Genomic Study Turns Up New Risk Factor Gene for Rheumatoid Arthritis

A genome-wide association study of patients with rheumatoid arthritis has turned up a previously unknown risk factor gene.

About 1% of the world's population is afflicted by rheumatoid arthritis, women three times more often than men. Onset is most frequent at 40 to 50 years of age, but no age is immune. The disease can present as a disabling and painful condition, which can lead to substantial loss of function and mobility.

Investigators from the Feinstein Institute for Medical Research (Manhasset, NY, USA) conducted a genome-wide association study of patients with rheumatoid arthritis in 2,418 cases as well as in 4,504 controls from North America. They reported in the June 7, 2009, online edition of the journal Nature Genetics that there was a critical rheumatoid arthritis association at the REL gene locus on chromosome 2p13 encoding the NF- kappaB family member c-Rel protein. REL is a key regulator of CD40, which works through the NF-kappaB pathway.

CD40 is a costimulatory protein found on antigen presenting cells and is required for their activation. It is a member of the tumor necrosis factor- (TNF)-receptor superfamily. This receptor has been found to be essential in mediating a broad variety of immune and inflammatory responses including T-cell-dependent immunoglobulin class switching, memory B- cell development, and germinal center formation.

NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that acts as a transcription factor. It is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized low-density lipoprotein (LDL), and bacterial or viral antigens. NF-kappaB plays a key role in regulating the immune response to infection. Consistent with this role, incorrect regulation of NF-kappaB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. Because NF-kappaB controls many genes involved in inflammation, it is not surprising that it is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, asthma, among others.

"The NF-kappaB is a key switching point for many cellular activities,” said first author Dr. Peter K. Gregersen, head of the center for genomics and human genetics at the Feinstein Institute for Medical Research. "There are a huge number of unknowns. These findings are clear--this pathway is involved--but there is a lot of work to be done.”

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Feinstein Institute for Medical Research