Genetic Mutation Increases Risk of Crohn's Disease

Nod2 Gene is Key

Researchers from the University of Michigan Medical School have identified a genetic mutation that increases the risk of Crohn's disease. The discovery provides the first insight into the complex causes and mechanisms of this chronic condition.

U-M scientist Gabriel Nuñez, M.D., with researchers from four other institutions, found that mutations in Nod2, a gene involved in the immune system's initial response to bacterial infection, significantly increased susceptibility to Crohn's disease. Having one copy of the mutated gene doubled the risk of Crohn's disease. Having two copies increased the risk 15- to 20-fold.

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 and tends to cluster in families. Symptoms include abdominal pain, diarrhea, fever and weight loss. The cause is unknown, but most scientists think the immune system over-reacts to viruses or bacteria in the intestine triggering an ongoing, uncontrolled inflammation.

"There is an important link between bacteria in the gut and genetic factors related to Crohn's disease," said Nuñez, an associate professor of pathology in the U-M Medical School and a scientist at the U-M's Comprehensive Cancer Center whose laboratory originally identified Nod2. "Nod2 could explain this missing-link connection between genes and bacteria."

The Nod2 gene is expressed predominantly 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 a molecule found in the outer membrane of certain types of bacteria.

Working with co-author Judy Cho, M.D., of the University of Chicago, Nuñez found that mutated forms of Nod2 lacked about three percent of the protein found with normal versions of the gene. The mutated gene was less effective at recognizing bacteria and triggering an immune response. So how does a less effective immune response by the gene trigger an over-active immune response in the gut? At this point, Nuñez, Cho and their collaborators say they have more questions than answers. More research will be needed to solve the puzzle.

U-M members of the research team included Yasunori Ogura, Ph.D., Naohiro Inohara, Ph.D. and Felicia Chen. The research was funded by the National Institutes of Health, the Crohn's and Colitis Foundation of America, the Scaife Family Foundation, the Meyerhoff IBD Center, the Logan Foundation and the Gastrointestinal Research Foundation.

- Sally Pobojewski

Read the complete story on the Web at:
www.med.umich.edu/opm/newspage/crohns.htm

See Gabriel Nunez's Web page at:
www.pathology.med.umich.edu/faculty/Nunez/biosketch.htm

For patient information on Crohn's disease, visit:
www.niddk.nih.gov/health/digest/pubs/crohns/crohns.htm