Leading the way to a cure

Lupus Research Update: 2008 Volume 1

Volume 1, 2008 - Online Edition | In This Issue

ALR Funded International Consortium Identifies Genes Linked to Lupus >
The Faces of Lupus: Eddie Kennison, Kansas City Chiefs >
Meet the Investigator — Mary K. Crow, M.D., Named Chair of Scientific Advisory Board >
Research Results — A New Clue in the Survival of Autoimmune B Cells >
Research Results — Narrowing Down a Lupus-Related Gene >
Research Results — Finding Hidden Clues to Children's Lupus Nephritis >
Research Results — Finding Ways to a Safer Pregnancy for Women with Lupus >
Drug Research and Development News >
Leaving a Legacy >

Research Results — Narrowing Down a Lupus-Related Gene

The incredible progress that is being made in identifying the genetic underpinnings of lupus provides one very important part of the puzzle required to unravel this extremely complex disease (see the update on ALR's SLEGEN Consortium on page 3 for more news). But without a greater understanding of just what those genes do, and how mutations or changes in them contribute to the disease, progress in preventing, treating or even curing lupus will be slow.

Thus, numerous researchers, including many funded by the Alliance for Lupus Research (ALR), are working to identify these processes. In early December, ALR grantee Lars Rönnblom, M.D., Ph.D., Professor of Rheumatology at Uppsala University in Sweden, was part of a team that published the results of their detective work in this arena in the online issue of the journal Human Molecular Genetics.

The work focuses on type I interferons, immune system proteins that trigger cellular responses to viruses. In people with lupus, these proteins are produced even in the absence of viral triggers, promoting and sustaining disease activity.

Dr. Rönnblom and his group, together with Professor Ann-Christine Syvänen at the genotyping platform in Uppsala, had earlier identified several genetic abnormalities on one gene that regulates type 1 interferon: the interferon regulatory factor 5 (IRF5) gene. The IRF5 gene also regulates the expression of other genes involved in the cellular life cycle, immune response and other activities that play important roles in autoimmunity. But identifying the specific function of IRF5 in lupus has been challenging, he said.

So he and his team sequenced, or "read," the complete IRF5 gene in 40 people with lupus and eight without to get a clearer picture of the specific polymorphisms, or variations, in the gene. They found numerous variants, which they tested in 485 people with lupus and 535 controls, narrowing them down to 18 that appeared to be linked with lupus.

After running complex statistical models on those 18 variants, they further narrowed them down to two that accounted for all the risk in people with lupus. One is related to the promoter region of the gene, which regulates the gene's activities. Basically, Dr. Rönnblom explained, the promoter variant increases the level of IRF5 the gene produces, which, in turn, regulates the production of interferon. Interestingly, he said, the second gene variant is related just to lupus; the promoter variant appears to also be related to other autoimmune conditions, including inflammatory bowel disease and multiple sclerosis.

"So it's tempting to speculate that the first variant could be responsible in general for the autoimmune phenomenon and the second for the lupus manifestations," he said.

Right now, of course, that's just speculation. Much work remains to be done to further understand the implications of these two variants in people with lupus and those with other autoimmune disorders, he said.

"We want to find out more about the defect and problem with the variants, what they are causing and how you can modulate them to modify the function or consequence of these genetic variants," he said. Human Molecular Genetics.

Sigurdsson S, Göring HH, Kristjansdottir G, Milani L, Nordmark G, Sandling J, Eloranta ML, Feng D, Sangster-Guity N, Gunnarsson I, Svenungsson E, Sturfelt G, Jönsen A, Truedsson L, Barnes BJ, Alm G, Rönnblom L, Syvänen AC. Comprehensive Evaluation of the Genetic Variants of Interferon Regulatory Factor 5 Reveals a Novel 5bp Length Polymorphism as Strong Risk Factor for Systemic Lupus Erythematosus. Hum Mol Genet. 2007 Dec 6; [Epub ahead of print]

Just the Facts

What the study showed:
Two specific variants on the IRF5 gene related to lupus.

What it means:
Further understanding the role of the variants in the disease process could lead to new targets for treatment. Understanding the genetic underpinnings of the disease may, one day, lead to therapies that might prevent lupus from occurring.

What's next:
Further validating and refining the findings.

ALR funding:

1.5 million

people in the U.S. have Lupus.

172 million

dollars committed to lupus research by the Lupus Research Alliance.

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