Spotlight on Research for 2006

August 2006 (historical)

Twin Study Reveals Three Genes Involved in Rheumatoid Arthritis

Scientists supported by the National Institute of Arthritis and Musculoskeletal Diseases (NIAMS) are a step closer to understanding the mechanisms of rheumatoid arthritis (RA), with the discovery of three key genes that are overexpressed in the disease.

RA, an inflammatory disease that damages the joints and in some cases internal organs, affects an estimated 2.1 million Americans. While the disease is believed to have a strong genetic component, concordance among identical twins (occurrence of the disorder in both individuals of a pair) is only 15 percent. This suggests that epigenetic changes - that is, changes in molecules that occur after the genome has been constructed - may be responsible for the disease's development.

To better understand what those changes might be, scientists led by Joseph Holoshitz, M.D., of the University of Michigan used a sophisticated technique called microarray to examine the expression of more than 20,000 genes at a time in 11 pairs of disease-discordant identical twins (meaning one twin had the disease, the other didn't). The examination led to the detection of differences in expression of 827 genes.

The most significantly overexpressed gene was laeverin, an enzyme that breaks down certain types of proteins; second was 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), important in a steroid pathway linked to inflammation and bone erosion; and third was cysteine-rich angiogenic inducer 61 (Cyr61), which is known for its role in angiogenesis, the formation of new blood vessels.

To help confirm that the genes are relevant to the disease, the scientists conducted subsequent studies on joint tissue samples taken from patients with RA and other forms of arthritis. All three genes were overexpressed in RA; 11β-HSD2 was also found in joint tissues from osteoarthritis patients. None of the three had previously been known to be present in inflamed joints, says Dr. Holoshitz.

These findings are exciting because they offer new insights into the mechanisms by which RA is mediated, says Dr. Holoshitz. "Once we know more about the mechanisms, we can think about ways to stop the aberrant process," he says. For example, if Cyr61 is found to indeed be responsible for abnormal angiogenesis in RA, scientists might be able to find a way to block it with drugs or genetic manipulation. Laeverin and 11β-HSD2, too, may be found to be targets for therapeutic intervention.

"Regardless of the therapeutic implications, from the basic standpoint it gives us new potential mechanisms to look at and to use as a guide for future research," Dr. Holoshitz says.

Other funders of this work include the National Institute of Allergy and Infectious Diseases; the National Heart, Lung, and Blood Institute; the Department of Veterans Affairs; the Arthritis Foundation; the American Heart Association; and the University of Michigan.

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 http://www.niams.nih.gov.

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Haas CS, et al. Identification of genes modulated in rheumatoid arthritis using complementary DNA microarray analysis of lymphoblastoid B cell lines from disease-discordant monozygotic twins. Arthritis Rheum. 2006:54 (7):2047-2060.