|Study Identifies Genetic Risk Factor for Rheumatoid
A genetic variation has been identified that increases the risk
of two chronic, autoimmune inflammatory diseases: rheumatoid arthritis
(RA) and systemic lupus erythematosus (lupus). These research findings
result from a long-time collaboration between the Intramural Research
Program (IRP) of the National Institute of Arthritis and Musculoskeletal
and Skin Diseases (NIAMS) and other organizations. NIAMS is part
of the National Institutes of Health.
These results appear in the Sept. 6 issue of the New England
Journal of Medicine.
"Although both diseases are believed to have a strong genetic
component, identifying the relevant genes has been extremely difficult," says
study coauthor Elaine Remmers, Ph.D., of the Genetics and Genomics
Branch of the Intramural Research Program at the National Institute
of Arthritis and Musculoskeletal and Skin Diseases. Dr. Remmers
and her colleagues tested variants within 13 candidate genes located
in a region of chromosome 2, which they had previously linked with
RA, for association with disease in large collections of RA 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, M.D., 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 RA 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 RA patient samples from the North American Rheumatoid
Arthritis Consortium (NARAC) as
compared with controls. The scientists replicated that result in
two independent collections of RA 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 RA 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 RA 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," says Dr. Gregersen.
The study's success, according to NIAMS Director Stephen I. Katz,
M.D., Ph.D., 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 RA 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 Dr. Gregersen, NIAMS Clinical Director
and Genetics and Genomics Branch Chief Daniel Kastner, M.D., Ph.D.,
and investigators at several academic health centers to facilitate
the collection and analysis of RA genetic samples.
Adds Dr. Remmers, "Although we do not yet know precisely how the
disease-associated variant of the STAT4 gene increases the risk
for developing RA or lupus, it is very exciting to know that this
gene plays a fundamental role in these important autoimmune diseases."
Both RA and lupus are considered autoimmune diseases, or diseases
in which the body’s immune system attacks healthy tissue. In RA,
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
Additional grant support for this research was provided by the
National Institute of Allergy and Infectious Diseases, the National
Center for Research Resources, the Rosalind Russell Medical Research
Center for Arthritis, and the Kirkland Scholar Award. The studies
were carried out, in part, at the General Clinical Research Centers
at Moffitt Hospital of the University of California San Francisco
and at The Feinstein Institute for Medical Research, with funds
provided by the National Center for Research Resources and the
U.S. Public Health Service.
Other contributors included the Arthritis Foundation, Biogen Idec,
Inc., the Boas Family, the Broad Institute of Harvard University
and the Massachusetts Institute of Technology, the Eileen Ludwig
Greenland Center for Rheumatoid Arthritis, Hanyang University College
of Medicine, Genentech, Inc., the Karolinska Institutet, the NIAMS
Intramural Research Program, the University of California Davis,
and the University of Texas M.D. Anderson Cancer Center.
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.
The National Institute of Allergy and Infectious Diseases (NIAID)
conducts and supports basic and applied research to better understand,
treat, and ultimately prevent infectious, immunologic, and allergic
The National Center for Research Resources (NCRR) provides clinical
and translational researchers with the training and tools they
need to understand, detect, treat, and prevent a wide range of
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Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
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