by Mary
Shomon
July 2004 --
A team of researchers has
discovered a genetic variation that doubles the risk for rheumatoid arthritis
(RA). The variation, referred to as a single nucleotide polymorphism (SNP,
pronounced "snip"), is present in about 28 percent of individuals with
rheumatoid arthritis and 17 percent of the general population. This discovery
resulted from a collaboration between scientists from the North American
Rheumatoid Arthritis Consortium (NARAC), led by Peter K. Gregersen, MD, of the
North Shore-Long Island Jewish Research Institute in Manhasset, NY, Celera
Diagnostics and Genomics Collaborative, Inc. The team's findings are being
published in the August 2004 issue of the American Journal of Human Genetics.
"This is an important discovery, really a major genetic variant identified
in a U.S. study that clearly seems to be involved in rheumatoid arthritis,"
said Stephen I. Katz, MD, PhD, director of the National Institute of Arthritis
and Musculoskeletal and Skin Diseases (NIAMS), the lead agency at the National
Institutes of Health (NIH) that supports NARAC.
While scientists still do not know the exact cause of RA, they do know it
is an autoimmune disease in which the body's natural immune system does not
function properly and attacks its own healthy joint tissues. This causes
inflammation and subsequent joint damage.
The SNP they linked to RA is located in a gene that codes for an enzyme
(called PTPN22) that is known to be involved in controlling the activation of
immune cells called T cells. Under normal conditions, the enzyme works as a
"negative regulator" -- meaning it inactivates a specific signaling molecule,
which in turn interrupts the communication lines and keeps immune cells from
becoming overactive. In cases where the SNP is present in one or both copies
of an individual's genes for this enzyme, the team found that the negative
regulation by this enzyme appears to be inefficient, so that T cells and other
immune cells are hyperresponsive, causing increased inflammation and tissue
damage.
"This is not an abnormal gene," said Dr. Gregersen. "It is present in a
substantial fraction of the normal population, so it's probably there for a
good reason. It may, in fact, help defend against infection." When it comes
to the genetics of complex diseases, context is everything. According to Dr.
Gregersen, a genetic variant in the setting of certain environments and in the
presence of other genes may have harmful effects, whereas the same genetic
variant may have beneficial effects in another genetic and environmental
context. "So this particular genetic variation may have contributed to the
survival of our ancestors. The price we have to pay for that, however, is
that some people are modestly predisposed to developing rheumatoid arthritis."
Using state-of-the-art technology developed by Celera Diagnostics, Ann B.
Begovich, PhD, director of inflammation, at Celera Diagnostics and her team
discovered the PTPN22 association. The technology allowed them -- in a short
period of time -- to look at tens of thousands of SNPs in thousands of DNA
samples from subjects with RA as well as normal control subjects. The
majority of the DNA samples analyzed in this study were carefully collected
from families with RA who contributed to the NARAC project. Genomics
Collaborative, Inc. provided additional samples.
"This collaboration has enabled us to make a significant contribution to a
very complex genetic problem in a relatively short period of time, something
that can only be achieved with a team effort," said Dr. Begovich.
The Arthritis Foundation has been an important supporter of NARAC. "This
critical discovery is an illustration of the power of public-private
partnerships to solve complex issues," said John H. Klippel, MD, the
foundation's president and CEO.
Research has previously shown that autoimmune diseases such as type 1
diabetes, lupus and thyroid disease tend to group in families, but there has
been no previous direct genetic connection to explain the phenomenon. Earlier
this year, a study published in Nature Genetics linked this same SNP with type
1 diabetes. Subsequent unpublished research by Dr. Gregersen and his
colleagues indicates that this particular gene variant may also increase risk
for other autoimmune diseases, such as systemic lupus and autoimmune thyroid
disease, as well as type 1 diabetes.
"NIH has provided strong scientific and financial support for the North
American Rheumatoid Arthritis Consortium over many years, and we are now
beginning to see the fruits of this investment," said Dr. Katz. "I expect
this discovery will spin off many more advances in the field." In addition to
NIAMS, the National Institute of Allergy and Infectious Diseases and the
Office of Research on Women's Health at the NIH also support NARAC.
The full text of this journal article in the August 2004 print issue of American Journal of Human Genetics is currently
available online from http://www.journals.uchicago.edu/AJHG.
 Rheumatoid arthritis is one of the autoimmune diseases explored in depth, with discussion of conventional and alternative diagnosis techniques and treatment solutions, in the best-selling book Living Well With Autoimmune Disease by Mary Shomon, now in its 4th printing.
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