Tracking the Crohn's gene

The 500,000 Americans who suffer from Crohn's disease can vouch that it's a pain in the you-know-where. A chronic gastrointestinal inflammation, Crohn's can cause stomachaches, diarrhea, fever, and weight loss. Although a cure is still a long time coming, researchers are beginning to understand the disease's genetic causes.

In summer 2000 Judy Cho, assistant professor of medicine, led a hunt for shared genetic mutations among 416 families with histories of Crohn's disease. The search was successful: in the May 31 Nature Cho's team identifies mutations of the immune-system gene Nod2 as a source of Crohn's. Patients whose dna contain one copy of a mutated Nod2 were twice as likely to develop Crohn's as patients with normal Nod2s. Patients with two copies were 15 to 20 times more susceptible.

Cho's hunt goes back to 1996, when she pinpointed chromosome 16 as a probable location of a Crohn's disease gene. In summer 2000, she joined forces with University of Michigan pathologist Gabriel Nuñez, who studies Nod1, a gene which, like Nod2, alerts the immune system when bacteria are present. The Nod2 gene, Nuñez noticed, lies on chromosome 16-and might be their culprit. Indeed, in 15 percent of Crohn's patients they studied, the Nod2 gene is 3 percent shorter than normal. The protein produced by that truncated gene is less effective at identifying bacteria and less reliable in signalling the immune system. This defect clearly played a role in the bacteria-induced inflammation characteristic of Crohn's.

Currently, doctors prescribe medications to control the inflammation and relieve other Crohn's symptoms. The identification of Nod2 suggests that doctors can treat the disease, or maybe even end it, by administering medication that corrects the irregularities in patients' mutated Nod2 genes. "It provides a completely new target for drug companies," says Cho-though she cautions that devising and perfecting such treatment "is going to take a while." A mutation increases susceptibility to Crohn's, but, Cho admits, "we don't think it's going to be useful as a predictive test. Most people who inherit these variants will not get Crohn's."

Crohn's appears to stem from a combination of environmental and genetic factors, and its causes and symptoms vary among patients. Cho's discovery is a long-awaited step forward.- Lucy Beiderman

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