Mutation in gene may play role in Crohn's

It may protect against disease

new treatments possible

October 27, 2006|By Michael Stroh | Michael Stroh,Sun Reporter

An international scientific team, including a group from the Johns Hopkins University, has pinpointed an unexpected gene mutation that appears to confer protection against Crohn's disease in some patients.

The finding potentially paves the way for new diagnostic tools and drugs to treat the debilitating intestinal condition, which affects more than 500,000 people in the U.S.

"This is an exciting piece of work," said Dr. Scott Snapper, a Crohn's disease researcher at Massachusetts General Hospital in Boston who was not involved in the study.

Crohn's disease is a chronic inflammation primarily of the small intestine. The ailment, typically diagnosed before age 30, causes diarrhea, abdominal pain, bleeding and weight loss. In some cases, the diarrhea and cramping can be so excruciating that patients are unable to leave home.

"Once you get it, you pretty much have it for life," says Dr. Steven Brant, director of the Meyerhoff Inflammatory Bowel Disease Genetics Laboratory at Johns Hopkins and a co-author on the paper, which appeared yesterday in the online edition of the journal Science.

The origins of Crohn's, one of several conditions known collectively as inflammatory bowel disease, is a mystery.

First described by American gastroenterologist Dr. Burrill B. Crohn in 1932, the condition is widely considered to be an autoimmune disease that arises when the body's immune cells launch an assault against harmless, naturally resident intestinal bacteria.

From epidemiological research and studies of identical twins, scientists know the disease is strongly influenced by genetics: Crohn's runs in families and is more common in certain ethnic populations, such as the Ashkenazi Jews of central and eastern European ancestry.

One such family in a Crohn's registry created by Hopkins researchers has 18 affected members, notes Brant.

In 2001, scientists identified the first major gene underlying Crohn's disease. Called Nod2, the gene regulates the immune system's response to bacteria in the gut. People with one flawed copy have twice the normal risk of developing the disease, researchers found. Two flawed copies and the risk jumps 20- to 40-fold.

Researchers have since uncovered a handful of other suspicious gene mutations thought to play a role in inflammatory bowel disease. But the new finding marks the first time researchers have identified a mutation that may actually help protect against Crohn's.

To find it, scientists sifted through the DNA of more than 550 volunteers with Crohn's, looking for tiny variations in more than 300,000 locations along the DNA molecule.

Scientists then compared the results with variations -- known as single nucleotide polymorphisms -- at the same locations in a similar number of healthy volunteers.

This comparison helped them pinpoint specific genes that are strongly associated with the condition.

Their strongest hit was a gene that codes for immune cell receptors to interleukin-23 -- a protein that regulates inflammation and helps the body fight bacterial infections.

Patients with Crohn's disease were roughly one-fourth as likely to have the variation found in healthy patients, leading researchers to conclude that it was somehow protective.

Initially, the discovery will mostly benefit drug companies, says senior author Dr. Judy Cho of Yale University. "There's no lack of drug targets for Crohn's disease. This helps the companies prioritize."

Currently, treatment options for Crohn's are relatively limited. Doctors typically attempt to suppress the immune system with steroids and other drugs. One of the most potent is Remicade, which blocks production of the inflammatory immune system protein called tumor necrosis factor.

But these drugs can have numerous side effects, and about half of all Crohn's patients eventually need to have part of their colon surgically removed, says Hopkins' Brant.

Some companies are already exploring new treatments based on IL-23. Centocor, a Pennsylvania-based subsidiary of Johnson & Johnson, is conducting clinical trials on a compound that blocks the IL-23 pathway.

But Cho cautions that scientists may have to tread carefully, since tinkering with the body's natural inflammation response could boost a person's infection or cancer risk.

"We don't know what the 20-year effect is," she says.

michael.stroh@baltsun.com

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