National Institute of Arthritis and Musculoskeletal and Skin Diseases

Embargoed for Release 
Monday, Sept. 2, 1996 
5 p.m. EDTe 

Contact: Elia Ben-Ari 
Office of Scientific and Health 
(301) 496-8188

Research on rats with an inflammatory arthritis that resembles rheumatoid arthritis has provided new clues to the nature of genes that are involved in determining arthritis susceptibility and severity. The findings are a significant step in the drive to identify specific genes involved in rheumatoid arthritis and other human autoimmune diseases. Identifying these genes will provide insights into the biochemical pathways that underlie these diseases and may provide new targets for treatment or prevention.

The localization of six distinct genetic regions that control inflammatory arthritis in rats is described in the September 1996 issue of Nature Genetics. The research was done by Dr. Elaine F. Remmers, Dr. Ronald L. Wilder, and their colleagues at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health in Bethesda, Md., and colleagues at the University of Utah, Salt Lake City.

To gain insight into possible causes of rheumatoid arthritis and other autoimmune diseases, Remmers, Wilder, and colleagues are studying rats with collagen-induced arthritis (CIA), an autoimmune inflammatory arthritis that resembles human rheumatoid arthritis. Through genetic analysis of rats with differing disease susceptibilities and severities, the researchers found that the genetic basis of CIA bears a striking similarity to what is known about the genetics of rheumatoid arthritis in humans.

In both diseases, multiple genes are involved. Remmers and colleagues report that in rats with CIA, as in humans, so-called MHC (major histocompatibility complex) genes, a family of genes known to play a role in the workings of the immune system, are clearly involved in determining susceptibility to arthritis in some--but not all--individuals. The researchers say the most significant aspect of their findings, however, is that they have localized several of the non- MHC genes that also affect arthritis susceptibility and severity in rats.

Rheumatoid arthritis is an often chronic inflammatory disease of the joints that affects about one percent of the population. It can cause destruction of the joints and surrounding tissues, leading to deformity and disability. In autoimmune diseases such as rheumatoid arthritis, the immune system turns against the body's own tissues. Just what causes the immune system to go awry in rheumatoid arthritis is still unclear.

Researchers believe that multiple genes are involved in determining disease susceptibility and severity in rheumatoid arthritis. To date, the only genes clearly shown to be associated with rheumatoid arthritis in humans are certain MHC genes. Scientists have had difficulty identifying additional genes involved in rheumatoid arthritis for several reasons, including the complex nature of multi-gene diseases, and the complicated and still poorly understood interaction between genetic and environmental factors in the cause and development of the disease.

Although certain MHC genes are associated with a tendency to develop rheumatoid arthritis in some populations, not all people with these genes develop rheumatoid arthritis, and other people who have these genes never develop the disease. There is also evidence that MHC genes may influence disease severity.

In their studies of rats with CIA, Remmers and colleagues found a clear association between susceptibility to arthritis and a genetic region known to contain MHC genes. However, some rats with arthritis do not have MHC gene involvement, and some that are positive for an "arthritis susceptible" MHC gene do not develop arthritis.

By doing a genetic analysis of 370 rats with an "arthritis susceptible" MHC gene, the researchers identified four additional, non-MHC genetic regions, on four different rat chromosomes, that are strongly linked to disease severity. They have identified a number of possible "candidate genes" known to be located in these four genetic regions. They found a fifth genetic region that may also be associated with arthritis.

Future work will focus on identifying the specific gene in each of these regions that is involved in determining arthritis severity or susceptibility. Identifying these genes will provide new information on the causes of inflammatory arthritis in these animals and should provide strong leads for finding the genetic and biochemical basis of rheumatoid arthritis and other autoimmune diseases in humans.

Reference: Elaine F. Remmers, Ryan E. Longman, Ying Du, Ann O'Hare, Grant W. Cannon, Marie M. Griffiths & Ronald L. Wilder. A genome scan localizes five non-MHC loci controlling collagen-induced arthritis in rats. Nature Genetics, 14: 82-85, Sept. 1996.

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The National Institute of Arthritis and Musculoskeletal and Skin Diseases, a component of the National Institutes of Health, leads the Federal biomedical research effort on arthritis by conducting and supporting research projects, research training, clinical trials, and epidemiologic studies, and through dissemination of health information and research results.

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