Gene Link to Crohn’s Disease Found
Two teams of researchers have independently identified the first gene that triggers Crohn’s disease, a debilitating disorder of the gastrointestinal system that affects at least half a million Americans.
People with one copy of the defective gene--which alters the immune system’s response to bacteria in the gut--have twice the normal risk of developing Crohn’s, while those with two copies of the gene have 15 to 20 times the risk.
“Finding this crucial genetic clue gives us our first real insight into the complex causes and mechanisms of Crohn’s disease,” said Dr. Judy Cho of the University of Chicago, who presented one of the papers Monday at the Digestive Diseases Week meeting in Atlanta.
“We have long suspected that both genetics and the environment played a role,” she added. “This finally allows us to begin to understand how they work together to cause this disease.”
Both papers are scheduled to be published in the May 31 issue of Nature, but the journal has placed them online at https://www.nature.com.
The discovery is “a seminal achievement that provides hope for better treatments for patients suffering from Crohn’s disease,” said Dr. Stephen James of the National Institute of Diabetes, Digestive and Kidney Diseases. And it “is a shining example of how genetic research will help expand our understanding of complex diseases such as Crohn’s.”
Crohn’s is a chronic inflammatory disease that affects primarily the small intestine. It usually strikes people before they reach age 30, causing abdominal pain, diarrhea, fever and weight loss. Symptoms can be mild, but also can be so severe that victims are unable to leave their homes because of diarrhea. It strikes between 150 and 200 of every 100,000 people in Western countries and the incidence is thought to be rising significantly, possibly because of changes in diet.
The primary therapy for Crohn’s is suppression of the immune system with steroids and other drugs, but such treatment has limited effectiveness and many side effects. Some research has suggested that cocktails of antibiotics are useful in eradicating the intestinal bacteria that are thought to produce the disease. Clinical trials to test the approach are underway in the United States and Australia.
Other University of Chicago researchers reported Monday at Digestive Diseases Week that a new drug called Remicade, which reduces inflammation by inhibiting production of an immune system protein called tumor necrosis factor, is useful in reducing flare-ups of the disease, as well as for treating flare-ups when they occur.
The ultimate treatment is surgery to remove damaged sections of the intestine, but that does not prevent recurrence of the disorder.
The impetus for the discovery of the new gene came from Dr. Gabriel Nunez of the University of Michigan, who had been studying an immune gene called Nod1. When a draft of the human genome was released last year, he examined it and found a very similar gene, called Nod2, in a region of chromosome 16, where researchers knew a Crohn’s gene was located.
He contacted Cho, whose team had accumulated DNA from 416 families with a history of Crohn’s. Together, they found the defective Nod2 in about 15% of Crohn’s patients. The mutated gene also is present in about 8% of healthy people, indicating that it increases the risk of the disorder, but that other factors must also interact for the disease to occur.
The second team, led by Dr. Jean-Pierre Hugot of the Foundation Jean Dausset in Paris, studied 235 Crohn’s families and independently reached the same conclusion: that mutations in Nod2 leave people more susceptible to Crohn’s.
The findings “clearly demonstrate that Crohn’s disease is a genetic disorder,” Hugot said. “Now, we have a gene and we have a function. That gives us one piece more toward the discovery of a mechanism.”
