The Surprising Link Between Rheumatoid Arthritis and Huntington’s Disease

Firestein

Researchers taking part in a multi-year study that required clinicians, biologists, and informatics people all working together, unearthed a surprising discovery that revealed an overlap between the causes of rheumatoid arthritis (RA) and Huntington’s disease.

By using new analytic tools, a team of researchers at the University of California San Diego School of Medicine and the Icahn School of Medicine at Mount Sinai decoded the epigenetic landscape (proteins and molecules that decorate DNA and help turn genes on and off) of RA, which led them to see a connection to the fatal and incurable genetic brain disease.

“Epigenetics is the study of how cells and organisms have changes in gene expression that are not related to changes in the sequence of the nucleotides in the DNA itself,” says Gary S. Firestein, MD, dean and associate vice chancellor of translational medicine at UC San Diego School of Medicine and lead author of the study. “The DNA can be decorated with a variety of molecules that play a critical role in when genes get turned on and when they get turned off, and that is influenced by many things including the environment, exposure to toxic chemicals, infections and so on.”

That thinking led the team down this pathway of trying to identify non-genetic or gene sequence causes that might contribute to susceptibility or severity of disease. Ultimately about 12 terabytes of data were generated that had to be crunched and analyzed in order to come up with the lists and priorities for genes and pathways that are unique to RA and differentiates RA from non-RA. 

The study, published online in Nature Communications, not only shows this unexpected connection between RA and Huntington’s disease, but opens up the possibility of new therapeutic targets and drugs for both conditions.

Firestein notes the research was a novel way to identify unexpected potential drug targets for treating a variety of diseases. He explains the research team’s approach involved developing a set of computational rules, called EpiSig, which integrated and reduced the number of epigenetic combinations in the genes of patients with RA, thereby allowing the team to identify new cell signaling pathways.

“We took a completely unbiased approach, looking at epigenetics of a disease like RA, analyzed it with some very novel algorithms, and used that to generate a list of genes and pathways that might be associated with the mechanism of disease,” he says. “And some of those are not surprising and are related to immunity because RA is an immune-mediated disease, but many of them were totally unanticipated with the best example being the Huntington’s disease pathway.”

The researchers looked at the epigenome in cells from the joints of patients with RA, while patients with osteoarthritis served as a control group. Both data sets were then analyzed through an expansive process that examines chromatin, DNA, and histone modifications.

Firestein notes the platform that was developed is disease agnostic and the methodology could apply to any disease, immune-mediated or even non-immune-mediated.

“The key is to find a cell type that plays a role in the disease and collect the same data that we collected for rheumatoid arthritis,” he says. “Then the same process could be used in order to identify genes and pathways that are abnormally regulated in any disease using the same methodology. RA is really an example of what we can do but it is not the only disease by a long shot.”

And while Huntington’s disease-related genes might play a role in rheumatoid arthritis, Firestein notes the reverse could also be true, in that some of the targets and the therapeutics for rheumatoid arthritis could conceivably be helpful in Huntington’s disease.

“This may allow us to be repurposing drugs that are thought to be specific for one disease but if there’s shared mechanisms between two different diseases that may appear very different clinically we may be able to get more bang for buck by using drugs that are designed for one disease in another,” he says. “This methodology can also be used to find connections between other diseases, not just rheumatoid arthritis.”

Keith Loria is an award-winning journalist who has been writing for major newspapers and magazines for close to 20 years, on topics as diverse as sports, business, and healthcare.