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Scientists pinpoint susceptibility gene for lupus
By Nancy Touchette

For the first time researchers have identified a gene that underlies the development of lupus, a devastating immune system disease. The disease appears to run in families, but until now no genes had emerged as clear risk factors. Now, a variant of a gene on chromosome 2, called programmed cell death 1 gene (PDCD1), appears to contribute to the disease in some lupus patients.

"This is a major advance," says John B. Harley, who studies lupus genetics at the University of Oklahoma in Oklahoma City. "We can only hope that it brings us closer to the day when this disease is understood."

Systemic lupus erythematosus, which affects mostly women, occurs when the immune system begins to attack the body's own cells. The disease can cause mild symptoms such as inflammation, joint pain, fever, and skin rashes or life-threatening kidney and blood-clotting problems.

Many genes—perhaps dozens—may be associated with lupus. Regions on chromosomes 1, 2, 6, and 11 are already thought to play a role in the disease. It is not known whether many mutations contribute to lupus or whether different forms of the disease are associated with different genetic mutations.

Marta E. Alarcon-Riquelme of the University of Uppsala in Uppsala, Sweden, and her collaborators recently found the gene using DNA from families with a high incidence of lupus. The gene was previously thought to reside on part of chromosome 2. They knew from the map of the human genome the identity of 8 genes in this region. One of these genes, called PDCD1, was an obvious candidate because it codes for a protein in immune cells.

The researchers checked for mutations in the PDCD1 gene in more than 2,500 individuals. They found that a single base pair was altered in 12 percent of the European family members and seven percent of Mexican family members with lupus. Members of African-American families with the disease did not harbor the mutation. Their findings appear in Nature Genetics.

"You're only as good as your map," says Harley. "Alarcon-Riquelme knew what sites to look for. She considered each gene in turn and found a mutation for which she could construct a plausible mechanism. It's a dream come true."

The genetic variation occurs in a region of the gene outside the part that codes for a protein sequence. The variant lies in a non-coding region that binds a protein involved in regulating the activity of the PDCD1 gene.

"The PDCD1 protein normally inhibits the activation of immune cells and keeps immune cells from dividing," says Alarcon-Riquelme. This should keep immune cells in check. "When PDCD1 is doing its job, B cells stop producing antibodies and this bad cycle comes to an end."

When the PDCD1 gene is mutated, however, the cycle continues, and the rogue antibodies go on to attack the normal cells of the body, according to Alarcon-Riquelme.

Experiments in mice also support the notion that the PDCD1 gene plays a role in lupus. Mice born without the rodent version of the gene develop lupus-like symptoms.

As yet undiscovered environmental factors probably play a role lupus. In the present study, five percent of the general population without the disease also had the mutation. And 7 percent of Mexican families with lupus harbored the mutation compared to two percent of control subjects. This indicates that the mutation alone does not necessarily cause the disease.

Geneticists have been studying lupus for decades with little headway, but Harley predicts more advances will come from the sequencing of the human genome. "It's astonishing that the human genome sequence has made the genetic side of understanding these diseases finite. It's not an infinite problem anymore," say Harley. "The environment is still infinite, however."

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Prokunina L, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet Published online October 28, 2002.
Arnett, F.C. Genetic studies of human lupus in families. Int Rev Immunol 19, 297-317 (2000).
Magnusson, V. et al. Fine mapping of the SLEB2 locus involved in susceptibility to systemic lupus erythematosus. Genomics 70, 307-314 (2000).

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