Genetic flaw found in painful gut disease.

Because roughly one in five people with Crohn's disease has a close relative who shares the illness, scientists have long suspected that the digestive disorder has an inherited component. Now, after years of genetic sleuthing, two independent research teams have identified a gene, called Nod2, that is mutated in many people with the disease.

This discovery and other research suggest that a defective protein encoded by the mutated gene induces immune cells to damage intestinal tissues.

Crohn's disease causes inflammation primarily in the small intestine, but it can attack any part of the digestive tract. In Western countries, the disease strikes 1 to 3 people per 1,000. Although it's seldom fatal, the disease causes chronic diarrhea, internal bleeding, and abdominal pain. Prolonged inflammation can ulcerate the intestinal lining and require surgery.

Anti-inflammatory drugs alleviate some symptoms, but there is no cure.

Research groups in Europe and the United States investigated a region on chromosome 16 where earlier research had found signs of a genetic flaw in some people with Crohn's disease.

Gilles Thomas, a medical geneticist at the Jean Dausset Foundation in Paris, and his colleagues examined blood samples from 179 people with Crohn's disease and from 261 of their relatives who are free of the disease. Inspection of chromosome 16 revealed that those with Crohn's were significantly more likely than the others to have the aberrant version of Nod2.

In the other new study, scientists at five U.S. research institutions sampled 416 people with Crohn's disease. People in this group were much more likely than their disease-free relatives to have the mutated Nod2 gene.

Both studies appear in the May 31 NATURE.

Having a single copy of the mutated Nod2 renders a person two to three times as likely to get Crohn's disease as is someone with a normal pair of Nod2 genes, says Gabriel Nunez, a pathologist at the University of Michigan in Ann Arbor and a coauthor of the U.S. study. People with two mutated copies of the gene have a 20- to 30-fold greater risk of developing Crohn's than people without a mutation, he says.

The precise mechanism underlying this increased risk remains hidden.

The Nod2 gene encodes a protein, dubbed Nod2, that is produced mainly by the white blood cells called monocytes. It may be that Nod2 is a bacteria-sensing protein that signals a cell when harmful microbes are present and merit an immune response, says Charles O. Elson, a gastroenterologist at the University of Alabama at Birmingham and chairman of the National Scientific Committee of the Crohn's and Colitis Foundation of America.

As such, Nod2 appears to be part of a primitive defense network of proteins that are "genetically hardwired to help us resist microbes," he says.

However, defective Nod2 encoded by the mutated gene may lose its capability to tell good bacteria from bad, he says. In some people, this loss could permit the immune response to go awry in the gut, causing the prolonged inflammation and intestinal damage that marks the disease, he says.

Besides faulty genes, bacteria in the gut and other environmental factors probably play a significant role in Crohn's disease. For example, when one identical twin has the disease, the chances of the other getting it are less than 50 percent, Elson says. That indicates that genetic predisposition, while important, doesn't strictly determine whether someone gets the disease, he says.

The researchers have already found other variations of Nod2, although they don't yet know what effects these may have. The abnormalities might influence the different ways that people with Crohn's disease respond to anti-inflammatory drugs, Thomas says.