First Crohn's Disease Gene Identified

N E W   Y O R K, May 21, 2001 -- Researchers say they have identified the first genetic abnormality associated with Crohn's disease, a finding that should help doctors better understand the devastating gastrointestinal disorder and lead to new drugs to treat it.

Crohn's disease is a serious inflammation of the gastrointestinal tract, causing diarrhea, crampy abdominal pain, fever, and at times rectal bleeding. Loss of appetite, weight loss and hospitalizations can also occur.

The disease, which currently affects about 500,000 Americans, is chronic. Most cases are diagnosed before age 30, but the disease can also be seen in the elderly. Episodes recur even after patients take medication, which usually tries to control the symptoms of inflammation.

The number of new cases has been increasing, reflecting changes in the environment and lifestyle, scientists say. The disease tends to cluster in families suggesting that genes play an important role.

Researchers believe faulty responses in Crohn's patients to microbes that live in the stomach may somehow trigger the immune system to attack the intestinal lining, causing it to ulcerate and break up.

Gene on Chromosome 16

Many genes are believed to be responsible for Crohn's disease. In 1996, researchers first reported that a susceptibility to the disorder mapped to a location on human chromosome 16.

Today researchers, from two groups, one European and the other American, are reporting they identified a specific gene, called Nod-2 on chromosome 16 that seems to be associated with the disease in approximately 15 percent to 20 percent of Crohn's patients.

The findings are published in two articles in the May 31 issue of the scientific journal Nature. The results are being reported early at a meeting today of the Digestive Disease Week Conference in Atlanta.

"Finding this crucial genetic clue gives us our first real insight into the complex causes of Crohn's disease,' says American study co-author Dr. Judith Cho, assistant professor of medicine and a researcher in the Martin Boyer Laboratories at the University of Chicago.

"We have long suspected that both genetics and environment played a role. This finally allows us to begin to understand how they work together to cause this disease."

European and American Groups Identify Same Gene

The American group analyzed 413, and the European group 179 Crohn's disease patients chosen from hundreds of families.

The Americans found a shortened version of the protein coded for by the Nod-2 gene was associated with the disease. The Europeans found that changes in a similar region of the protein (and gene) were related to the disease.

The finding, the researchers say, connect the disease with a primitive arm of the immune system known as the "innate" or non-specific immune system in the body. Nod-2 encodes a protein found in monocytes, or cells that can detect and engulf foreign invaders.

The Nod-2 protein helps the monocytes recognize and respond to the presence of lipopolysaccharides, a component of the outer cell wall of certain types of bacteria.

Gene Affects Bacteria Identification

The American group found that the truncated protein in test tube experiments did not respond well to the bacterial cell wall to stimulate the inflammation pathway.

The authors theorize that this deficit in the early immune response may result in an exaggerated inflammatory or immune response by the more sophisticated immune system that targets specific antigens, or specific foreign entities, with T and B cells and antibodies.

In Crohn's disease patients, the authors suggest, the specific immune system attacks the bacteria in the gut inappropriately. More research, however, needs to be done to understand how this might happen.

"By providing clues to disease pathways," Cho says, "and directing us to related proteins the identification of the Nod-2 mutations may accelerate the process of finding subsequent Crohn's disease-associated mutations."

By understanding how these genes interact with each other and the environment, Cho says new treatments can be developed, which ultimately may also be targeted better to specific patients.

No Screening Yet, But Drugs May Come Sooner

"We may be able to define which strains of intestinal bacteria interact with Nod-2 to increase or decrease intestinal inflammation," she says.

Nod-2 is related to a gene found in plants that provides resistance to bacteria.

Cho says the gene should not be used to currently screen for Crohn's disease because people who are not affected also carry the mutation. Other genes that also play a role in the disease have yet to be identified before screening can be done.