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Severe lupus has a genetic signature
By Adam Marcus

Researchers have identified fourteen genes that doctors could potentially use to predict the severity of lupus, a debilitating disorder in which immune cells attack the skin, blood, joints and other organs. Each of the fourteen genes appears to be controlled by a family of proteins, known collectively as interferon, that play a role in lupus.

People with severe lupus, who make up about half of all cases, suffer life-threatening flare-ups in the kidneys, heart or brain. Doctors have long wanted a tool to predict which patients are most vulnerable to flare-ups, and where these episodes might occur. The newly identified genes, discovered using 'gene chip' technology, could help.

"We're hoping to use the data from the gene chips to see if we can predict when patients are going to have flares of their disease or maybe have other complications of lupus," says Timothy Behrens of the University of Minnesota, who led the study.

The use of gene chips in lupus is still experimental, but the technology—glass slides or microchips containing DNA—has been used to assess cancers, including breast tumors and lymphomas.

"We are going to see gene [screening] in the clinical realm, to make an early diagnosis or to make sure of the diagnosis," predicts Michelle Petri, a lupus expert at Johns Hopkins University School of Medicine in Baltimore.

The work could also lead to new therapies for the disease, which hasn't seen a new drug in 25 years. Indeed, Behrens has already been contacted by drug companies interested in designing chemicals to block interferon or receptors on cells that respond to the proteins.

In the study, which appears in Proceedings of the National Academy of Sciences, the researchers analyzed blood from 48 lupus patients and 42 healthy individuals. A total of 161 genes were either more or less active in patients than in the healthy group.

Fourteen of the genes were more active in the patients with severe lupus. Since interferon controls them, the scientists call the cluster the "interferon expression signature" (IFN).

Lupus, or systemic lupus erythematosus, affects about a half-million Americans, and potentially millions more worldwide. Like other 'auto-immune' diseases, lupus primarily affects women, though the reasons for this are not well understood. Drugs can treat the condition, but there is no cure and the disease worsens over time.

Previous research has shown that people with severe lupus tend to have increased levels of interferon. But the amount in blood is so small that testing is difficult and unreliable. Gene chips can get around this problem.

"You see [interferon at work] so easily in the genes being expressed in the blood cells," says Behrens. "I think it's going to be a lot more reliable" than conventional blood tests.

"One could envision having a small chip with a small number of genes that could tell us if this interferon profile is there," says Peter Gregersen, director of the center for genomics and genetics at North Shore Long Island Jewish Research Institute, in Manhasset, New York, and a co-author of the study.

Gregersen is already working with other colleagues on ways to use gene chips to classify patients with rheumatoid arthritis, another autoimmune disease. They hope to generate a gene signature that will predict a person's chance of responding to therapies that help only a limited number of patients.

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Baechler, E. et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA Published online February 10, 2003.

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