Crohn’s and Parkinson’s in cahoots?

Gene mutations found in Crohn’s patients suggest possible link with Parkinson’s disease

Rachel Flehinger
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NEW YORK—Researchers at Mount Sinai Health System have discovered a pair of gene mutations that suggest a genetic link between Crohn’s disease and Parkinson’s disease, and offers the potential for earlier detection, treatment and prevention for Crohn’s disease. The mutation was present in the LRRK2 gene, which is the major known cause of Parkinson’s disease and is found more often in those with Crohn’s. The mutations were found to be more prevalent in people of Ashkenazi Jewish descent than non-Jewish subjects.
“Crohn’s disease is a complex disorder with multiple genes and environmental factors involved, which disproportionally affects individuals of Ashkenazi Jewish ancestry,” explained lead researcher Inga Peter, professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai. “The presence of shared LRRK2 mutations in patients with Crohn’s disease and Parkinson’s disease provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.”
Crohn’s disease is an autoimmune bowel disease that causes inflammation of the digestive tract and a host of painful, debilitating and sometimes life-threatening symptoms and complications. It has long been established that Eastern European Jews have a disproportional risk of developing Crohn’s disease—studies find the disease to be five to seven times more prevalent in Jews—suggesting that the reasons are likely to be genetic rather than environmental or behavioral. There are a number of theories seeking to explain this variation. One theory suggests that the active immune systems of Jewish communities helped them in fighting tuberculosis in the early 1900s, but may have increased the likelihood of an autoimmune disease like Crohn’s disease when tuberculosis was mostly eradicated.
Regardless of the reason why the risk is so much higher in the Jewish population, Mount Sinai researchers began their study there, exploring the genetic mutations present in samples of Ashkenazim with and without Crohn’s disease. They found that mutations in the LRRK2 gene were present more frequently in people with Crohn’s disease than people without it.
Next, they undertook an expanded study to explore the possibility of a genetic link between Crohn’s and Parkinson’s which included 24,750 people including patients with Crohn’s, Parkinson’s and no disease at all (each group consisted of Jewish and non-Jewish subjects). There they found two LRRK2 mutations: a “risk mutation” found more commonly in patients with Crohn’s, and a “protective mutation” more commonly found in those without the disease. These mutations were found in both Jewish and non-Jewish populations.
“We tested to see if the mutations were unique to the Ashkenazi population,” says Peter. “We found that the mutation is universal. While the mutation occurs in greater frequency in the Ashkenazi population, it has the same effect across the general population.”
Additionally, the study found that in patients with the risk mutation, they developed the disease on average six years earlier than those who did not carry the mutation. Likewise, those patients had the disease develop more often in the small intestine, making it harder to manage and treat. Conversely, patients with the protective mutation, what Peters refers to as nature-created drugs, can provide clues to ways to keep the disease at bay.
“Defining the biology of naturally occurring protective mutations is quite important, because they define desired outcomes for potentially new therapies,” explained the study’s co-author Dr. Judy H. Cho, director of the Sanford Grossman Center for Integrative Studies in Irritable Bowel Disease and the Charles F. Bronfman Institute for Personalized Medicine at the Icahn School of Medicine.
The findings of the study offer widespread potential for the diagnosis and treatment of Crohn’s disease. The LRRK2 is a large and very important gene being studied in multiple ways, as it is also related to leprosy and some non-skin cancers. One potential area for further research would involve LRRK2 inhibitors to reduce risk, or repurposing existing compounds that target the gene for Crohn’s management. Additionally, the Crohn’s information could be helpful in preventing or mitigating Parkinson’s. The age of onset for Crohn’s is generally in one’s 20s, while Parkinson’s often doesn’t appear until an individual is in their 50s, offering some 25 to 30 years to try and prevent Parkinson’s in those found to have the mutation. Likewise, physicians could potentially screen Ashkenazim for the mutation before symptoms appear to afford a better chance of managing symptoms and severity of the disease.
“Identifying genetic mutations associated with disease risk is an effective way to better understand disease mechanisms, identify individuals at risk and develop novel drug targets to treat the disease,” Peter added. “Our research may also help identify individuals who would benefit the most of LRRK2-directed therapies, thereby contributing to the field of personalized medicine.”

Rachel Flehinger

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