Researchers at Brigham and Women’s Hospital (BWH) and the Broad Institute
of MIT and Harvard have discovered a gene involved in rheumatoid
arthritis, a painful autoimmune disease that affects 2.1 million Americans
and can destroy cartilage and bone within the afflicted joint.
In a study led by Robert Plenge, an instructor in medicine at
Harvard Medical School and physician at Harvard-affiliated BWH, researchers used gene chip technology to screen the
genomes of 397 rheumatoid arthritis sufferers for DNA sequences
different from those in the broader population.
Gene chip technology has revolutionized genetic studies by allowing
researchers to examine hundreds of thousands of bits of DNA at a time,
screening vast numbers of genes that previously had to be examined one
at a time in slow, painstaking laboratory work.
Researchers compared the genomes of rheumatoid arthritis sufferers with
a sample of the general population, in this case, 1,211 participants in
the Framingham Heart Study. Thirty-eight researchers from 13
institutions examined 116,204 places in the genome that prior studies
had identified as varying from person to person. The examination of
these sites, called single nucleotide polymorphisms, turned up one
place on chromosome six that differed significantly in the rheumatoid
arthritis sufferers from the general population.
Plenge said the location, given the technical name of 6q23, isn’t
within a known gene, but it is near a gene known to be involved in
inflammation. It is likely, Plenge said, that the 6q23 genetic variants
interact with the inflammation gene in some way.
“There’s a lot we don’t know about gene regulation,” Plenge said.
“Genetic variants influence neighboring genes, we just don’t know how
they influence neighboring genes. Maybe they increase expression or
decrease expression. Or maybe they change the tissues in which they’re
expressed or the timing of expression and development.”
The study, published in the journal Nature Genetics, is part of an
ongoing effort at Brigham and Women’s Hospital focused on rheumatoid
arthritis. Called the Brigham and Women’s Hospital Rheumatoid Arthritis
Sequential Study (BRASS), the effort is a multi-pronged program to
gather genetic, clinical, and demographic data in order to better
understand and develop new treatments for the condition.
Rheumatoid arthritis is an autoimmune disease in which the body’s own
defenses attack a person’s joints, causing pain, swelling, and
stiffness. It typically begins in middle age and afflicts women more
than men. It can vary considerably in severity, from occasional
flare-ups to serious joint damage.
One difficulty in fighting the disease is its complexity. Genetics,
environment, and lifestyle are all known to play a role among the
factors that determine who gets the disease and who doesn’t.
“Risk to RA [rheumatoid arthritis] is conferred by a collection of
both genetic variants and of environmental exposures. We know that
smoking is a risk factor, but there are probably other environmental
exposures, too. Add chance and bad luck, and all that together is what
leads to rheumatoid arthritis,” Plenge said.
The find is a significant advance in science’s knowledge of the
disease’s genetic roots. Despite decades of study, only two genes were
known to be involved in rheumatoid arthritis before this year.
Including this most recent discovery, three new genes have been
identified as playing some role, Plenge said.
Identifying 6q23 is just the start of the work, however. The next
step is to discover whether and how it interacts with the nearby
inflammation gene, called TNFAIP3. Once they understand what it does,
researchers will be better able to evaluate whether it’s a good target
for drug treatment or for a test to identify those at risk for
“There’s a lot more traditional experimentation that has to happen
to answer the question of whether it changes expression, changes the
cell type, the timing, or some other specific condition,” Plenge said.
“There’s no doubt the genetic variation at this region influences the
risk of rheumatoid arthritis, we just don’t know how it influences the