Searching Deep and Wide: Advances in the Molecular Understanding of Dental Caries and Periodontal Disease

Abstract

During the past decades, remarkable progress has been made in the understanding of the molecular basis of the 2 most common oral diseases, dental caries and periodontal disease. Improvements in our knowledge of the diseases’ underlying biology have illuminated previously unrecognized aspects of their pathogenesis. Importantly, the key role of the oral (supragingival and subgingival) microbiome is now well recognized, and both diseases are now best understood as dysbiotic. From a host susceptibility standpoint, some progress has been made in dissecting the “hyperinflammatory” trait and other pathways of susceptibility underlying periodontitis, and novel susceptibility loci have been reported for dental caries. Nevertheless, there is a long road to the translation of these findings and the realization of precision oral health. There is promise and hope that the rapidly increasing capacity of generating multiomics data layers and the aggregation of study samples and cohorts comprising thousands of participants will accelerate the discovery and translation processes. A first key element in this process has been the identification and interrogation of biologically informed disease traits—these “deep” or “precise” traits have the potential of revealing biologically homogeneous disease signatures and genetic susceptibility loci that might present with overlapping or heterogeneous clinical signs. A second key element has been the formation of international consortia with the goals of combining and harmonizing oral health data of thousands of individuals from diverse settings—these “wide” collaborative approaches leverage the power of large sample sizes and are aimed toward the discovery or validation of genetic influences that would otherwise be impossible to detect. Importantly, advancements via these directions require an unprecedented engagement of systems biology and team science models. The article highlights novel insights into the molecular basis of dental caries and chronic periodontitis that have been gained from recent and ongoing studies involving “deep” and “wide” analytical approaches.

Introduction

Despite advances in the science and practice of dentistry, the 2 most common oral diseases, dental caries and periodontitis, persist as clinical and public health problems. Substantial proportions of adults suffer from periodontal disease worldwide, while prevalence estimates for severe periodontitis range between 5% and 15% (Dye 2012). The prevalence of severe periodontitis increases by age. It confers a sustained systemic inflammatory burden and is associated with several general health conditions and outcomes, including impaired glycemic control among diabetics (Teeuw et al. 2010). At the same time, dental caries is the most prevalent disease worldwide (Frencken et al. 2017). Both diseases have human and economic costs and remain as unsolved problems worldwide (Petersen et al. 2005)—they can and often do lead to tooth loss, as well as multilevel impacts on individuals, their families, communities, and the health care system.

Advances in the Basic Understanding of Dental Caries and Periodontitis as Disease Entities

During the past 2 decades, enormous strides have been made in the oral health domain toward better understanding dental caries and periodontitis as disease entities. These major advances have been made mainly with regards to the underlying biology and thus they have illuminated previously unrecognized aspects of their pathogenesis. Importantly, the key role of the oral (supragingival and subgingival) microbiome has been well recognized (Wade 2013), and both diseases are now best understood as dysbiotic. From a host susceptibility standpoint, progress has been made in dissecting the inflammatory axis contribution, “hyperinflammatory” trait, and other pathways of susceptibility underlying periodontitis (Cekici et al. 2014). Arguably, better knowledge and understanding of the biological processes underlying these conditions can help optimize the conduct of mechanistic research, development of pharmacotherapies, and all preventive and disease management efforts (Divaris 2017a).

Another major thrust forward has been delivered via the emerging individual susceptibility knowledge base that is being generated in the current era of the genome (Divaris 2019). During the past decade, several efforts from multiple groups around the world have investigated the genomic basis of caries (Shaffer et al. 2011; Shaffer et al. 2013; Zeng et al. 2013; Divaris 2017b; Ballantine et al. 2018; Morelli et al. 2019) and periodontitis (Schaefer et al. 2009; Schaefer et al. 2010; Bochenek et al. 2013; Divaris et al. 2013; Teumer et al. 2013; Offenbacher et al. 2016; Sanders et al. 2017; Schaefer 2018; Morelli et al. 2019). Although the oral health genomics field is still in its early stages, there is reasonable hope and justified expectation that some actionable findings will lead to direct improvements in clinical care (Kornman and Polverini 2014; Divaris 2017a). A landmark, international collaborative effort combined genome-wide association data from the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) consortium and the UK Biobank (Shungin et al. 2019) and recently reported the discovery of 47 novel loci for dental caries/tooth morbidity and affirmed previous reports of an association between SIGLEC5 and periodontitis (Munz et al. 2017; Tong et al. 2019). However, a long road remains for the validation and eventual translation of these findings and the realization of precision oral health, as evidenced in other fields of health care.

The Promise of Precision (Oral) Health and Care

The precision medicine (and health care, in general) initiative (Collins and Varmus 2015) has been met with substantial enthusiasm, activity, and actual investment from multiple stakeholders—the public and the private sectors, community, and academic stakeholders. Parallel efforts have emphasized the importance of a “population approach” in the precision health discourse (Khoury et al. 2012) and the practical gains emanating from it (Sivadas and Scaria 2019). Under this paradigm, precision health care is one that is at the intersection of accounting for one’s environment, culture, lifestyle, and individual susceptibility—and it may be applied in a similar fashion to individuals or populations. Table 1 lists the definitions of concepts and terms commonly used and relevant in the context of precision health.

Table 1.

Definition or Description of Terms and Concepts Common and Relevant in the Context of Precision Health.

Term/Concept	Definition/Description
Dysbiosis	A status of microbial-ecological imbalance, typically characterized by pathological shifts of the microbiome due to host innate factors (e.g., genetics and physiology) or environmental (e.g., diet) influences. Although this is not an absolute association, dysbiosis tends to be characterized by dominance of selected species versus microbial diversity.
Endophenotype	An intermediate component of a disease process that is predictive of the disease but tends to be more biologically homogeneous and heritable than the endpoint disease itself (e.g., blood lipids for cardiovascular disease, microbial or inflammatory load for periodontal disease).
Genome	The entirety of genetic material, including genes and other genetic information necessary for building and maintaining the function of an organism (e.g., the human genome comprises over 3 billion DNA base pairs).
Heterogeneity	The state or quality of being diverse in nature or content (e.g., varying effects of a drug according to individuals’ genetic makeup).
High-throughput sequencing	Methods that enable the generation of thousands or millions of nucleotide sequences simultaneously. High-throughput sequencing technologies have enabled the study of genes, genomes, and other features in a fraction of the time and cost than what would be needed using Sanger sequencing.
Multiomics	An analytical approach wherein information emanating from multiple aspects of biology (e.g., genome, epigenome, transcriptome, proteome, metabolome) is measured and considered jointly.
Population approach	An approach to health that aims to improve the health of the population as a whole and reduce health disparities. This is typically achieved via various large-scale health promotion strategies or the alleviation of the impact of the social determinants of health—as opposed to individual, person-level, strategies.
Precision health care	An approach to health care wherein people’s variabilities in genetic makeup, environment, and lifestyle are taken into consideration (e.g., customization of preventive or therapeutic regimens according to genetic makeup, smoking status).

Little practical progress has been made to date in the development of precision health care in the oral health domain. However, the rapidly increasing capacity of generating multiomics data layers, the relatively easy access to the oral cavity for biospecimen collection, and the aggregation of study samples and cohorts comprising thousands of participants are certain to accelerate the discovery and translation processes. In this context and considering a “wide” investigative approach, the formation of the GLIDE consortium (Shungin et al. 2015) has been a landmark evolvement, analogous to the formation of large consortia for anthropometric traits and cardiometabolic conditions. An example of a “deep” investigative approach is offered in a recent genomic investigation that created and then interrogated novel, biologically informed traits (i.e., including information about subgingival pathogen colonization and local inflammatory response) reported by Offenbacher et al. (2016). The premise of that approach revolved around the notion that otherwise biologically homogeneous periodontal disease entities may be diluted or masked by varying clinical presentations (i.e., affected by numerous environmental and upstream factors)—and, unless these biologically defined categories are uncovered and defined, the discovery of the genetic determinants may be hindered.

What Does “Deep” and “Wide” Mean?

The argument made here is essentially a call for intentional, coordinated, and collaborative efforts across the entire spectrum of oral health research (including the foundational sciences, clinical and population research) to accelerate discovery, validation, translation, and implementation (Figure). In this model, we argue that general research directions for the advancement of the molecular understanding of oral health and disease, including “deep” and “wide” approaches, are likely needed to decisively advance the field. Large-scale studies and consortia with harmonized data are likely to facilitate the discovery of genomic influences on clinically defined dental caries and periodontal disease or their proxies. At the same time, investment in the genetic interrogation of biologically informed traits, encompassing additional omics layers of information known to be influential (e.g., microbiome for dental caries and inflammatory mediators for periodontal disease), is also key for the identification of biologically driven disease subtypes and well aligned with the notion of precision medicine. However, a biologically informed approach is unlikely to happen at a very large scale at least currently, due to cost and logistical issues. Simultaneously, applied and translational studies, as well as experimental and mechanistic investigations, are warranted for the acceleration of knowledge and evidence transfer from the stage of discovery to application.

Figure.

Depiction of general research directions for the advancement of the molecular understanding of oral health and disease. The central thesis is that experimental, basic, and biologically informed (i.e., “deep”) and population-based or large-scale (i.e., “wide”) research approaches are needed to decisively advance the knowledge base for the realization of precision health. Green rectangular boxes include specific investigative strategies; orange callout boxes include example biological intermediates and specific requirements for the realization of “wide” and “deep” research initiatives, respectively; the blue double arrows illustrate the desirable crosstalk between these general research directions. In the oral health domain, it is expected that large-scale studies and consortia with harmonized data will facilitate the discovery of genomic influences on clinically defined dental caries and periodontal disease or their proxies. At the same time, investment in the genetic interrogation of biologically informed traits, encompassing additional omics layers of information known to be influential (e.g., microbiome for dental caries and inflammatory mediators for periodontal disease), is key for the identification of biologically driven disease subtypes, aligned with the notion of precision health and care. Clinical and translational studies are warranted for the acceleration of knowledge and evidence transfer from the stage of discovery to application.

A prime example of a combined “deep and wide” approach has been reported for periodontitis by Offenbacher et al. (2018), wherein a genome-wide significant signal (i.e., a novel genetic locus (IL37) encoding for interleukin 37, a regulatory cytokine that dampens the immune response) for crevicular fluid interleukin-1β expression, was first discovered from a population-based study. Then, this finding was confirmed via an array of experimental methods (i.e., using animal models), validated using a new sample of human participants, externally replicated using independent population-based cohorts, supported by a prospective investigation of incident tooth loss, and examined for associations with other systemic health associations (e.g., history of stroke). Although the practical clinical utility of this novel genetic finding remains to be investigated, this report is an example of an intentional crosstalk and collaboration between population, clinical, and basic scientists. Frameworks for integrative, multiomics investigations or combined “deep” and “wide” studies of dental caries have been introduced, among others, by Nyvad et al. (2013) and Divaris (2016). Along these lines, we have proposed that precision dentistry, including genomic influences on oral health and disease, may be best examined in the context of well-characterized communities (versus convenience clinical samples), and the impact of contextual factors (e.g., geography and social disadvantage) may be explainable via mechanistic (i.e., biological) research (Divaris and Joshi 2018). This intentional crosstalk has the potential to create favorable synergies and opportunities for discovery, promote interprofessional collaboration, and accelerate the translational process.

Challenges and Opportunities for the Advancement of Research Informing Precision Oral Health and Care

Measurement of oral health and disease endpoints is perhaps the most obvious and influential issue needing to be tackled. Arguably, measures that capture the biological basis of oral disease (e.g., the presence of a dysbiotic oral microbiome, aberrant inflammation and progressive clinical attachment loss, sustained and progressive demineralization of tooth structures), as well as its clinical heterogeneity, are more suitable for precision oral health research and practice applications (Divaris 2016, 2017a). To provide one specific example, tooth loss is known to affect the measurement of dental caries and periodontitis experience (Haworth et al. 2018), especially in large, cross-sectional samples. Importantly, such samples are the most common vehicles for the conduct of genome-wide association studies, where the acquisition of large sample sizes is naturally prioritized over the existence of detailed records or other clinical information sources. Of note, the GLIDE report of novel dental caries loci among approximately half a million individuals (Shungin et al. 2019) successfully incorporated self-reported “denture wear” as an analytical proxy for dental caries–oriented genetic analyses in the UK Biobank contributing sample. At the same time, systematic efforts to address the possible misclassification bias introduced by tooth loss in the ascertainment of periodontitis have been reported (Morelli et al. 2017; Morelli et al. 2018). These approaches often lead to development of new disease classification systems (Beck et al. 2018) that may inform and complement the consensus taxonomies (Papapanou et al. 2018).

Several new opportunities that have emerged in the context of precision medicine revolve around the efficient and effective combination of multiple data layers (Auffray and Hood 2012), most frequently of omics nature (i.e., genomics, proteomics, metabolomics, transcriptomics, metagenomics, etc.). Naturally, unprecedented demands are placed on data science and biological interpretation of such big data in the context of systems biology (Chen and Snyder 2013). Technological and bioinformatics evolvements that have enabled the generation of thousands or millions of nucleotide sequences simultaneously have driven most advances thus far (Divaris 2019). High-throughput sequencing applications allow for the study of genes, genomes, and other features of an organism in a fraction of the time and cost compared to what would be needed using traditional sequencing.

Making sense and navigating the sea of omics is not a challenge unique to the oral health domain. Arguably, a concerted effort by multiple stakeholders to embrace an implementation science approach is warranted (Chambers et al. 2016). The author proposes that several cross-cutting notions and themes are relevant to the translation of discoveries in the framework of precision and P4 (predictive, preventive, personalized, and participatory) oral health care (Table 2). Although this is not an exhaustive or absolute list of activities, several of these stand out and appear as well supported by the literature. For example, creating “learning” health care systems (Chambers et al. 2016) appears as an attractive health care model and a meaningful process endpoint. Intentional collaborative efforts and resource/data sharing, public- and private-sector partnerships, community engagement, and bold investments in science and education (Cesario et al. 2014) would also appear as priorities. From an aspirational perspective, addressing several if not all of these challenges will likely help accelerate improvements in all people’s oral health and care, the health of all of us.

Table 2.

Cross-Cutting Notions and Themes Relevant to the Translation of Discoveries in the Framework of Precision and P4 (Predictive, Preventive, Personalized, and Participatory) Oral Health Care to Accelerate Improvements in All People’s Oral Health and Care.

Appreciation and operationalization of systems biology

Intentional translational efforts

Use of an implementation science framework

Strive to create “learning” health care systems

Support collaborations at all levels, including interdisciplinary and interprofessional

Sharing of resources, results, data, and protocols

Embracement of new and potentially disruptive technologies

Engage the community

Investments in education

Create partnerships (e.g., public and private sector) to accelerate discovery and implementation

Author Contributions

K. Divaris, contributed to conception, design, data acquisition, analysis, and interpretation, drafted and critically revised the manuscript. The author gave final approval and agree to be accountable for all aspects of the work.