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Scientists Pinpoint Gene Behind Autoimmune Diseases

'Hot signal' on chromosome 17 could be target for therapies against lupus, other disorders

WEDNESDAY, March 21, 2007 (HealthDay News) -- Variations in one specific gene appear to be behind several different autoimmune and auto-inflammatory diseases.

The pinpointed region of chromosome 17, called NALP1, could be a new target for treatment, said the authors of a study in the March 22 issue of the New England Journal of Medicine.

"This part of the immune system may respond to triggers coming from the environment, like bacteria or viruses, and there are indications that you can turn it off. So, we're very, very hopeful that there may be drugs that allow us to do that," said the study's senior author, Dr. Richard A. Spritz, who directs the Human Medical Genetics Program at the University of Colorado at Denver and Health Sciences Center.

Spritz added, "That's not going to help people with childhood diabetes, where the damage is already complete. But, for a number of chronic autoimmune disorders, like lupus and vitiligo, if you turn off the autoimmune process, the body could repair itself."

Some 80 autoimmune and auto-inflammatory disorders, which occur when the immune system malfunctions and starts destroying normal tissue, affect between 15 million and 25 million people in the United States, particularly women.

A few of the autoimmune diseases are caused by mutations in single genes, but most appear to be more complex. Scientists suspect that some genes may predispose individuals to one or more diseases, whereas other genes may predispose individuals to autoimmune and auto-inflammatory diseases in general.

"There has been a feeling for decades that autoimmune diseases are somehow related," said Dr. Peter Gregersen, author of an accompanying editorial in the journal and director of the Robert S. Boas Center for Genomics and Human Genetics at the Feinstein Institute for Medical Research in Manhasset, N.Y.

Interactions between gene variants and environmental factors also play a role in triggering the onset of a disease.

Spritz and his colleagues have long focused on patients with vitiligo, a disorder in which pigment cells are destroyed, resulting in white patches on the skin and sometimes the hair. Individuals with vitiligo tend also to have other autoimmune and auto-inflammatory diseases, as do their relatives. But the combinations of diseases are not very consistent.

"They probably have genes that predispose more toward autoimmunity in general and not specific disorders," Spritz said.

The team did a systematic genetic analysis of 656 persons from 114 extended families in the United States and United Kingdom who had multiple autoimmune diseases, including vitiligo. This led them to a number of genetic possibilities, but the "hottest" signal was a region on chromosome 17, which had shown up previously as possibly harboring a lupus gene in families who also had vitiligo.

A closer examination revealed a collection of variations in a specific gene, NALP1.

"We don't really know which one causes the disease, but we can use the variations that we see as flags or markers of variations," Spritz explained. "These could be the ones that cause the disease or tell us about the ones that do."

But NALP1 is probably only part of the picture.

"This can't be the whole story," Spritz said. "This is one of probably many genes that predispose to autoimmunity, but it looks like it may be involved in a pretty big way, which is why we were able to find it."

The gene is connected to the body's primitive immune system, which is involved with the earliest responses to outside attacks.

"It probably has a big effect, and it probably interacts in some complex way with other genes and other risk factors," Spritz pointed out. "We know a lot about this gene. It was not an anonymous gene that you would have to start from ground zero studying. We know that it's part of the surveillance system for attack by bacteria or viruses, part of the innate immune system."

"This work is really nice and elegant, and it's also provocative," Gregersen said. "It raises the issue of whether this gene might be involved in more common disorders."

He added that the research was a good example of "a successful, family-based approach to gene identification and an example of how new genes identified that way can raise new connections among different diseases."

More information

The U.S. National Library of Medicine has more about autoimmune disorders.

SOURCES: Richard A. Spritz M.D., director, Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora; Peter K. Gregersen, M.D., director, Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, North Shore Long Island Jewish Health System, Manhasset, N.Y., and professor of medicine and pathology, New York University School of Medicine, New York City; March 22, 2007, New England Journal of Medicine
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