MANHASSET, N.Y., Sept. 6 /PRNewswire-USNewswire/ -- 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.
"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. For more
information, please visit http://www.FeinsteinInstitute.org or
Contact: Jamie Talan
SOURCE The Feinstein Institute for Medical Research