Researchers find mutated gene contributes to development of periodontal disease
Divaris and his collaborators linked a genetic mutation to increased likelihood of periodontal disease.
Adams School of Dentistry researcher Kimon Divaris, DMD, PhD, along with collaborators from the University of Pennsylvania, have found that patients diagnosed with clonal hematopoiesis of indeterminate potential (CHIP), may be more likely to develop gum disease and show higher rates of inflammation throughout the body, according to a recent study. The research was recently published in the journal Cell.
Other authors from the University of North Carolina-Chapel Hill included Di Wu, PhD, Associate Professor in the Departments of Biomedical Sciences, Adams School of Dentistry, and Biostatistics, Gillings School of Global Public Health, James D. Beck, PhD, Emeritus Professor of Periodontology, Adams School of Dentistry, and Kari E. North, PhD, Professor of Epidemiology and Associate Dean for Research, Gillings School of Global Public Health.
Divaris, along with the study’s co-lead author, Penn’s Hui Wang, studied nearly 5,000 adults and found a higher occurrence of periodontal disease and gum inflammation in adults with a specific DNMT3A gene mutation associated with CHIP. CHIP is a non-cancerous condition where hematopoietic cells start growing abnormally due to age-related mutations, while there is no sign of hematologic disease or malignancy. These mutated cells multiply and produce mutated pro-inflammatory white blood cells. The study found a causal link between mutations in the DNMT3A gene and inflammatory bone loss and identified an FDA-approved drug that could reverse this age-related disorder.
“The first observation of this association was crucial, because it emanated from a sizeable and well-characterized community-based sample of approximately 5,000 middle-aged and elderly adults. These data demonstrated for the first time the association between CHIP and periodontal disease,” Divaris said.
Using mouse models, the researchers transplanted bone marrow cells and found that the mutated cells grew excessively and contributed to high levels of pro-inflammatory mediators in gum tissues. This also led to an increase in the cells that form bone-eating cells in the bone marrow and in the body’s inflammatory response.
In the mice receiving these mutant cells, researchers noticed an increase in naturally occurring gum disease and worsened symptoms of artificially induced gum disease and arthritis. Crucially, the team found that treating these mice with a drug called rapamycin helped alleviate the effects of the mutation.
This suggests that clonal hematopoiesis driven by mutations like those found in DNMT3A might be treatable to prevent inflammatory bone diseases such as periodontitis.
“First and foremost, the elucidation of a specific mechanism linking aging with mutated stem cell clones, hyper-inflammatory states and periodontitis provides targets for mitigating this biological pathway. In this paper, we demonstrated that rapamycin, an FDA-approved drug with immunosuppressant properties prevents CHIP-induced inflammatory bone loss. This immediately opens the possibility of treating periodontitis and other inflammatory bone diseases in humans in the near future,” Divaris said.
Divaris said the team science approach to this study was an ideal example of an intentional, systematic and mutually beneficial collaboration between institutions and a larger network of investigators whose expertise complemented the work.
“From our side at UNC-Chapel Hill, we were thrilled to see that our ability to interrogate large-scale human clinical and genomics data contributed to an intriguing biological story that was then elegantly demonstrated and comprehensively characterized using multi-model experimental approaches at the University of Pennsylvania.”
The observational evidence of association between CHIP and periodontitis was generated in the ARIC study, which is well known for its contribution to growing evidence base of oral-systemic associations.
“The ARIC study is one of the first large epidemiologic studies that included collection of biological samples and dental examinations of several clinical measures on all teeth. There have been 63 ARIC publications to-date contributing to our understanding of periodontitis’ association with systemic conditions,” Beck said. “Collectively, these ARIC-based investigations found that periodontal disease is positively associated with systemic diseases and conditions including peripheral artery disease, incident coronary heart disease and stroke, cognitive decline, subclinical atherosclerosis, kidney disease, and cancer—supporting an overarching hypothesis that inflammation may be the common cause.”
Adams School of Dentistry’s Di Wu, PhD.
“This work is a prime example of leveraging clinical and molecular data collected from population-based cohorts with rigorous data analysis to generate a novel biological hypothesis and then test it in a comprehensive and integrative manner,” Wu said. “Importantly, this important translational scientific discovery could not have happened without the elegant collaborative team effort that drove this work, including data scientists, clinicians, basic scientists, epidemiologists, from 11 different institutions.”
According to George Hajishengallis, DDS, PhD, Thomas W. Evans Centennial Professor in the Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, “our combined findings that human CHIP is associated with increased prevalence of periodontitis and that this association is likely to be causal based on a preclinical mouse model of CHIP indicate that screening for CHIP mutations among older adults may identify high-risk individuals who can benefit from preventive treatments.”
“Besides the real-world impact of these important discoveries, it is very satisfying to experience the establishment of successful collaborative partnerships and networks that not only lead to high-impact science but also facilitate continuous learning from each other,” Divaris said.
