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GastroEndoNews.com

People with a genetic predisposition to intestinal inflammation—with or without a formal diagnosis of inflammatory bowel disease—have a higher risk for developing Parkinson’s disease, according to a new genetic database analysis.

Researchers found that when such individuals had Parkinson’s disease, they were more likely to develop it earlier in life than those without an inflammation-based genetic risk.

“We believe that the shared mechanism between IBD and Parkinson’s disease is immunity dysregulation and the presence of chronic inflammation,” said senior investigator Inga Peter, PhD, the vice chair and a professor in the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, in New York City.

The current research follows up on previous results published by Dr. Peter and her colleagues, which showed that IBD patients have a higher risk for Parkinson’s disease (JAMA Neurol 2018;75[8]:939-946).

“What we found puzzling previously was that these are seemingly unrelated diseases, so in this study we wanted to understand whether it’s truly a diagnosis of IBD that increases the risk of Parkinson’s or if it is chronic inflammation generally,” Dr. Peter said.

To that end, her team analyzed genetic data from 406 patients with Parkinson’s disease and 184 controls without Parkinson’s, as well as 1,070 patients with IBD and 189 controls without IBD. The investigators derived polygenic risk scores (PRS) by accounting for the cumulative effects of genes known to predispose individuals to Parkinson’s disease, Crohn’s disease, ulcerative colitis and, more broadly, IBD.

“A PRS for IBD is a continuous score that can indicate risk of intestinal inflammation even in the absence of full-blown IBD,” Dr. Peter noted.

PRS for IBD Correlated With Parkinson’s

According to the findings, which were presented at the 2022 Crohn’s and Colitis Congress, the PRS for IBD, Crohn’s disease and ulcerative colitis all significantly correlated with Parkinson’s disease, conferring up to a 48% increased risk for the neurodegenerative disease (odds ratio [OR], 1.38, 1.48 and 1.35 per standard deviation of PRS, respectively, for IBD, Crohn’s and ulcerative colitis; P<0.05 for all). Individuals with the highest IBD PRS also developed Parkinson’s disease an average of about four years earlier than those with the lowest IBD PRS (60 vs. 64 years; P=0.0002).

Dr. Peter’s team also found that the genes that overlapped between PRS for Parkinson’s disease and PRS for IBD were immune related and also were enriched in the pathways associated with illnesses such as type 1 diabetes, rheumatoid arthritis and lupus and with response to infections such as tuberculosis, Epstein-Barr virus infection and viral myocarditis.

A possible mechanism for the relationship between intestinal inflammation and Parkinson’s disease is that immune mediators, such as inflammatory cytokines, circulate and cross the blood–brain barrier, causing neuroinflammation and, in turn, Parkinson’s disease, Dr. Peter said.

“It might be sufficient to just have ongoing inflammation at a grade that may never reach fully that of IBD, which is an important finding because instead of screening IBD patients specifically for early Parkinson’s disease, we may want to screen for a high IBD PRS, whether or not a person has IBD,” she said.

Dr. Peter noted that rolling out such a screening program would have to wait until these results are validated in independent cohorts and when preventive strategies are available for Parkinson’s disease. “Once that is the case and we have established optimal screening cutoffs and thresholds for the PRS, early screening might be helpful in preventing Parkinson’s,” she said.

David Rubin, MD, the chair of the National Scientific Advisory Committee of the Crohn’s & Colitis Foundation, and the Joseph B. Kirsner Professor of Medicine and the chief of gastroenterology at the University of Chicago Medicine, commended Dr. Peter’s group for isolating the shared genetic link between IBD and Parkinson’s disease, and “importantly, finding that immunity is a contributing factor in the development of Parkinson’s.”

Associations With Other Neurodegenerative Diseases

“It’s worth noting that there is also limited literature pointing to associations between IBD and Alzheimer’s disease [abstract Sa514, DDW 2021], another neurodegenerative disease, and that the IBD treatments natalizumab and ozanimod are used to treat multiple sclerosis,” said Dr. Rubin, who was not involved with the current study. He added that it also would be useful to determine whether the risk for Parkinson’s disease decreases if intestinal inflammation is well controlled.

Dr. Rubin agreed that the research points to potential opportunities for Parkinson’s disease screening and surveillance, but noted some ethical considerations that need to be taken into account when rolling out pleiotropic genetic screening programs.

“When you obtain consent to perform genetic testing for one condition and those genes have implications for other diseases, you need to fully disclose and counsel patients and their family members, since they may also carry a similar polygenic risk score,” said Dr. Rubin, who is also an associate faculty member at the MacLean Center for Clinical Medical Ethics at the University of Chicago. “Knowing this may affect a patient’s willingness to proceed with genetic testing and may reveal a duty to inform other family members of their risks.”