Clinical Research // Dental Genetics

Ariadne Letra, DDS, PhD

Using genetics research to discover links between underlying conditions.

It’s easy to imagine a genetic variant leading to a clinical presentation like congenitally missing teeth—but what if that same variant also leads to colon cancer decades later?

Ariadne Letra, DDS, PhD, and her research team are unraveling genetic connections with the help of large sample sizes and genome-wide association studies of patients with dental abnormalities and systemic diseases.

A professor in the departments of Oral and Craniofacial Sciences and Endodontics, and a member of the Center for Craniofacial and Dental Genetics, School of Dental Medicine, Letra’s current research interests began when scientific publications were associating congenitally missing teeth with colorectal cancer. Those publications examined families that had hereditary tooth agenesis—the congenital absence of teeth—in which several of those family members also had colorectal cancer.

With a research background in the genetics underlying oral and craniofacial abnormalities, Letra knew that tooth agenesis and colorectal cancer have significant genetic underpinnings on their own. Nevertheless, the potential genetic overlap between oral health and systemic health conditions sparked her interest in exploring whether shared genetic variants contribute to comorbid presentations. “We may have different manifestations of a genetic variant in different organ systems,” Letra explains.

Using the NIH colorectal cancer registry, Letra and her team have identified individuals who had both colorectal cancer and missing teeth to look for genetic associations correlating with the co-occurrence of both conditions. However, Letra cautions that correlation does not equal causation, as these conditions might co-occur by chance alone. Although, when sample sizes are large, she explains, “Those two well-described and detailed conditions appearing together, compared to controls, increases the likelihood that the association is true.”

She and her team identified multiple genetic variants correlating with both clinical conditions, indicating that shared common genetic variants may play a role. While still only associations, she and her team are following up on the genetic candidates through laboratory work to assess functional roles through in vitro studies, cell models, and animal models. These experiments lay the foundation for future studies validating the pathological involvement of these genomic associations.

In her endodontic clinic, Letra noticed another correlation. She saw that some patients with necrotic pulp, typically treated with a root canal, also exhibited apical periodontitis—an inflammatory condition that can lead to the deterioration of bone beneath the affected tooth.

After conducting a GWAS to find genes associated with apical periodontitis, she was surprised to see that some positively associated genes had known implications in other systemic health conditions. Letra found a robust link with hypertension and, more recently, has validated the potential connection of apical periodontitis with cardiovascular disease and risk factors.

These systemic health correlations spurred her research to look at all dental diseases of an inflammatory nature and look for positive genetic associations with other systemic diseases using the All of Us research program database, which melds genetic data with patient electronic health records. The All of Us research program aims to recruit one million individuals, providing a sample size capable of highlighting candidate genetic variants within the context of clinical data.

“I think the potential association of a craniofacial defect (like cleft palate) or an inflammatory condition that’s common (like a necrotic pulp) with underlying additional systemic health is intriguing,” says Letra. Her recent studies have also validated shared genetic associations between dental conditions and diabetes, as well as identifying new pathways, like estrogen metabolism, that may explain why some of these dental conditions also have a sex bias.

With this knowledge, Letra is confident that we are not far from treating and following up with dental patients holistically. Letra explains that examining genetic, dental and medical records together will lead to more precision-based preventive and therapeutic strategies in the future.

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