Researchers have identified a new risk factor gene for rheumatoid arthritis. The gene, named REL, is a member of the NF-κB family, which seems to play a big role in regulating the body's immune response.

The researchers conducted a genome-wide association study of rheumatoid arthritis in 2,418 cases and 4,504 controls from North America.

Rheumatoid arthritis is a form of arthritis that causes pain, swelling, stiffness and loss of function in the joints, affecting any joint but most common in the wrist and fingers. Rheumatoid arthritis often starts between ages 25 and 55 and more women than men get rheumatoid arthritis.

Rheumatoid arthritis is an autoimmune disease, which means the arthritis results from the immune system attacking the body's own tissues. About one percent of the population will develop rheumatoid arthritis, which can be crippling.

“The NF-κB is a key switching point for many cellular activities,” said Peter K. Gregersen, lead author of the study. Gregersen is part of a nationwide consortium of investigators seeking to identify risk genes for rheumatoid arthritis. 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. REL pathway is a key regulator of CD40, which works through the NF-κB 

“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, 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 rheumatoid arthritis. In the latest study, the scientists analyzed samples from 4,000 rheumatoid arthritis 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 rheumatoid arthritis. 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 rheumatoid arthritis. “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.
References:
1. Peter K. Gregersen, , et al. REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis. Nature Genetics 41, 820 - 823 (2009). doi:10.1038/ng.395.
2. U.S. National Library of Medicine, National Institutes of Health.