Genes and their regulatory 'tags' conspire to promote rheumatoid arthritis
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| By James Heilman, MD [CC-BY-SA-3.0 license via Wikimedia Commons] |
In one of the first genome-wide studies to hunt for both genes
and their regulatory "tags" in patients suffering from a common
disease, researchers have found a clear role for the tags in mediating genetic
risk for rheumatoid arthritis (RA), an immune disorder that afflicts an
estimated 1.5 million American adults. By teasing apart the tagging events that
result from RA from those that help cause it, the scientists say they were able
to spot tagged DNA sequences that may be important for the development of RA.
And they suspect their experimental method can be applied to predict similar
risk factors for other common, noninfectious diseases, like type II diabetes
and heart ailments. In a report published inNature Biotechnology Jan. 20, the researchers at Johns Hopkins
and the Karolinska Institutet say their study bridges the gap between
whole-genome genetic sequencing and diseases that have no single or direct
genetic cause. Most genetic changes associated with disease do not occur in
protein-coding regions of DNA, but in their regulatory regions, explains Andrew
Feinberg, M.D., M.P.H., a Gilman scholar, professor of molecular medicine and
director of the Center for Epigenetics at the Johns Hopkins University School
of Medicine's Institute for Basic Biomedical Sciences. "Our study analyzed
both and shows how genetics and epigenetics can work together to cause
disease," he says.
Rheumatoid arthritis is a debilitating disease that causes
inflammation, stiffness, pain and disfigurement in joints, especially the small
joints of the hands and feet. It is thought to be an autoimmune disease,
meaning that the body's immune system attacks its own tissues, an assault led
primarily by white blood cells. According to Feinberg, several DNA mutations
are known to confer risk for RA, but there seem to be additional factors that
suppress or enhance that risk. One probable factor involves chemical
"tags" that attach to DNA sequences, part of a so-called epigenetic
system that helps regulate when and how DNA sequences are "read," how
they're used to create proteins and how they affect the onset or progress of
disease.
To complicate matters, Feinberg notes, the attachment of the
tags to particular DNA sequences can itself be regulated by genes. "The
details of what causes a particular sequence to be tagged are unclear, but it
seems that some tagging events depend on certain DNA sequences. In other words,
those tagging events are under genetic control," he says. Other tagging
events, however, seem to depend on cellular processes and environmental
changes, some of which could be the result, rather than the cause, of disease.
To tease apart these two types of tagging events, the
researchers catalogued DNA sequences and their tagging patterns in the white
blood cells of more than 300 people with and without one form of RA.
The team then began filtering out the tags that did not appear
to affect RA risk. For example, if tags were seen on the same DNA sequence in
those with and without RA, it was assumed that the tags at those sites were
irrelevant to the cause or development of the disease. Then, from among the
RA-relevant tags, they narrowed in on tags whose placement seemed to be
dependent on DNA sequence. Finally, they made sure that the DNA sequences
identified were themselves more prevalent in patients with RA. In this way,
they created a list of DNA sequences associated with altered DNA tagging
patterns, both of which were associated with RA.
Ultimately, the team identified 10 DNA sites that were tagged
differently in RA patients and whose tagging seemed to affect risk for RA. Nine
of the 10 sites were within a region of the genome known to play an important
role in autoimmune diseases, while the 10th was on a gene that had never before
been associated with the disease. "Since RA is a disease in which the
body's immune system turns on itself, current treatments often involve
suppressing the entire immune system, which can have serious side
effects," Feinberg says. "The results of this study may allow
clinicians to instead directly target the culpable genes and/or their
tags."
"Our method allows us to predict which tagging sites are
most important in the development of a disease. In this study, we looked for
tagging sites under genetic control, but similar tags can be triggered by
environmental exposures, like smoking, so there are many applications for this
type of work," says Yun Liu, Ph.D., a lead researcher on the project.
The study also may shed light on how evolution works, explains
Feinberg. "It seems that natural selection might not simply be selecting
for an individual's current fitness level but also for the adaptability of
future generations given an unknown future. We think that certain genetic
sequences may be biologically beneficial and conserved over time because they
increase the amount of variation found in tagging patterns, giving individuals
a greater chance of adapting to environmental changes."
Other authors of the report include Martin J. Aryee, M. Daniele
Fallin, Arni Runarsson and Margaret Taub of the Johns Hopkins University School
of Medicine; and Leonid Padyukov, Espen Hesselberg, Lovisa Reinius, Nathalie
Acevedo, Marcus Ronninger, Lementy Shchetynsky, Annika Scheynius, Juha Kere,
Lars Alfredsson, Lars Klareskog and Tomas J. Ekström of the Karolinska
Institutet, Sweden.
This work was supported by grants from the National Institutes
of Health's Centers of Excellence in Genomic Science (5P50HG003233), the
Swedish Research Council, the Swedish COMBINE project, the Swedish Foundation
for Strategic Research, AFA Insurance and the European Research Council.
Source: Johns Hopkins Medicine
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