"The finding that this gene appears to play a role across ethnic groups is very exciting. It suggests that this is going to be an important gene for explaining what causes lupus," says Susana Serrate-Sztein, M.D., chief of the rheumatic diseases branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), which helped fund the study.
The study, reported by Betty P. Tsao, Ph.D., and her colleagues in the February 15, 1997, issue of the Journal of Clinical Investigation, was an international collaboration led by researchers at the University of California, Los Angeles (UCLA) and Cedars-Sinai Research Institute in Los Angeles. The work was funded by the NIAMS, part of the National Institutes of Health (NIH); the NIH Office of Research on Women's Health; and the American Lupus Society.
The scientists used clues from other researchers' genetic analyses of mice with lupus-like illnesses to guide their search for human lupus genes. "The region we identified is probably similar to a corresponding region on chromosome 1 linked to disease in all of the lupus mouse strains studied to date. That suggests that we may be at some very important locus that controls immune response not only in mouse but also man," says Bevra H. Hahn, M.D., chief of rheumatology at UCLA and a senior author of the paper.
In autoimmune diseases such as lupus, the immune system goes awry and produces autoantibodies—antibodies that react against the body's own healthy cells and tissues. These autoantibodies contribute to the inflammation and tissue damage seen in people with lupus. The disease can affect many parts of the body, including the joints, kidneys, skin, heart, lungs, blood vessels, and brain. Scientists do not know exactly what causes lupus, and there is no way yet to prevent or cure the disease.
"There is considerable evidence that the development of SLE has a strong genetic basis," writes Brian L. Kotzin, M.D., in an editorial that accompanies the paper. "For example, studies of families with an affected member suggest that a sibling has a 20-fold increased risk of developing SLE compared to the general population."
Like other autoimmune diseases, such as rheumatoid arthritis and type 1 diabetes, lupus is considered a genetically complex disorder. This means that more than one gene determines whether a person will get the disorder, and that disease genes interact with one another and with triggers from the environment—for example, a virus or even sunlight—to produce disease. Identifying each of the multiple genes involved in complex disorders is much harder than finding the genes that cause single-gene disorders such as Huntington's disease or sickle-cell disease.
"Humans have a total of about 50,000 to 100,000 genes," notes Tsao, first author of the paper and an associate professor of rheumatology at UCLA. "Now we have narrowed down the location of the disease gene to a region that contains about 500 genes, and we are continuing to narrow it down."
With the aid of colleagues around the world, the research team at UCLA gathered genetic material (DNA) and medical records of people with lupus from the United States, Taiwan, the People's Republic of China, South Korea and England. They analyzed DNA from 52 pairs of siblings with lupus from 43 families of Caucasian, African-American or Asian descent, looking specifically at the region of human chromosome 1 that corresponds to the genetic region shown to play a role in mice with lupus.
"We collected families that have at least two siblings with lupus," says Tsao. "We compared the siblings with lupus to other, unaffected siblings to see whether there was a pattern of increased sharing of genetic markers in this region of chromosome 1 in people with lupus."
"Our hypothesis was that if this lupus gene is conserved between [i.e., plays a role in both] mice and humans, then it's likely to be conserved among multiple ethnic groups. The [genetic] differences between mouse and human are far greater than the differences between these ethnic groups," explains Tsao. Last year, NIAMS-supported researchers identified a gene associated with increased risk of lupus kidney disease—a common complication of lupus—in African Americans, but whether this gene plays a role in other ethnic groups is still unclear.
Tsao and colleagues found that the same region at one end of chromosome 1 was linked to lupus in people from all three ethnic groups that they studied. "This would suggest that this is a very important gene that controls autoimmunity somewhat independent of ethnicity," says Hahn. "It also means that it's going to be easier to figure out what it is, because we have a wider range of people able to give us DNA."
Besides finding a link between lupus and genetic markers on chromosome 1, Tsao and colleagues found that people with these markers tended to have higher blood levels of an autoantibody known to be involved in lupus (called IgG anti-chromatin). This finding, too, is similar to what researchers have observed in mice with lupus-like disease. Tsao says that since lupus is an antibody-mediated disease, it was encouraging to find that production of this antibody correlates with the genetic region on chromosome 1 that is linked to disease.
The researchers are excited about what the future may hold. "I expect that there will be genes discovered that we did not understand had anything to do with this particular disease or the immune response in general," says Hahn. "We will have whole new ideas [about why people get the disease]. That should result in some kind of therapeutic intervention, to target the mechanisms that have gone awry," she says.
B.L. Kotzin. Susceptibility loci for lupus: A guiding light from murine models? Journal of Clinical Investigation, Feb. 15, 1997.
The National Institute of Arthritis and Musculoskeletal and Skin Diseases 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.
Funding for this study was also provided by Mr. Richard Dreyfuss and Bertram Maltz, M.D.
Outside Researchers Available for Comment:
These investigators all are involved in studying the genetics of lupus.
Dr. Brian Kotzin
National Jewish Medical and Research Center
Dr. Jane Salmon
The Hospital for Special Surgery/New York Hospital
Cornell University Medical College
New York, New York
Dr. John Harley
Oklahoma Medical Research Foundation
Oklahoma City, Oklahoma
Lupus Foundation of America
Media Contact: Mr. Duane Peters
1300 Piccard Drive, Suite 200
Rockville, Maryland 20850