New Risk Gene for Rheumatoid Arthritis and Lupus Opens Door to More Effective Treatments

Sep 06, 2007, 01:00 ET from The Feinstein Institute for Medical Research

    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 or
     Contact: Jamie Talan

SOURCE The Feinstein Institute for Medical Research