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After a Crohn's Gene, Then What?

By Anna Gillis

On the Front Page...

Shortly after the press announced the discovery of the first gene linked to Crohn's disease, Dr. Judy H. Cho started getting calls. Since May "there's been a small flurry of people wanting to get tested," says Cho, a researcher at the University of Chicago Hospitals.


NIH grantees Cho and Dr. Gabriel Nuņez of the University of Michigan's School of Medicine made the connection between the gene called Nod2 and the debilitating digestive disease and published the results in the May 31 issue of Nature. Cho, who had collected DNA from 416 families with Crohn's disease, began collaborating with Nuņez after he contacted her with his findings on Nod2. Nuņez had been looking for genes that were similar to Nod1, which he was studying. Using public database information resulting from the Human Genome Project, he found Nod2 and learned it was on chromosome 16 in an area previously associated with Crohn's disease.

Having one flawed copy of the gene doubles a person's chances of developing Crohn's, an autoimmune disorder that affects 500,000 people in the United States. Having two copies can increase the risk 15 to 40 fold. Three different mutations can bring on the disease. If these genetic variants did not exist, the prevalence of Crohn's disease would be 15 to 20 percent lower.

Pleased that the Human Genome Project database made it possible to link Nod2 and Crohn's, Dr. Stephen James, deputy director of NIDDK's Division of Digestive Diseases and Nutrition, points out that the flipside is "more and more, we will find genes and not know why the mutation matters."

After all, having a mutated Nod2 does not guarantee that the disease will develop, and there are probably other genes with roles. "Crohn's is like diabetes in that mutated genes are not enough to bring on the disease. A significant fraction of healthy people carries the Nod2 risk alleles. It's definitely a combination of factors," Cho says. Without a clear-cut, single cause for Crohn's, Cho says she's "not excited about using Nod2 as a predictive tool, though it will probably happen." When her callers ask, she does not recommend testing outside a research setting.

Instead, Cho sees Nod2 as a useful tool to understand what factors work together to bring on the disease. "Because most people with a Nod2 mutation don't get the disease, it has to be a subtle perturbation [at work]," says Cho.

In Crohn's, the immune system attacks the digestive tract, causing abdominal pain, cramping, diarrhea, rectal bleeding and sometimes holes in tissue. The prevailing theory has been that the intestinal immune system overreacts to bacteria or viruses and starts an uncontrolled inflammation of the intestines. "What we've seen is 180 degrees different," says Cho. The shortened protein produced by the mutated gene was less effective in recognizing lipopolysaccharides, components in bacterial membranes, and in triggering the release of the substances that launch an immune response.

So, how is a less responsive immune system triggering inflammation? Frankly, the researchers don't know. Nuņez's group reported in the Feb. 16 issue of the Journal of Biological Chemistry that Nod2 is expressed in monocytes, cells that engulf bacteria and other invaders to the body. The group suggested that normal protein reacts with lipopolysaccharides and then signals activation of nuclear factor kappa B, a substance that in turn stimulates output of cytokines, proteins that regulate the intensity and duration of immune responses.

Monocytes, the body's first line of defense, are part of the innate immune system. "The innate immune system is ancient," says Cho. "What it does is recognize a pattern, a broad class of molecular patterns." Cho and Nuņez speculate that the adaptive immune system, which is more advanced and includes B and T cells, overreacts when the innate immune system fails to respond to the bacteria.

The findings highlight the importance of the innate immune system, says James. The innate immune system has always been important in the study of plant resistance to disease, but in animal studies, innate immunity became less important in the 1970s when researchers began looking at specific, or adaptive, immunity. In the past 4 or 5 years, there's been a renewal of interest, adds Cho. Interestingly, the human Nod2 gene has a counterpart in tomatoes that allows the plants to fight off Cladosporium fulvum, a fungus that causes tomato leaf mold.

Besides helping unravel the disease, Nod2 may be useful in the creation of novel compounds that go beyond treating symptoms, says Cho, whose lab will begin studying how monocyte-derived cells respond to drugs.

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