Ulcerative colitis and Crohn's "tend to occur together," Richard Duerr, associate professor of medicine and human genetics at the University of Pittsburgh, told BioWorld Today. "The two may share some genetic susceptibility factors and differ at others."

Together, Crohn's disease and ulcerative colitis make up the category of inflammatory bowel disease. Crohn's disease is patchier than ulcerative colitis, which usually shows a sharp boundary between affected and unaffected tissue. Ulcerative colitis also is limited to the colon and to the inner lining of the colon, whereas Crohn's disease can show up anywhere in the gut and spreads throughout the walls of the organs it affects.

But both are what Duerr called "immune-mediated diseases," to distinguish them from autoimmunity: While the body attacks its own tissues in autoimmune disease, both Crohn's and ulcerative colitis begin as a host defense reaction that doesn't know when to quit. "Once inflammation has been triggered, it just keeps going," Duerr said.

In the Oct. 26, 2006, issue of Sciencexpress, the online version of Science, first author Duerr and his colleagues from the Inflammatory Bowel Disease Genetics Consortium reported on one such susceptibility factor - though the strongest finding was of a gene variant that was a protective rather than a risk factor, prompting senior author Judy Cho, an associate professor in the departments of medicine and genetics at Yale University School of Medicine, to say that the finding "may lead us to think about the genetics of health as much as about the genetics of disease."

Because inflammatory bowel disease occurs more frequently in some ethnic groups than others, and Ashkenazi Jews often are affected, the researchers searched for single nucleotide polymorphisms associated with ileal Crohn's in one group of Jewish ancestry, and one non-Jewish group.

The scan identified three SNPs that were strongly associated with Crohn's disease: two in a known Crohn's associated gene named CARD15, and a third in a novel gene that turned out to code for part of the immune cell receptor for the pro-inflammatory cytokine interleukin-23.

In a surprise finding, 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," Duerr said.

He said that his next goal is to find out how the different receptor versions are conferring risk or protection: "It's going to be key to find out the mechanisms of protection" to see whether they could be imitated in the clinic.

An antibody blocking interleukin-23 already is in clinical trials, though not because it blocks interleukin-23. In 2004, scientists from the National Institute of Allergy and Infectious Diseases reported in the New England Journal of Medicine that a monoclonal antibody against another interleukin receptor induced remission in some patients with active Crohn's disease. "That particular antibody was developed to target interleukin-12," Duerr said, "but as it turns out, it is directed against a shared subunit" of interleukins 12 and 23. "So perhaps, really some of the effects are because they are blocking interleukin-23, as well," he said.

Duerr also said that the beneficial effects of blocking IL-23 will not be limited to inflammatory bowel disease, and he stressed that he and his colleagues have not tested the gene's involvement in anything else, but said that "our guess is that this pathway, and possibly some of these receptor polymorphisms, are going to be important in many immune-mediated diseases" including asthma, rheumatoid arthritis and multiple sclerosis.

The IBD Genetics Consortium comprises the University of Pittsburgh; Yale University in New Haven, Conn.; Cedars-Sinai Medical Center in Los Angeles; the University of Chicago; Johns Hopkins University in Baltimore; Université de Montréal; Mount Sinai Hospital in Toronto and the University of Toronto.

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