Newswise — An international team of researchers has identified another gene mutation linked to the inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis.

The team, including Johns Hopkins gastroenterologists and geneticists, says the novel mutation is in the interleukin-23 (IL-23) gene receptor present in healthy people without Crohn's disease but rare in those with the disease.

IL-23 is a protein that regulates chronic inflammation and helps the body fight bacterial infections. Its receptor, IL23R, is present on lymphocytes and macrophages, white blood cells responsible for mounting immune response to infections. IL-23 has long been linked to IBD and autoimmune psoriasis, but this new genetic variation in the protein's receptor offers a novel pathway for tracking the disease process and for potential drug treatments.

Results of the study, by a consortium of researchers from Hopkins and six other American and Canadian institutions, appears in Science Express, an online publication of the journal Science, on Oct. 26.

"The IL-23 receptor variation we discovered appears to affect the IL-23 pathway, altering the body's response to chronic inflammation, which may trigger autoimmune disease," says study co-author Steven R. Brant, M.D., associate professor of medicine and director of research and the genetics laboratories of Hopkins' Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center. "The fact that this gene has already been implicated in other autoimmune disease like psoriasis offers strong evidence that we are on the right track.

In the Crohn's study, researchers located the IL23R disease-associated protein variant by scanning nearly all of the 22,000 genes that make up the human genome. The study looked at 547 test subjects with Crohn's disease and 548 healthy controls. Patients were recruited from six of the seven centers in the consortium. Researchers examined more than 300,000 variations in the genetic code, known as single nucleotide polymorphisms or SNPs, to identify which of the variations among these 22,000 genes can explain the genetic predisposition to developing Crohn's disease. SNPs are commonly occurring variations in our DNA code that are routinely used as a method for finding genetic links to diseases. Researchers scanned the genomes using a relatively new technology that allows researchers to study variations found in nearly all human genes for association with diseases.

Researchers found that test subjects with Crohn's disease were roughly fourfold less likely to have an SNP variation that alters an important amino acid of the IL-23 receptor gene.

More than 1 million Americans have Crohn's disease or ulcerative colitis. Because IBD tends to run in families and is more prevalent in certain ethnic populations, scientists have long suspected that there is a significant genetic component. A previous study, conducted in part at Hopkins, identified another gene mutation on the CARD15/NOD2 gene, common in people with Crohn's disease, but Brant says the new gene is a better candidate for drug treatments.

"IL-23 is directly linked to an inflammatory pathway, making it a better candidate for drug therapies than CARD15/NOD2," he says.

Brant says the team has identified additional gene variations potentially related to Crohn's disease, and the consortium will investigate these as well.

"As more genes associated with Crohn's disease are discovered, we envision a time when gene testing may provide important guidance regarding the prognosis and treatment of each patient," says co-author Themistocles Dassopoulos, M.D., an assistant professor of medicine at the Meyerhoff Inflammatory Bowel Disease Center.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases.

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Science Express, an online publication of the journal Science, on Oct. 26 (26-Oct-2006)