Scientists at The Feinstein Institute for Medical Research and a team of collaborators from across the country have identified a new risk factor gene for rheumatoid arthritis. The paper will be published in Nature Genetics and the finding brings light to the nature of the disease. The gene, dubbed REL, is a member of the NF-B family, important transcription factors that have many roles in the body. The NF-B family seems to have a big hand in regulating the body’s immune response as well.
“The NF-is a key switching point for many cellular activities,” said Peter K. Gregersen, MD, head of the Robert S. Boas Center for Genomics and Human Genetics at the Feinstein Institute and lead author of the study. Dr. Gregersen is part of a nationwide consortium of investigators seeking to identify risk genes for rheumatoid arthritis (RA). The hope is to figure out the genetic triggers and identify treatments that block this autoimmune process. In theory, such advances can point the way to understanding other autoimmune disorders. About one percent of the population will develop rheumatoid arthritis, which can be crippling.
REL is a key regulator of CD40, which works through the NF-pathway.
“This paper represents the latest in a series of important publications chronicling an exceptionally productive collaboration between extramural and intramural scientists through the North American Rheumatoid Arthritis Consortium,” said Daniel Kastner, MD, PhD, clinical director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. “In describing yet another gene in the CD40 signaling pathway that is involved in rheumatoid arthritis susceptibility, this paper reinforces the possibility of targeting this pathway in selected patients with this debilitating illness.”
The consortium has helped identify many genes involved in rheumatoid arthritis but this genetic finding is significant because of its key role in immune system regulation. It did not reveal itself in previous genetic studies because the sample size was just not large enough. In previous studies, genetic samples from about 2,000 patients were used to identify markers associated with risk for RA. In the latest study, the scientists analyzed samples from 4,000 RA patients and controls.
According to Dr. Gregersen, this particular genetic variant is rather common, found in about a third of people in North America. That means that it must confer an important survival advantage. That said, scientists need to figure out its role in increasing the risk for RA. Next on the research agenda is to see if they can measure how the gene is regulated under specific conditions that set the stage for RA. “There are a huge number of unknowns,” said Dr. Gregersen. “These findings are clear — this pathway is involved — but there is a lot of work to be done.”
Genetic differences between individuals help scientists understand many diseases. But this is just the beginning, added Dr. Gregersen. Today, most markers that are used to identify genes represent variants that occur in more than five percent of the population. The next wave in genetic screening will have to include the variants that occur in less than one percent of the population.
In addition to the Feinstein Institute, part of the North Shore-LIJ Health System, other
centers that are part of the RA consortium include: the University of Texas, MD Anderson Cancer Center; the Genetics and Genomics Branch of the National Institute of Arthritis, Musculoskeletal and Skin Diseases; the Rowe Program in Genetics, University of California at Davis; the Russell Medical Research Center for Arthritis, Department of Medicine, University of California, San Francisco; Brigham and Women’s Hospital at Harvard Medical School; University of Colorado Denver School of Medicine; University of Nebraska Medical Center; Central Hospital in Finland; University of Pittsburgh Medical Center; University of Alabama at Birmingham; Mount Sinai Hospital; University Health Network in Ontario, Canada; and Celera.
The work was supported by grants from the US National Institutes of Health NO1-AR-2-2263 (P.K.G.), RO1 AR44422 (P.K.G.) and by the Eileen Ludwig Greenland Center for Rheumatoid Arthritis and the Muriel Fusfeld Foundation. The work was also supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and by grants from the Canadian Institutes for Health Research (MOP79321) and Ontario Research Fund (RE01061) and a Canada Research Chair to K.A.S.