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New Risk Gene For Rheumatoid
Arthritis And Lupus Opens Door To More Effective Treatments
07
Sept 2007
As
edited by Joint-Pain-Forum.com
Scientists
at The Feinstein Institute for Medical Research have identified a
critical gene that increases a person's risk for rheumatoid arthritis
and systemic lupus erythematosus, and may be involved with other
autoimmune diseases.
The genetic link, described in
the September 6th issue of the New England Journal of Medicine, was a
collaborative effort led by Peter K. Gregersen, MD, head of The
Feinstein Institute's Robert S. Boas Center for Genomics &
Human Genetics. A decade ago, Dr. Gregersen helped bring together
scientists from a dozen institutes to pool patients and add strength in
numbers as they collectively hunt for genes. More recently, the North
American Rheumatoid Arthritis Consortium (NARAC) studied a region
identified on chromosome 2 in previous linkage studies conducted by the
same team. In the latest study, they analyzed DNA from 2,500 patients
with rheumatoid arthritis (RA) or lupus. Genetic mapping enabled them
to identify STAT4 as a culprit in susceptibility to both diseases.
"This
work required the collection and genotyping of thousands of RA and
lupus patients and volunteers, a task that would have been difficult to
accomplish without the strong partnerships we forged," said Stephen I.
Katz, MD, PhD, director of the National Institute of Arthritis and
Musculoskeletal and Skin Diseases (NIAMS). The federal institute has
supported NARAC since its inception.
"Identifying
STAT4 as the relevant gene on chromosome 2 is very exciting," added
Elaine Remmers, PhD, a lead author in the NEJM study on STAT4 and a
staff scientist in the NIAMS's Genetics and Genomics Branch. "We now
are faced with trying to figure out how this variant of STAT4 increases
a person's risk."
About 22 percent of people in the
United States inherit this particular form of STAT4. Having this
variant of STAT4 confers a 30 percent increased risk for developing
rheumatoid arthritis. People with two copies of STAT4 have a 60 percent
increased risk, Dr. Gregersen said. Rheumatoid arthritis is a painful
inflammatory condition of the joints. It is an autoimmune disease,
which means the body's immune system recognizes a product in the lining
of the joint as foreign and wages an attack. Patients with lupus, also
an autoimmune disease, have about double the risk compared to people
without this variant of STAT4.
In a companion study
by Dr. Gregersen and his colleagues, STAT4 popped up as an important
risk gene in a population of patients in Korea. This paper is published
this month in Molecular Medicine.
One percent of
people will develop rheumatoid arthritis. There are probably dozens of
genes, perhaps more, involved in triggering complex diseases like
rheumatoid arthritis.
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Article
adapted by
www.Joint-Pain-Forum.com from original press release.
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"Identifying this risk gene is
important because it points us in the right direction," said Dr.
Gregersen, who also just completed a whole genome-wide association
study of rheumatoid arthritis that will appear later this month in the
NEJM. The study is online as of September 6th with an accompanying
editorial. In this paper, the scientists identified another risk gene
-- TRAF1-C5.
"The identification of these two new
autoimmunity genes has profound significance for our understanding of
these complex diseases and our ability to develop more specific
diagnostic tests and therapies," said Lindsey Criswell, MD, PhD,
professor of medicine at UCSF and a co-investigator on both studies.
A
lot is known about the STAT4 gene and the protein it makes. STAT4 is a
signaling molecule that mediates the effects of immune system cytokines
such as IL12 and some types of interferon. STAT4 controls the
differentiation of T- cells into TH1 cells and may contribute to the
development of TH17 cells, both of which seem to have a role in
maintaining chronic inflammation in the body.
Inhibiting
STAT4 can prevent or ameliorate arthritis in animal models of
rheumatoid arthritis, suggesting that STAT4 could be a target for new
therapies. The discovery of STAT4 can ultimately help scientists
unravel the triggers for the disease, help in the development of a test
to confirm a diagnosis and perhaps even help predict who will respond
to treatments.
The NARAC and collaborators at Celera
Diagnostics previously identified PTPN22 as another risk gene in 2004.
PTPN22 influences the "trigger point" for activation of T-cells --
immune cells normally called on to wage battle against infection. In
autoimmune diseases like rheumatoid arthritis, PTPN22 appears to put
people at higher risk of a wayward T-cell response. Dr. Gregersen said
that the two genes -- PTPN22 and STAT4 -- appear to work independently
to increase the risk for rheumatoid arthritis.
These
are the first RA genes to be discovered since the 1980s when scientists
reported detailed association with genetic variants in the HLA region
known as the "shared epitope," work for which Dr. Gregersen is still
widely recognized. The key to the new genetic discoveries, Dr.
Gregersen said, is to have "more patients and controls. With higher
numbers of volunteers, we will have more power to pull out additional
new genes and figure out what they do in triggering these diseases.
Continued international collaboration with colleagues at the Karolinska
Institute in Stockholm will be critical for these efforts."
In
addition to Drs. Gregersen, Criswell and Remmers, the NARAC
investigators on the STAT4 study include Christopher Amos, PhD, of The
University of Texas M.D. Anderson Cancer Center; Daniel Kastner MD,
PhD, of NIAMS's Genetics and Genomic Branch; Michael F. Seldin MD, PhD,
of the University of California, Davis; and Robert M. Plenge, MD, PhD,
of the Brigham and Women's Hospital. Timothy W. Behrens, MD, senior
director of immunology, tissue growth & repair at Genentech,
Inc. was a key collaborator on the lupus research.
The
NARAC team is also part of the whole genome association study to be
published later this month in the NEJM. Other collaborators on this
study include Lars Klareskog of the Karolinska Institute; Mark
Seielstad of the Genome Institute of Singapore; and John Carulli, PhD,
and Evan Beckman, MD, of Biogen Idec in Cambridge, Ma.
Headquartered
in Manhasset, NY, The Feinstein Institute for Medical Research is home
to international scientific leaders in Parkinson's disease, Alzheimer's
disease, psychiatric disorders, rheumatoid arthritis, lupus, sepsis,
inflammatory bowel disease, diabetes, human genetics, leukemia,
lymphoma, neuroimmunology, and medicinal chemistry. The Feinstein
Institute, part of the North Shore-LIJ Health System, ranks in the top
6th percentile of all National Institutes of Health grants awarded to
research centers. Feinstein researchers are developing new drugs and
drug targets, and producing results where science meets the patient.
The
Feinstein Institute for Medical Research
http://www.FeinsteinInstitute.org
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