U of C scientist finds gene linked to long-term digestive tract disease

By Jennifer Bussell

University researchers have identified a gene linked to Crohn’s disease, a long-term inflammatory disease of the digestive tract that affects nearly half a million Americans. The team, headed by Judy Cho, professor in the department of medicine, and Gabriel Nunez of the University of Michigan, presented their discovery at a digestive disease meeting in Atlanta this week. Their study, along with that of an independent group of European researchers that found the same conclusion, will have papers published in the journal Nature on May 31.

“The main value [of this discovery] is in teaching us how the gene evolves and how the pharmaceutical corporations can use it to develop better therapies,” Cho said.

The researchers identified the gene, called Nod2, by examining the DNA of 416 families with a history of Crohn’s disease. They found a 15 percent incidence of the disease in those with a defective version of Nod2, compared to an eight percent incidence in healthy people.

Scientists are still not sure what causes Crohn’s disease, but they believe it to result from a combination of genetic and environmental factors. Crohn’s disease usually develops in individuals before they reach the age of 30, and involves diarrhea, abdominal pain, fever, and weight loss. “We know that one thing that causes it is these mutations in Nod2,” Cho said. “We know that there are at least three specific genetic variations in the proteins.”

The genetic variations that lead to the disease are called “risk alleles.” A person with one risk allele has a one to two-fold increased risk of developing Crohn’s, while someone with two risk alleles has a fifteen to twenty-fold increased risk. “Not all people with the gene defects get the disease,” Cho said. “It’s a combination of multiple genes plus the environment.”

The Nod2 gene produces a protein (also called Nod2) that is involved in the response of monocyte immune cells to bacteria. In the most dramatic of the three mutations of defective Nod2, the insertion of a single amino acid causes the protein to be truncated by three percent, preventing Nod2 from recognizing harmful bacteria in the intestine. “The truncated version does not react normally to bacteria,” Cho said. “This may cause overreaction on the part of the cell or the whole organism to cause inflammation.”

The impetus for the research came when Nunez contacted Cho in order to collaborate on an investigation of the DNA she had collected. Nunez was investigating the Nod1 immune gene, but when the human genome sequence was released last year, he found the similar Nod2 gene on chromosome 16. “We’ve been collecting DNA for this project since 1995,” Cho said.

A team led by Dr. Jean-Pierre Hugot of the Foundation Jean Dausset in Paris conducted research in 1996 indicating that a gene for Crohn’s disease was localized in chromosome 16. Hugot’s team was trying to identify the gene using the positional approach, which Cho calls a “very long process.”

“With the completion of the human genome sequence, they probably could have gotten this work done a lot faster,” Cho said.

Hugot’s team presented the same conclusion as Cho’s at this week’s Atlanta meeting and will also publish in the May 31 edition of Nature. “This was a classic case of two independent groups,” Cho said.

Cho and Nunez identified Nod2 using the “candidate gene approach,” which involves genome mapping, to find linkage between a gene and Crohn’s disease in the region initially described by the French group.

Though the researchers have linked Nod2 to an increased incidence of Crohn’s disease, they caution against the assumption that the gene is a direct cause. “This is just one of many genes,” Cho said. “These are complex disorders. We hope that finding the first gene will help in finding other genes. We are not recommending that unaffected family members [of those with Crohn’s disease] be tested. We are in the process of setting up research protocols to start testing who should be tested.”

Between 150 and 200 out of every 100,000 people in the Western hemisphere develop Crohn’s disease. The disorder is often treated with steroids, dietary supplements, or surgery to remove the diseased part of the intestine.

A paper presented at the Atlanta conference by Stephen Hanauer, University professor in the department of medicine, reports that Remicade, an expensive new intravenous drug, may be able to treat Crohn’s disease in the long-term without the side effects of steroids.

Hanauer found that after 30 weeks of treatment with the drug, 45 percent of patients receiving a high dose were free of symptoms, as compared to 39 percent of those receiving a low dose of Remicade and 21 percent of those receiving a placebo.

Remicade was approved in 1998 for short-term treatment of Crohn’s, but the new research indicates that it may also be effective in the long-term.

Remicade reduces the inflammation of the digestive tract by inhibiting production of the immune system protein tumor necrosis factor. This enables it to both treat and prevent the inflammation caused by the disease.

The steroids currently used in long-term treatment suppress the entire immune system and may cause acne, weight gain, facial hair, diabetes, cataracts and osteoporosis.

The side effects developed by patients in the Remicade study were less serious than those associated with steroids. They included hives or other allergic reactions, though there is a small chance of patients developing tuberculosis or sepsis.

Hanauer’s study of 573 patients was founded by Remicade’s manufacturer. The 58 percent of those helped by a first dose continued taking the drug in a low or high dose or a placebo for 30 weeks.

A two-hour IV treatment of Remicade for a 155-pound patient costs approximately $1700. This is necessary once every eight weeks and does not include nursing costs.