moreover, inflammatory bowel disease often runs in families, making the pinpointing of the responsible genes especially important if we are to find ways to better treat or even prevent IBD," said first author of the study, Richard H. Duerr, M.D., associate professor of medicine and human genetics at the University of Pittsburgh.

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.

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). In addition to the University of Pittsburgh and Yale, the consortium's member institutions include Cedars-Sinai Medical Center in Los Angeles, the University of Chicago, Johns Hopkins University, Université de Montréal, Mount Sinai Hospital in Toronto and the University of Toronto.

Because IBD tends to run in families and is more frequently seen 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 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. For comparison, they looked for the presence of these SNPs in a similar number of people without IBD.

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 located 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 Dr. Duerr. "We are not sure yet what it means in terms of improving treatments for IBD patients. But, we speculate 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 (UPMC).

In an early stage clinical trial led by other investigators, IBD patients given a monoclonal antibody that blocks IL-23 and a related inflammatory mediator saw their conditions improve. 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 IBD, 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.

The authors caution that more must be understood about the role the IL-23 pathway serves in protecting against other diseases before seeking to block or manipulate its activity with drugs or other means.

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In addition to Dr. Duerr, other authors from the University of Pittsburgh include Miguel Regueiro, M.D., associate professor of medicine at the School of Medicine and co-director of UPMC's Inflammatory Bowel Disease Center; and M. Michael Barmada, Ph.D., associate professor of human genetics, Graduate School of Public Health.


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