Researchers discover mutations that increase risk of Crohn’s

Judy Cho, Assistant Professor in Medicine

A team of researchers at the University, the University of Michigan and others has identified the first genetic abnormality that increases susceptibility to Crohn’s disease.

In the May 31 issue of Nature, the researchers reported that mutations of 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.

“Finding this crucial genetic clue gives us our first real insight into the complex causes and mechanisms of Crohn’s disease,” said study co-author Judy Cho, Assistant Professor in Medicine and a researcher in the Martin Boyer Laboratories at the University. “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.”

“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,” said co-author Gabriel NuÒez, associate professor of pathology at the University of Michigan and a researcher at Michigan’s Comprehensive Cancer Center. “The discovery of Nod2 may explain this missing-link connection between genes and bacteria.”

Stephen James, deputy director of the Division of Digestive Diseases and Nutrition at the National Institute of Diabetes and Digestive and Kidney Diseases said, “This discovery is a shining example of how genetic research will help expand our understanding of complex diseases such as Crohn’s. It’s a seminal achievement that provides hope for better treatments for patients suffering from the disease,” he added.

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. Symptoms range from mild to severe.

The cause is unknown. Although everything from diet to emotional stress has been suggested, the prevailing theory is that in patients with Crohn’s disease, 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.

The disease tends to cluster in certain families, suggesting that genes play an important 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 lipopolysaccharide, a component of the outer membrane of certain types of bacteria.

Cho, NuÒez 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 NuÒez. “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 subsequently 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 people with Crohn’s disease have the altered form of the gene. Having one copy doubles the risk of Crohn’s disease. Having two copies increases the risk 15 to 20 fold.

The discovery is a good example of the benefits to be expected from the completion of the Human Genome Project. NuÒez, a specialist in programmed cell death, was initially interested in Nod1. When he scanned the Web-based human genome databases for similar genes, he uncovered a very closely related gene, Nod2, located in the precise genomic region previously implicated as containing a Crohn’s disease gene.

NuÒez contacted Cho, who, together with investigators at the University of Pittsburgh and Johns Hopkins University, had acquired a large repository of DNA from families with the disease. Together they determined that mutations of Nod2 increased the risk of Crohn’s disease and how the mutation altered the protein’s function.

This is just the first of several genes that increases risk for Crohn’s disease, noted the authors.

“By providing clues to disease pathways,” said Cho, “and directing us to related proteins, the identification of Nod2 mutations may accelerate the process of finding subsequent Crohn’s disease-associated mutations. If we can figure out how these genes interact with each other and the environment,” she added, “we may someday be able to develop better treatments as well as determine which treatments will work best in which patients. We may be able to define which strains of intestinal bacteria interact with Nod2 to increase or decrease intestinal inflammation.”

Additional authors of the paper from the University are Denise Bonen, Research Associate and Assistant Professor in the Gastroenterology Section in Medicine; Dan Nicolae, Assistant Professor in Statistics; Richard Ramos, Research Technician in Medicine; Heidi Britton, Research Technician in the Inflammatory Bowel Disease Center; Thomas Moran, Research Technician in the Inflammatory Bowel Disease Center; Reda Karaliuskas, Project Coordinator, Barbara Kirschner, Professor in Pediatrics; and Steven Hanauer, the Gastrointestinal Research Foundation Professor in Medicine.