Scientists have long suspected that autoimmune diseases such as rheumatoid arthritis (RA) result from a combination of genetic and environmental factors. Now, with partial funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a research team working to understand the genetic aspect of RA has identified one culprit: a specific genetic variation, called a single nucleotide polymorphism (SNP), that increases RA risk twofold.

The SNP is located within a gene that codes for an enzyme called PTPN22. The enzyme is known to be involved in controlling the activation of white blood cells called T cells that play an important role in the body’s immune system. Under normal conditions, the enzyme works as a negative regulator: it inactivates a specific signaling molecule which, in turn, interrupts the communications and keeps immune cells from becoming overactive. However, in cases where the SNP is present in one or both copies of a person’s genes for this enzyme, the team found that the negative regulation by the enzyme appears to be inefficient, allowing T cells and other immune cells to respond too vigorously, causing increased inflammation and tissue damage.

In itself, the SNP is not abnormal, says coauthor Peter K. Gregersen, M.D., of the North Shore—Long Island Jewish Research Institute, who leads the North American Rheumatoid Arthritis Consortium (NARAC). The variation occurs in about 17 percent of the general population, so it likely has a purpose, such as defending against infection. In certain environments and in the presence of other genes, however, the genetic variation may have harmful effects.

Scientists say the implications of this finding go beyond a better understanding of RA risk; it may also help explain why different autoimmune diseases tend to run in families. Earlier this year, a study published in Nature Genetics linked this same SNP with type 1 diabetes, an autoimmune disease in which the immune system attacks the body’s insulin-producing cells. Subsequent work by Dr. Gregersen and his colleagues suggests that the same variant may also increase the risk of other autoimmune diseases, including lupus and autoimmune thyroiditis as well.

NARAC is a National Institutes of Health and Arthritis Foundation-funded multicenter collaboration formed in 1997 to learn more about the genes associated with RA by studying families with more than one member affected by the disease. RA is a disease in which the body’s immune system mistakenly attacks the joint linings and, often, other body tissues, leading to joint pain, inflammation and damage.

In addition to NIAMS, this work was also supported by the National Institute of Allergy and Infectious Diseases, the National Human Genome Research Institute, the National Center for Research Resources, the NIH Office of Research on Women’s Health and the Arthritis Foundation.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services?National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases, the training of basic and clinical scientists to carry out this research and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information Clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at www.niams.nih.gov.

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Begovich A, et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. American Journal of Human Genetics 2004;75(2):330-337