Pediatric Researchers Find Possible 'Master Switch' Gene In Juvenile Arthritis

Researchers have found
that a gene region known to play a role in some varieties of adult
rheumatoid arthritis is also present in all types of childhood arthritis.
The researchers say the responsible gene may be a "master switch" that
helps turn on the debilitating disease.



Researchers at The Children's Hospital of Philadelphia reported on the
link between the gene region and juvenile idiopathic arthritis (JIA),
formerly called juvenile rheumatoid arthritis. The genetic variant is on
chromosome 9 in a region housing two genes, TRAF1 and C5. The TRAF1 gene
codes for a protein that regulates tumor necrosis factor, a chemical
strongly associated with JIA. However, the researchers say further study is
needed to determine whether the TRAF1 gene or the C5 gene is altered in the
disease.



The study appears in the July 2008 issue of Arthritis & Rheumatism.
Lead authors are Terri H. Finkel, M.D., Ph.D.; Hakon Hakonarson, M.D.
Ph.D., director of the Center for Applied Genomics; and Edward M. Behrens,
M.D., all of Children's Hospital.



"There are only a few genes that may act as master switches like this
to regulate autoimmune diseases," said Finkel, the chief of Rheumatology at
Children's Hospital. "This switch we discovered probably has to be an 'ON'
gene and when it interacts with other genes and environmental triggers, a
child may get juvenile arthritis."



The study compared 67 Caucasian patients being treated for JIA to 1,952
healthy Caucasian control subjects recruited within the hospital's patient
network. While the cause of JIA is unknown, results from this study back up
past research that shows arthritis arises in a genetically susceptible
individual due to environmental factors.



About 300,000 children in the U.S. have JIA, of which about 1,500
children are seen at Children's Hospital. JIA is the inflammation of the
lining tissues of a joint and often causes stiffness and pain. While there
is no cure for JIA, medicines and physical therapy can help maintain
movement and reduce swelling and pain. Researchers have previously
identified seven subtypes of JIA.



"We think this finding may be a clue to the specific disease pathway
that leads to arthritis," said Behrens, a pediatric rheumatologist at
Children's Hospital. "We currently use medicines called tumor necrosis
factor blockers to treat children with JIA. However, not all children
respond to these drugs, and other children may develop severe allergic
reactions and other side effects. If we can fully identify all the genes
that interact with environmental risk factors, we might develop more
targeted treatments with fewer side effects."
















"The high-resolution genome-wide association approach has very markedly
enhanced our ability to identify disease genes in complex disorders such as
JIA, and what is remarkable about this discovery is that it appears there
may be a common genetic factor predisposing to all seven forms of the
disease," said Dr. Hakonarson.



The study was supported by an Institutional Research Development Award
from Children's Hospital and development research awards from the Cotswold
Foundation, the Nickolett Fund, and the Arthritis Foundation of Eastern
Pennsylvania.



Other authors are Jonathan P. Bradfield, B.S.; Cecilia E. Kim; LeKenya
Linton, R.N., A.S.; Tracy Casalunovo, M.S.; Edward C. Frackelton, B.A.;
Erin Santa B.A.; F. George Otieno, M.S.; Joseph T. Glessner, M.S.; Rosetta
M. Chiavacci, B.S.N., and Struan F.A. Grant, Ph.D. All are from the
Children's Hospital of Philadelphia.



About The Children's Hospital of Philadelphia: The Children's Hospital
of Philadelphia was founded in 1855 as the nation's first pediatric
hospital. Through its long-standing commitment to providing exceptional
patient care, training new generations of pediatric healthcare
professionals and pioneering major research initiatives, Children's
Hospital has fostered many discoveries that have benefited children
worldwide. Its pediatric research program is among the largest in the
country, ranking third in National Institutes of Health funding. In
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