Researchers Identify Genes That
Increase Rheumatoid Arthritis Risk
Researchers in the United States and Sweden
have identified a genetic region associated with increased risk of rheumatoid arthritis
(RA), a chronic and debilitating inflammatory disease of the joints that affects an
estimated 2.1 million Americans. The U.S. arm of the study involved a long-time
collaboration between intramural researchers of the National Institute of Arthritis and
Musculoskeletal and Skin Diseases (NIAMS) and other organizations. NIAMS is one of 27
institutes and centers at the National Institutes of Health. The results appeared in the
New England Journal of Medicine.
Using the relatively new genome-wide
association approach — which makes it possible to analyze between 300,000 and 500,000
single nucleotide polymorphisms (SNPs, or small differences in DNA that are distributed
throughout a person’s genetic code) — researchers in both countries searched for
genetic differences in blood samples from people with RA compared to controls. The U.S.
group compared 908 samples from patients provided by the North American Rheumatoid
Arthritis Consortium (NARAC) — a group of investigators working together to identify
the genetic factors that contribute to RA — with those from 1,282 people without RA
(controls). The Swedish group compared 676 samples from the Swedish Epidemiological
Investigation of Rheumatoid Arthritis (EIRA) with 673 controls.
Both groups' searches led them to a region
of chromosome 9 containing two genes relevant to chronic inflammation: TRAF1 (encoding
tumor necrosis factor receptor-associated factor 1) and C5 (encoding complement component
5).
"The whole-genome screening method
lets us identify genes that contribute to disease-susceptibility without imposing our
preconceived notions of the disease. We expected to come up with something new," says
Elaine F. Remmers, Ph.D., of the Genetics and Genomics Branch of the NIAMS Intramural
Research Program and an author of the study. "We were thrilled to find out that
TRAF1-C5 showed association not only in the samples that we did with NARAC but also
independently in the Swedish group. By combining our information, we were able to make a
much stronger case [for a TRAF1-C5 association]. The combined evidence was pretty
impressive."
Remmers says the TRAF1-C5 region was the
third of three major susceptibility chromosomal regions for RA identified by their whole
genome screen. The first two, HLA-DRB1 and PTPN22, had already been well established.
She says that it's not yet known how the
genes in the TRAF1-C5 region influence RA risk. Nor can scientists say which of the two
genes is causing the disease. "Actually, both genes are very interesting
candidates," she says. "They both control inflammatory processes that really are
relevant for the disease, so we could easily envision either of them playing a role —
or both."
The hope is that by learning more about the
genes and their role in the disease, scientists may find clues to influencing treatment of
the disease. "We are hoping that we will find variants in either of the genes that
will lead us to new targets for therapy. Once we understand how the RA-associated variants
work, we may be able interfere with the pathways the variants are influencing and either
prevent the disease or block its progression."
According to coauthor Daniel Kastner, M.D.,
Ph.D., NIAMS clinical director and chief of the NIAMS Genetics and Genomics Branch,
"The success of the study can be attributed in part to the productive, longstanding
collaboration between NIAMS intramural researchers and other scientists that the Institute
supports around the country." NARAC was established 10 years ago by coauthor Peter K.
Gregersen, M.D., at the Feinstein Institute for Medical Research, the North Shore Long
Island Jewish Health System, in order to facilitate the collection and analysis of RA
genetic samples. Kastner was also a key early member of the NARAC, as were many other
investigators at several academic health centers across the United States.
In addition to NIAMS, other support for the
U.S. study came from the National Center for Research Resources, the Arthritis Foundation,
grants from the Boas Family and the Eileen Ludwig Greenland Center for Rheumatoid
Arthritis (Feinstein Institute for Medical Research), the Rosalind Russell Medical
Research Center for Arthritis and the Kirkland Scholar Award (University of California,
San Francisco).
Support for the Swedish arm of the study
came from the Swedish Medical Research Council, the Swedish Council for Working Life and
Social Research, the King Gustaf V’s 80-Year Foundation, the Swedish Rheumatism
Foundation, the Stockholm County Council, the AFA insurance company and the Agency for
Science Technology and Research, Singapore.
