The University Record, June 4, 2001

Team of researchers finds first gene that increases risk of Crohn’s disease

By Sally Pobojewski
Medical School Communications

A team of researchers from the U-M, the University of Chicago and other institutions has identified the first genetic mutation that increases susceptibility to Crohn’s disease.

In the May 31 issue of Nature, the researchers report that mutations in Nod2, a gene involved in the immune system’s initial response to bacterial infection, significantly increase the risk of Crohn’s disease. A companion paper by French scientists in the same journal confirms the link in a different group of patients. This is just the first of several genes that increases the risk for Crohn’s disease, the authors note.

“It has been known for a long time that there is an important link between bacteria residing in the gut and genetic factors for the development of Crohn’s disease,” says co-author Gabriel Nuņez, U-M associate professor of pathology. “The discovery of Nod2 may explain this missing-link connection between genes and bacteria.”

“Finding this crucial genetic clue gives us our first real insight into the complex causes and mechanisms of Crohn’s disease,” says study co-author Judy 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 the environment played a role. This finally allows us to begin to understand how they work together to cause this disease.”

Crohn’s is a chronic inflammatory disease of the gastrointestinal tract, usually the small intestine. It affects about 500,000 people in the United States, most often before age 30, causing abdominal pain, diarrhea, fever and weight loss.

The cause is unknown. Although everything from diet to emotional stress has been suggested, the prevailing theory is that the intestinal immune system overreacts to viral or bacterial agents and initiates an ongoing, uncontrolled inflammation of the intestine. Treatments are based on controlling inflammation through suppressing the immune response.

Crohn’s disease tends to cluster in certain families, suggesting that genes play a role.

This finding connects the disease with an arm of the immune system known as the innate immune system. The Nod2 gene is predominantly found in monocytes, primitive defensive cells that can detect and engulf invaders. Nod2 encodes a protein that helps the innate immune system recognize and respond to the presence of lipopolysaccharides, a component of the outer membrane of certain types of bacteria.

Cho, Nuņez and colleagues found that the mutated forms of Nod2 were truncated; about 3 percent of the protein was missing. This altered version of the protein was much less effective in recognizing the bacterial components and triggering the release of chemical signals that launch an immune response.

“Nod2, and the closely related Nod1, appear to function as intracellular receptors for lipopolysaccharide,” said Nuņez. “They are involved in the innate immune system’s response to bacterial components. We found that the truncated version of Nod2 is much less responsive to the presence of these bacterial components.”

How a less responsive immune system triggers inflammation is unclear. The authors theorize that this early deficit in sensing bacteria by the innate immune system might result in an exaggerated inflammatory response by the adaptive immune system, which reacts more slowly but produces very targeted weapons against invaders and retains a lasting “memory” of prior infections.

It is clear, however, that the mutations play an important role in the development of Crohn’s disease. About 8 percent of Caucasians have one abnormal version of Nod2. About 15 percent of Crohn’s patients have the altered form of the gene. Having one copy doubles the risk of Crohn’s disease. Having two copies increases the risk 15–20 times.

Other U-M researchers involved in the project include Yasunori Ogura, research fellow; Naohiro Inohara, assistant research scientist; and Felicia Chen health science research associate.