| NATIONAL INSTITUTES OF HEALTH |
National Institute of Arthritis and Musculoskeletal and Skin Diseases |
| March 6, 1996 |
Office of Scientific and Health Communications |
Researchers supported by the National Institutes of Health (NIH) have identified a gene associated with increased risk of lupus kidney disease in African Americans. Variations in this gene affect the ability of immune cells to remove potentially harmful molecules from the body. This finding is a significant step towards enabling doctors to predict who is at risk for lupus and its complications and to take steps to minimize that risk. Systemic lupus erythematosus (SLE, or lupus) is an autoimmune disease that is three times more common in African Americans than in white Americans, and also tends to be more severe in African Americans.
"We found an inherited susceptibility factor that is important in determining the severity of disease in a population [African Americans] that gets more severe disease," said Jane E. Salmon, M.D., of The Hospital for Special Surgery/New York Hospital, Cornell University Medical College, in New York City, who led the collaborative, multicenter research study.
Research indicates that lupus is caused by a complex interplay of genetic and environmental factors. "These results are very important in helping us understand the genetic factors that play a role in determining who is at risk for the potentially lethal complications of lupus," said Stephen I. Katz, M.D., Ph.D., director of the NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), which funded the study. The results also provide clues to the cause of lupus, particularly lupus nephritis, the kidney disease that can be a serious complication of SLE and can lead to kidney failure.
This study, reported in the March 1, 1996 issue of the Journal of Clinical Investigation,* also involved NIAMS researchers at the NIH campus in Bethesda, Md., as well as researchers at University of Texas Health Science Center in Houston, Texas; State University of New York Health Science Center, Brooklyn, N.Y.; and Northwestern University School of Medicine, Chicago, Ill.
Investigators at these medical research centers studied 257 African Americans with lupus and 139 African Americans without the disease. The researchers looked at a gene that controls production of proteins called Fc receptors, which help certain white blood cells capture and destroy potentially harmful molecules called immune complexes. The researchers found that, among African Americans with lupus, those with lupus nephritis had an increased likelihood of having the gene for a form of the Fc receptor that has a low efficiency for capturing immune complexes. Excessive buildup of immune complexes in the kidneys is known to be associated with lupus nephritis.
"Our results suggest that inheriting a low capacity for removing immune complexes plays a role in determining predisposition to lupus kidney disease," Salmon said. "By unraveling the causes of the disease we can begin to design better treatments, and predict those who are likely to get lupus nephritis and take steps to prevent it."
Immune complexes are formed when normal antibodies react with foreign substances that invade the body, such as viruses or bacteria. In lupus, the immune system goes awry and produces abnormal antibodies-called autoantibodies-that combine with substances from the body's own tissues to form immune complexes. These immune complexes circulate in the bloodstream and are deposited in various tissues.
Excessive buildup of immune complexes in tissues or organs can trigger the inflammation that causes tissue injury in lupus. The joints, skin, kidneys, lungs, heart, nervous system and blood vessels can be affected. Defects in removal of immune complexes from the body are particularly profound in people with kidney complications of lupus. The signs and symptoms of lupus differ from one person to another, and the disease can range from mild to severe. Ninety percent of people with lupus are women, and the disease most often strikes during the childbearing years.
The particular Fc receptor gene that the investigators studied comes in two forms: one form (H131) codes for Fc receptors that are highly efficient at removing immune complexes; the other form (R131) codes for Fc receptors with low efficiency. The researchers examined the distribution of these two forms of the Fc receptor gene among African Americans with and without lupus, and among those African American lupus patients with or without kidney disease. They found that people with lupus more often had the gene for the less efficient form of this particular Fc receptor. People with lupus nephritis had an even more pronounced tendency to have the low-efficiency Fc receptor gene.
"We are exploring genes for additional Fc receptor molecules and other genes that may predispose people to lupus and its complications," said Robert P. Kimberly, M.D., director of the multipurpose arthritis center at the Hospital for Special Surgery, and a study collaborator. "This will allow us to define biological risk factors in different ethnic groups, and the degree to which these factors contribute to the prevalence and severity of lupus in various populations."
Researchers supported by the NIAMS are working to identify other genes involved in determining susceptibility to lupus. They have evidence that multiple genes contribute to disease susceptibility, and that no single gene can by itself cause the disease.
"In the future," said Salmon, "we will be able to put together a risk factor profile that predicts outcome for lupus patients, and we'll be able to decide whether we should use more or less aggressive treatments, depending on the person's likelihood of getting severe disease." She added: "Being able to do these studies in a collaboration between multiple research centers was one of the crucial components to success."
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 lupus and other rheumatic diseases 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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Reference: FcgRIIA alleles are heritable risk factors for lupus nephritis in African Americans. Jane E. Salmon, Sean Millard, Leah A. Schachter, Frank C. Arnett, Ellen M. Ginzler, Mark F. Gourley, Rosalind Ramsey-Goldman, Margaret G.E. Peterson, and Robert P. Kimberly. Journal of Clinical Investigation , March 1, 1996.