Study identifies genetic risk factor for rheumatoid arthritis, lupus
A genetic variation has been identified that increases the risk of two chronic, autoimmune inflammatory diseases: rheumatoid arthritis and systemic lupus erythematosus. These research findings result from a long-time collaboration between the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and other organizations, including UC Davis Health System. NIAMS is part of the National Institutes of Health.
The results appeared in the Sept. 6 issue of the New England Journal of Medicine.
Michael Seldin, chair of the Rowe Program in Genetics and a professor in the UC Davis Department of Biochemistry and Molecular Medicine, assisted in both the design and analysis of the study. The work is an outgrowth of previous collaborations conducted by the North American Rheumatoid Arthritis Consortium, of which Seldin is a founding investigator.
“This study has broad implications for both understanding the genetic variations that predispose toward autoimmune disease, and providing insight into critical steps that determine abnormal T-cell responses,” said Seldin. “This research could lead to earlier diagnosis and treatment approaches to certain subgroups of subjects with either rheumatoid arthritis or systemic lupus.”
— Michael Seldin, chair of the Rowe Program in Genetics
Study coauthor Elaine Remmers, of the Genetics and Genomics Branch of the Intramural Research Program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, said, "Although both diseases are believed to have a strong genetic component, identifying the relevant genes has been extremely difficult." Remmers and her colleagues tested variants within 13 candidate genes located in a region of chromosome 2, which they had previously linked with rheumatoid arthritis, for association with disease in large collections of rheumatoid arthritis and lupus patients and controls. Among the variants were several disease-associated single nucleotide polymorphisms (SNPs) — small differences in DNA sequence that represent the most common genetic variations between individuals — in a large segment of the STAT4 gene. The STAT4 gene encodes a protein that plays an important role in the regulation and activation of certain cells of the immune system.
"It may be too early to predict the impact of identifying the STAT4 gene as a susceptibility locus for rheumatoid arthritis — whether the presence of the variant and others will serve as a predictor of disease, disease outcome or response to therapy," says coauthor and NARAC principal investigator Peter K. Gregersen, of The Feinstein Institute for Medical Research, part of the North Shore Long Island Jewish Health System, in Manhasset, N.Y. "It also remains to be found whether the STAT4 pathway plays such a crucial role in rheumatoid arthritis and lupus that new therapies targeting this pathway would be effective in these and perhaps other autoimmune diseases."
One variant form of the gene was present at a significantly higher frequency in rheumatoid arthritis patient samples from the North American Rheumatoid Arthritis Consortium (NARAC) as compared with controls. The scientists replicated that result in two independent collections of rheumatoid arthritis cases and controls.
The researchers also found that the same variant of the STAT4 gene was even more strongly linked with lupus in three independent collections of patients and controls. Frequency data on the genetic profiles of the patients and controls suggest that individuals who carry two copies of the disease-risk variant form of the STAT4 gene have a 60 percent increased risk for rheumatoid arthritis and more than double the risk for lupus compared with people who carry no copies of the variant form. The research also suggests a shared disease pathway for rheumatoid arthritis and lupus.
"For this complex disease, rheumatoid arthritis, this is the first instance of a genetic linkage study leading to a chromosomal location, which then, in a genetic association study, identified a disease susceptibility gene," said Gregersen.
The study's success, according to NIAMS Director Stephen I. Katz, can be attributed in part to the uncommon and longstanding collaboration between NIAMS intramural researchers and other scientists the institute supports around the country.
"This work required the collection and genotyping of thousands of rheumatoid arthritis and lupus cases and controls, a task that would have been difficult to accomplish without the strong partnerships we forged," he says. NARAC was established 10 years ago by Gregersen, NIAMS Clinical Director and Genetics and Genomics Branch Chief Daniel Kastner, and investigators at several academic health centers to facilitate the collection and analysis of rheumatoid arthritis genetic samples.
Adds Remmers, "Although we do not yet know precisely how the disease-associated variant of the STAT4 gene increases the risk for developing rheumatoid arthritis or lupus, it is very exciting to know that this gene plays a fundamental role in these important autoimmune diseases."
Both rheumatoid arthritis and lupus are considered autoimmune diseases, or diseases in which the body's immune system attacks healthy tissue. In rheumatoid arthritis, the immune system attacks the linings of the joints and sometimes other organs. In lupus, it attacks the internal organs, joints and skin. If not well controlled, both diseases can lead to significant disability.