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Gene Flaw Suspected in Crohn's Disease

Mutation could dramatically raise risk for some

MONDAY, May 21, 2001 (HealthDayNews) -- A shortened version of a gene that helps the immune system supervise the gut's native bacteria is the prime suspect in at least some cases of Crohn's disease, new studies show.

In two independent efforts reported today in the journal Nature, researchers say they've discovered the flaw in the inherited gene, called Nod2, which helps the body distinguish between friendly and hostile microbes in the gastric tract.

A glitch in the gene, a distant relative of one in plants that helps flora defend themselves from bacteria, renders its protein product shorter. People with two flawed copies of it may be 17 times at risk for Crohn's.

"It's not clear exactly how this confers susceptibility, except that the gut bacteria that are there normally are driving the disease," says Dr. Charles Elson, a gut expert at the University of Alabama in Birmingham and chairman of the national scientific advisory committee for the Crohn's and Colitis Foundation of America. "This is more at the understanding-the-disease level than coming up with a new treatment in a few years."

Elson and other experts say Crohn's is probably tied to multiple gene errors, probably at least a dozen.

Crohn's disease is a painful, potentially debilitating disorder in which inflammation periodically attacks the lining of the small and large bowel, causing ulcers and erosion of the tissue, which can ultimately require surgery to repair.

Approximately 500,000 Americans have Crohn's disease, according to the Crohn's group. The malady has become more common in recent decades, perhaps reflecting changes in diet or environmental factors.

It has been known for some time that Crohn's has a genetic component. Studies of twins, which are extremely useful at establishing such connections, show that if one twin has the condition her sibling has about a 50 percent chance of also developing it. And people whose parent or sibling has the disorder have an 8 percent chance of also suffering from Crohn's, Elson says. The rate among the population at large is about one in 1,000 people.

In earlier work, scientists had narrowed the location of a potential susceptibility gene to chromosome 16. Now, teams of researchers in Europe and the United States have isolated the mutation and the protein it directs. That protein is Nod2, which helps white blood cells called monocytes distinguish between resident and invading bacteria by activating a chemical called nuclear factor NF-kB, which is important in regulating the inflammatory process.

"We think that this Nod gene may control this sort of surveillance of these normal bacteria that live in the bowel," says Dr. Gabriel Nuñez, a University of Michigan pathologist and co-author of one of the Nature papers.

The mutation leaves Nod2 about 3 percent shorter than usual, and it may confuse monocytes into turning on the gut's friendly bugs, sparking inflammation that destroys tissue in the area.

Nuñez and his colleagues looked for mutations in Nod2 in families with bowel problems as well as groups of people without the condition.

Patients with Crohn's were 50 percent more likely than healthy subjects to carry at least one mutant copy of Nod2, while those with two bad versions were about 17 times more likely to have the disease.

"What's very important now is to find out whether sporadic cases involve the same gene" as well, says Nuñez, who adds that it's possible that Nod2 mutations may merely modify the severity of bowel attacks but not cause them.

In the second study, led by Jean-Pierre Hugot, of Robert Debré Hospital in Paris, the researchers also linked abbreviated Nod2 to an increased risk of Crohn's. However, they write, "Genetic susceptibility to [the disease] is not limited to chromosome 16 and at least five additional loci have been implicated."

The latest finding should help scientists pinpoint those other instructions, Hugot's group writes. "It will also contribute to the identification of associated environmental factors and focus the search for specific therapies."

The researchers plan to discuss their findings this week at the Digestive Disease Week conference in Atlanta, Ga.

What To Do

This finding is a new road discovered, but it could take years to develop a usable therapy from it.

To find out more about Crohn's disease, visit the Crohn's and Colitis Foundation of America. You can also try Jackson Gastroenterology .

Read other HealthDay articles about Crohn's disease.

Visit Veritas Medicine to find out what experimental therapies are out there for Crohn's.

SOURCES: Interviews with Gabriel Nuñez, M.D., associate professor of pathology, University of Michigan Medical School, Ann Arbor; Charles Elson, M.D., professor of medicine, University of Alabama, Birmingham, and chairman, national scientific advisory committee, Crohn's and Colitis Foundation of America; May 31, 2001 Nature
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