Kimon Divaris

Exploring the genetic basis of chronic periodontitis: a genome-wide association study

Chronic periodontitis (CP) is a common oral disease that confers substantial systemic inflammatory and microbial burden and is a major cause of tooth loss. Here, we present the results of a genome-wide association study of CP that was carried out in a cohort of 4504 European Americans (EA) participating in the Atherosclerosis Risk in Communities (ARIC) Study (mean age—62 years, moderate CP—43% and severe CP—17%). We detected no genome-wide significant association signals for CP; however, we found suggestive evidence of association (P < 5 × 10−6) for six loci, including NIN, NPY, WNT5A for severe CP and NCR2, EMR1, 10p15 for moderate CP. Three of these loci had concordant effect size and direction in an independent sample of 656 adult EA participants of the Health, Aging, and Body Composition (Health ABC) Study. Meta-analysis pooled estimates were severe CP (n = 958 versus health: n = 1909)—NPY, rs2521634 [G]: odds ratio [OR = 1.49 (95% confidence interval (CI = 1.28–1.73, P = 3.5 × 10−7))]; moderate CP (n = 2293)—NCR2, rs7762544 [G]: OR = 1.40 (95% CI = 1.24–1.59, P = 7.5 × 10−8), EMR1, rs3826782 [A]: OR = 2.01 (95% CI = 1.52–2.65, P = 8.2 × 10−7). Canonical pathway analysis indicated significant enrichment of nervous system signaling, cellular immune response and cytokine signaling pathways. A significant interaction of NUAK1 (rs11112872, interaction P = 2.9 × 10−9) with smoking in ARIC was not replicated in Health ABC, although estimates of heritable variance in severe CP explained by all single nucleotide polymorphisms increased from 18 to 52% with the inclusion of a genome-wide interaction term with smoking. These genome-wide association results provide information on multiple candidate regions and pathways for interrogation in future genetic studies of CP.

Oral Health Literacy among Female Caregivers: Impact on Oral Health Outcomes in Early Childhood

The aim of this study was to investigate the association of female caregivers’ oral health literacy with their knowledge, behaviors, and the reported oral health status of their young children. Data on caregivers’ literacy, knowledge, behaviors, and children’s oral health status were used from structured interviews with 1158 caregiver/child dyads from a low-income population. Literacy was measured with REALD-30. Caregivers’ and children’s median ages were 25 yrs (range = 17-65) and 15 mos (range = 1-59), respectively. The mean literacy score was 15.8 (SD = 5.3; range = 1-30). Adjusted for age, education, and number of children, low literacy scores (< 13 REALD-30) were associated with decreased knowledge (OR = 1.86; 95% CI = 1.41, 2.45) and poorer reported oral health status (OR = 1.44; 95% CI = 1.02, 2.05). Lower caregiver literacy was associated with deleterious oral health behaviors, including nighttime bottle use and no daily brushing/cleaning. Caregiver oral health literacy has a multidimensional impact on reported oral health outcomes in infants and young children.

Genome-wide Association Study of Periodontal Pathogen Colonization

Pathological shifts of the human microbiome are characteristic of many diseases, including chronic periodontitis. To date, there is limited evidence on host genetic risk loci associated with periodontal pathogen colonization. We conducted a genome-wide association (GWA) study among 1,020 white participants of the Atherosclerosis Risk in Communities Study, whose periodontal diagnosis ranged from healthy to severe chronic periodontitis, and for whom “checkerboard” DNA-DNA hybridization quantification of 8 periodontal pathogens was performed. We examined 3 traits: “high red” and “high orange” bacterial complexes, and “high” Aggregatibacter actinomycetemcomitans (Aa) colonization. Genotyping was performed on the Affymetrix 6.0 platform. Imputation to 2.5 million markers was based on HapMap II-CEU, and a multiple-test correction was applied (genome-wide threshold of p < 5 × 10−8). We detected no genome-wide significant signals. However, 13 loci, including KCNK1, FBXO38, UHRF2, IL33, RUNX2, TRPS1, CAMTA1, and VAMP3, provided suggestive evidence (p < 5 × 10−6) of association. All associations reported for “red” and “orange” complex microbiota, but not for Aa, had the same effect direction in a second sample of 123 African-American participants. None of these polymorphisms was associated with periodontitis diagnosis. Investigations replicating these findings may lead to an improved understanding of the complex nature of host-microbiome interactions that characterizes states of health and disease.

The Ethical Imperative of Addressing Oral Health Disparities A Unifying Framework

Health disparities are preventable differences in the burden of disease or opportunities to achieve optimal health that are experienced by socially disadvantaged population groups. Reducing health disparities has been identified as an ethical imperative by the World Health Organization’s Commission on Social Determinants of Health and numerous other national and international bodies. Significant progress has been made over the past years in identifying vulnerable groups, and ‘distal’ factors including political, economic, social, and community characteristics are now considered pivotal. It is thus unsurprising that the remarkable advances in the science and practice of dentistry have not led to notable reductions in oral health disparities. In this review, we summarize recent work and emphasize the need for a solid theoretical framing to guide oral health disparities research. We provide a theoretical framework outlining pathways that operate across the continuum of oral health determinants during the lifecourse and highlight potential areas for intervention. Because oral health disparities emanate from the unequal distribution of social, political, economic, and environmental resources, tangible progress is likely to be realized only by a global movement and concerted efforts by all stakeholders, including policymakers, the civil society, and academic, professional, and scientific bodies.

The Relationship of Oral Health Literacy and Self-Efficacy With Oral Health Status and Dental Neglect

OBJECTIVES We examined the associations of oral health literacy (OHL) with oral health status (OHS) and dental neglect (DN), and we explored whether self-efficacy mediated or modified these associations. METHODS We used interview data collected from 1280 female clients of the Special Supplemental Nutrition Program for Women, Infants and Children from 2007 to 2009 as part of the Carolina Oral Health Literacy Project. We measured OHL with a validated word recognition test (REALD-30), and we measured OHS with the self-reported National Health and Nutrition Examination Survey item. Analyses used descriptive, bivariate, and multivariate methods. RESULTS Less than one third of participants rated their OHS as very good or excellent. Higher OHL was associated with better OHS (for a 10-unit REALD increase: multivariate prevalence ratio = 1.29; 95% confidence interval = 1.08, 1.54). OHL was not correlated with DN, but self-efficacy showed a strong negative correlation with DN. Self-efficacy remained significantly associated with DN in a fully adjusted model that included OHL. CONCLUSIONS Increased OHL was associated with better OHS but not with DN. Self-efficacy was a strong correlate of DN and may mediate the effects of literacy on OHS.

Chronic Periodontitis Genome-wide Association Studies Gene-centric and Gene Set Enrichment Analyses

Recent genome-wide association studies (GWAS) of chronic periodontitis (CP) offer rich data sources for the investigation of candidate genes, functional elements, and pathways. We used GWAS data of CP (n = 4,504) and periodontal pathogen colonization (n = 1,020) from a cohort of adult Americans of European descent participating in the Atherosclerosis Risk in Communities study and employed a MAGENTA approach (i.e., meta-analysis gene set enrichment of variant associations) to obtain gene-centric and gene set association results corrected for gene size, number of single-nucleotide polymorphisms, and local linkage disequilibrium characteristics based on the human genome build 18 (National Center for Biotechnology Information build 36). We used the Gene Ontology, Ingenuity, KEGG, Panther, Reactome, and Biocarta databases for gene set enrichment analyses. Six genes showed evidence of statistically significant association: 4 with severe CP (NIN, p = 1.6 × 10−7; ABHD12B, p = 3.6 × 10−7; WHAMM, p = 1.7 × 10−6; AP3B2, p = 2.2 × 10−6) and 2 with high periodontal pathogen colonization (red complex–KCNK1, p = 3.4 × 10−7; Porphyromonas gingivalis–DAB2IP, p = 1.0 × 10−6). Top-ranked genes for moderate CP were HGD (p = 1.4 × 10−5), ZNF675 (p = 1.5 × 10−5), TNFRSF10C (p = 2.0 × 10−5), and EMR1 (p = 2.0 × 10−5). Loci containing NIN, EMR1, KCNK1, and DAB2IP had showed suggestive evidence of association in the earlier single-nucleotide polymorphism–based analyses, whereas WHAMM and AP2B2 emerged as novel candidates. The top gene sets included severe CP (“endoplasmic reticulum membrane,” “cytochrome P450,” “microsome,” and “oxidation reduction”) and moderate CP (“regulation of gene expression,” “zinc ion binding,” “BMP signaling pathway,” and “ruffle”). Gene-centric analyses offer a promising avenue for efficient interrogation of large-scale GWAS data. These results highlight genes in previously identified loci and new candidate genes and pathways possibly associated with CP, which will need to be validated via replication and mechanistic studies.

Genome-wide association study of biologically-informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease

Genome-wide association studies (GWAS) of chronic periodontitis (CP) defined by clinical criteria alone have had modest success to-date. Here, we refine the CP phenotype by supplementing clinical data with biological intermediates of microbial burden (levels of eight periodontal pathogens) and local inflammatory response (gingival crevicular fluid IL-1β) and derive periodontal complex traits (PCTs) via principal component analysis. PCTs were carried forward to GWAS (∼2.5 million markers) to identify PCT-associated loci among 975 European American adult participants of the Dental ARIC study. We sought to validate these findings for CP in the larger ARIC cohort (n = 821 participants with severe CP, 2031—moderate CP, 1914—healthy/mild disease) and an independent German sample including 717 aggressive periodontitis cases and 4210 controls. We identified six PCTs with distinct microbial community/IL-1β structures, although with overlapping clinical presentations. PCT1 was characterized by a uniformly high pathogen load, whereas PCT3 and PCT5 were dominated by Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, respectively. We detected genome-wide significant signals for PCT1 (CLEC19A, TRA, GGTA2P, TM9SF2, IFI16, RBMS3), PCT4 (HPVC1) and PCT5 (SLC15A4, PKP2, SNRPN). Overall, the highlighted loci included genes associated with immune response and epithelial barrier function. With the exception of associations of BEGAIN with severe and UBE3D with moderate CP, no other loci were associated with CP in ARIC or aggressive periodontitis in the German sample. Although not associated with current clinically determined periodontal disease taxonomies, upon replication and mechanistic validation these candidate loci may highlight dysbiotic microbial community structures and altered inflammatory/immune responses underlying biological sub-types of CP.

Predicting Dental Caries Outcomes in Children A “Risky” Concept

In recent years, unprecedented gains in the understanding of the biology and mechanisms underlying human health and disease have been made. In the domain of oral health, although much remains to be learned, the complex interactions between different systems in play have begun to unravel: host genome, oral microbiome with its transcriptome, proteome and metabolome, and more distal influences, including relevant behaviors and environmental exposures. A reasonable expectation is that this emerging body of knowledge can help improve the oral health and optimize care for individuals and populations. These goals are articulated by the National Institutes of Health as “precision medicine” and the elimination of health disparities. Key processes in these efforts are the discovery of causal factors or mechanistic pathways and the identification of individuals or population segments that are most likely to develop (any or severe forms of) oral disease. This article critically reviews the fundamental concepts of risk assessment and outcome prediction, as they relate to early childhood caries (ECC)—a common complex disease with significant negative impacts on children, their families, and the health system. The article highlights recent work and advances in methods available to estimate caries risk and derive person-level caries propensities. It further discusses the reasons for their limited utility in predicting individual ECC outcomes and informing clinical decision making. Critical issues identified include the misconception of defining dental caries as a tooth or surface-level condition versus a person-level disease; the fallacy of applying population-level parameters to individuals, termed privatization of risk; and the inadequacy of using frequentist versus Bayesian modeling approaches to derive individual disease propensity estimates. The article concludes with the notion that accurate caries risk assessment at the population level and “precision dentistry” at the person level are both desirable and achievable but must be based on high-quality longitudinal data and rigorous methodology.

Surface-specific efficacy of fluoride varnish in caries prevention in the primary dentition: results of a community randomized clinical trial.

Objectives: Fluoride varnish (FV) is efficacious in caries prevention although its effects among different tooth surfaces are poorly understood. This study sought to determine the extent to which caries-preventive effects of a community intervention that included FV application among preschool-aged children varied according to primary tooth anatomy and baseline tooth pathology. Methods: Secondary analysis was undertaken of data from a community-randomized controlled trial among 543 3- to 5-year-old Aboriginal children in 30 Northern Territory Australian communities. Children in intervention communities received community health promotion and FV application once every 6 months. Net caries (d3mfs) risk and 95% confidence limits (CL) were estimated for the control and intervention arms, and stratified according to tooth anatomy/location and baseline pathology (sound, enamel opacity, hypoplastic defect or precavitated carious lesion). The intervention’s efficacy was quantified using generalized estimating equation modeling accounting for study design and clustering. The assumption of efficacy homogeneity was tested using a Wald χ2 test with a p < 0.2 criterion and post hoc pairwise comparisons. Results: The intervention resulted in a 25% reduction (relative risk, RR = 0.75; 95% CL = 0.71, 0.80) in the 2-year surface-level caries risk. There was substantial heterogeneity in FV efficacy by baseline surface pathology: RRs were 0.73 for sound, 0.77 for opaque, 0.90 for precavitated, and 0.92 for hypoplastic surfaces. Among sound surfaces, maxillary anterior facials received significantly more benefit (RR = 0.62) compared to pits and fissures (RR = 0.78). Conclusion: The intervention had greatest efficacy on surfaces that were sound at baseline. Among those sound surfaces, maxillary anterior facials received most caries-preventive benefit.

Comparison of Bacterial Community Composition of Primary and Persistent Endodontic Infections Using Pyrosequencing

INTRODUCTION Elucidating the microbial ecology of endodontic infections (EIs) is a necessary step in developing effective intracanal antimicrobials. The aim of the present study was to investigate the bacterial composition of symptomatic and asymptomatic primary and persistent infections in a Greek population using high-throughput sequencing methods. METHODS 16S amplicon pyrosequencing of 48 root canal bacterial samples was conducted, and sequencing data were analyzed using an oral microbiome-specific and a generic (Greengenes) database. Bacterial abundance and diversity were examined by EI type (primary or persistent), and statistical analysis was performed by using non-parametric and parametric tests accounting for clustered data. RESULTS Bacteroidetes was the most abundant phylum in both infection groups. Significant, albeit weak associations of bacterial diversity were found, as measured by UniFrac distances with infection type (analyses of similarity, R = 0.087, P = .005) and symptoms (analyses of similarity, R = 0.055, P = .047). Persistent infections were significantly enriched for Proteobacteria and Tenericutes compared with primary ones; at the genus level, significant differences were noted for 14 taxa, including increased enrichment of persistent infections for Lactobacillus, Streptococcus, and Sphingomonas. More but less abundant phyla were identified using the Greengenes database; among those, Cyanobacteria (0.018%) and Acidobacteria (0.007%) were significantly enriched among persistent infections. Persistent infections showed higher phylogenetic diversity (PD) (asymptomatic: PD = 9.2, standard error [SE] = 1.3; symptomatic: PD = 8.2, SE = 0.7) compared with primary infections (asymptomatic: PD = 5.9, SE = 0.8; symptomatic: PD = 7.4, SE = 1.0). CONCLUSIONS The present study revealed a high bacterial diversity of EI and suggests that persistent infections may have more diverse bacterial communities than primary infections.