The study, coordinated by the National Institute of Arthritis and Musculoskeletal and Skin Diseases' (NIAMS) Specialized Center of Research in Scleroderma at the University of Texas-Houston Health Science Center, has implicated the gene for the protein fibrillin-1 as a possible susceptibility gene for scleroderma, a disease characterized by tissue scarring within skin, internal organs and small blood vessels. Fibrillin-1 is also known to be responsible for a scleroderma-like condition in a mouse model of the human disease.
Frank C. Arnett, M.D., of the University of Texas-Houston Medical School, and his colleagues there and at the University of Oklahoma, Norman, and the Choctaw Nation Hospital, Talahina, Okla., used genetic markers and epidemiology to identify chromosomal areas linked to scleroderma in a Choctaw population with a known high prevalence of the disease. Working with 18 Choctaw scleroderma patients and 77 healthy Choctaw individuals, the scientists analyzed sites on human chromosomes 15q and 2q that corresponded to locations identified in the scleroderma mouse models. Concurrently, the scientists examined the ancestral origins of the Choctaw scleroderma patients using census and historical records dating back to the 1800s.
Their investigation revealed a specific DNA sequence on chromosome 15q that occurred with a frequency significantly higher in the Choctaw scleroderma patients than in healthy Choctaw controls. That sequence, or haplotype, on chromosome 15q also contained genetic markers for the fibrillin-1 gene. At the same time, the genealogical evidence showed that the Choctaw scleroderma cases could be traced to five families in the mid-18th-century. From these findings, the researchers concluded that the haplotype on chromosome 15q containing the fibrillin-1 gene was associated with scleroderma in the Choctaw patients. Furthermore, this haplotype may have been inherited from common disease "founders" about 10 generations back (founders are people who are the first to have a particular gene or genes in a family tree). The findings, according to the authors, are specific to descendants of the five families, not to Choctaws in general, making the greater incidence of scleroderma among Choctaws a familial rather than ethnic phenomenon.
"Genetic and environmental factors have been implicated in scleroderma," said NIAMS Director Stephen I. Katz, M.D., Ph.D. "This confluence of genealogy and genetics, with help from animal modeling studies, provides compelling evidence for a genetic component, at least in this population."
The study, published in the October issue of Arthritis & Rheumatism, moves scleroderma research a step closer to identifying a susceptibility gene. An editorial on the study, by John B. Harley, M.D., Ph.D., and Barbara R. Neas, Ph.D., of the University of Oklahoma, appeared in the same issue. The work was co-funded by two other agencies of the National Institutes of Health (NIH), the National Human Genome Research Institute and the National Institute of General Medical Sciences, as well as the Scleroderma Foundation/United Scleroderma Foundation, the RGK Foundation and the University of Texas-Houston. The NIAMS Specialized Center of Research in Scleroderma is co-funded by the NIH Office of Research on Women's Health and the Office of Research on Minority Health.
Scleroderma is an autoimmune disorder that occurs more frequently in women than in men, usually between the ages of 45 and 55. The hallmark of scleroderma is widespread thickening of the skin. The form of scleroderma in this study, called systemic sclerosis, also involves fibrosis or scarring of tissues in the lungs, heart, kidneys, intestinal tract, muscles and joints. Although the cause of the disease is unknown, researchers believe that both environmental and genetic factors may play a role in scleroderma.
The National Institute of Arthritis and Musculoskeletal and Skin Diseases, a component of the National Institutes of Health, leads and coordinates the federal medical research effort in scleroderma by conducting and supporting research projects, research training, clinical trials, and epidemiological studies, and by disseminating health and research information.
To interview Dr. Arnett, contact:
Office of Public Affairs
University of Texas-Houston Medical Center
2Harley JB, Neas BR. Oklahoma Choctaw and systemic sclerosis: the founder effect and genetic susceptibility. Arthritis & Rheumatism 1998;41(10):1725-28.