Mariana Bezamat

Periodontal disease and dental caries are two oral conditions that have been associated with atherosclerotic cardiovascular disease (ASCVD). However, it is unclear if one of the key mechanisms involved in this association could be a shared genetic susceptibility. The goal of this study was to explore whether there is an intersection of genetic loci among individuals with comprehensive oral examinations and subclinical ASCVD screenings. We leveraged data from oral and medical examinations obtained from the Dental and Heart Strategies Concentrating on Risk Evaluation (Dental/Heart SCORE) projects. Genome-wide association studies (GWASs) were performed independently in 552 participants (aged 45–75 years). The decayed, missing, or filled teeth index (DMFT) and periodontal disease indices were used to reflect oral conditions; coronary artery calcium scores (CAC) and carotid intima media thickness (CIMT) were analyzed as subclinical ASCVD traits. Single nucleotide variant (SNV) associations with oral and ASCVD traits were found; however, there were only a few regions of suggestive genetic loci overlap between these conditions. The most robust associations found for each phenotype are as follows: DMFT with rs79198416 (near CDC73/KCNT2; p = 7.57E-07), periodontal disease with rs73870587 (DIPK2A, p = 7.38E-08); CIMT with rs113152669 (LRP1B p = 4.07E-07), and CAC with rs76676138 (CNTNAP2; p = 2.47E-19). Although genetic associations were identified for each of the phenotypes of interest in the GWASs, there were no regions of shared genetic loci that significantly intersected across phenotypes. Thus, our results suggest that incorporation of environmental, behavioral, microbiome-related factors, and larger sample sizes, are warranted in future studies between oral and cardiovascular health.

Objectives: Dental caries and periodontitis are among the most prevalent chronic diseases worldwide and have been associated with atherosclerotic cardiovascular diseases (ASCVD). This study aimed to determine (1) the independent associations between subclinical ASCVD markers (carotid intima media thickness [CIMT] and coronary artery calcification [CAC]) and quantitative indices of oral disease including the decayed, missing, and filled teeth (DMFT) index, gingivitis parameters, periodontal status, and number of teeth lost and (2) the extent to which metabolites altered in individuals with oral disease overlapped with those altered in individuals with ASCVD. Methods: We used data from 552 participants recruited through the Dental Strategies Concentrating on Risk Evaluation project. Oral examinations were conducted, and CIMT and CAC were measured. Multiple linear regression models were constructed with CIMT and CAC as dependent variables in the epidemiologic analysis. In the metabolomic analysis, logistic or linear regression was used to test 1,228 metabolites for association with each phenotype adjusted for age, sex, race, blood pressure, smoking, diabetes, cholesterol, high-sensitivity C-reactive protein, and interleukin-6. Results: None of the oral disease markers were significant predictors of ASCVD markers in the fully adjusted models. However, critical lipid and lipid-signaling pathway metabolites were significantly associated with gingivitis, periodontitis, and DMFT: the lysophospholipid pathway (odds ratio [OR] = 2.29, false discovery rate [FDR]–adjusted P = 0.038) and arachidonate with gingivitis (OR = 2.35, FDR-adjusted P = 0.015), the sphingolipid metabolism pathway with periodontitis (OR = 2.09, FDR-adjusted P = 0.029), and borderline associations between plasmalogen and lysophospholipid pathways and DMFT (P = 0.055). Further, the same metabolite from the sphingolipid metabolism pathway, sphingomyelin (d17:1/14:0, d16:1/15:0), was inversely associated with both CIMT (β = −0.14, FDR-adjusted P = 0.014) and gingivitis (OR = 0.04, FDR-adjusted P = 0.033). Conclusions: The discovery of a common sphingomyelin metabolite in both disease processes is a novel finding suggesting that gingivitis and periodontitis may be associated with some overlapping metabolic pathways associated with ASCVD and indicating potential shared mechanisms among these diseases. Knowledge Transfer Statement: The same metabolites may be altered in atherosclerosis and oral disease. Specifically, a common sphingomyelin metabolite was inversely associated with gingivitis and carotid intima media thickness, a subclinical marker of atherosclerotic cardiovascular disease. These findings can provide valuable insights for future mechanistic studies to establish potential causal relationships, with the hope of influencing disease prevention and targeted early treatment.

To characterize drug hypersensitivity associated with dental treatments.

Erosive tooth wear is a multifactorial condition of an increasing prevalence. There is a need for discovering individual genetic predisposition for the development of this condition. Considering that the chromosome X locus was previously shown to be associated with dental caries, the aim of the present study was to look for the association between this locus and erosive tooth wear when dietary habits are considered as a co-factor. Saliva samples, erosive wear experience data, and dietary information from 16- to 18-year-old dental patients (n = 705) were used. Genotyping analyses were performed, and thereafter, analyses considering diet and oral hygiene data, using logistic regression, with the assumption that erosive tooth wear is a complex gene-environment model. Genotypic analyses revealed an association between chromosome X marker rs1324156 and erosive tooth wear phenotype. Logistic regression analysis showed that, in the presence of less common allele of rs12687601 and rs1324156, erosive tooth wear more likely develops when associated with numerous dietary variables from the questionnaire. These results indicate that erosive tooth wear may be the result of gene-environment interactions.

Atherosclerotic cardiovascular diseases (ACVD) and oral infections such as periodontal disease, dental caries, and apical periodontitis are diseases that affect a great portion of the worldwide population. Both are complex in nature and several studies show that they share etiological factors but a causal relationship between them has not been yet established due to the lack of well-designed clinical trials. Many studies in the recent years show convincing evidence of different mechanisms that might be involved in this association including chronic inflammation and immune response. However, some of these mechanisms are controversial because of confounding factors. It has been suggested that maladaptive inflammatory reactivity, determined in part by single nucleotide polymorphisms (SNPs) in pathway genes, could influence the association between oral infections, and cardiovascular diseases as pleiotropic genes. That is, these conditions could be outcomes of similar inflammatory pathways. Phenomics, the study of the changes in phenotypes or traits considering environmental variables and genetics is efficient in assessing and determining pleiotropic genes. Future research should focus on analyzing a combination of oral inflammatory conditions instead of focusing on one inflammatory phenotype alone and consider pleiotropy as a mechanistic contributor for these associations. Further, prospective observational studies seeking to follow the development of oral disease and subclinical ACVD will foster the understanding of the impact of oral health on general systemic health. Lastly, to demonstrate that oral infections would increase risk for subclinical ACVD development, clinical trials proposing to treat those infections considering genetic background and all other confounders are needed.

Early-stage cancer diagnosis is critical for higher survival rates. Because early cancers can be difficult to detect, our focus is on the identification of cancer risk markers such as pleiotropic genes involved in the etiology of both craniofacial conditions and cancers. In this study we aimed to test if our previously detected association between ERN1 rs196929 marker and oral health outcomes would be detected in individuals diagnosed with cancer as well as in a subpopulation of individuals who also had one or more teeth missing due to dental caries, periodontal disease, or periapical lesions. We genotyped a total of 1,671 subjects and selected a subset of 1,421 subjects for stratified analysis of cancer types; three hundred and twelve self-reported a diagnosis of various cancer types and 1,109 reported never receiving a diagnosis of cancer. Our results showed a statistically significant association between the rs196929 in ERN1, and cancer overall in both the additive and dominant models (OR = 1.37, 95% C.I. 1.06–1.79, p = 0.014). When we stratified the analysis for each cancer type, our results show that the rs196929 ERN1 variant is associated with skin cancer (OR = 2.07, 95% C.I. 1.27–3.37, p = 0.003) and breast cancer (OR = 1.83, 95% C.I. 1.13–2.99, p = 0.013) in the subset of patients that had tooth loss. An additional nominal association between the rs196929 in ERN1 and male’s reproductive system cancers (OR = 1.96, 95% C.I. 1.07–3.59, p = 0.028) was identified. We hope that our study helps guide future genetic studies on these cancers and this specific genetic variant as well as drive attention to the potential for oral health outcomes to serve as indicators for cancer risk. The early identification of genetic markers and/or oral conditions that indicate increased cancer risk could positively impact cancer outcomes and survival rates with timely implementation of preventive and diagnostic measures. In conclusion, our results suggest that the genetic variant in ERN1 (rs196929) is associated with increased risk of skin and breast cancers.

Molar incisor hypomineralization (MIH) is an enamel condition characterized by lesions ranging in color from white to brown which present rapid caries progression, and mainly affects permanent first molars and incisors. These enamel defects usually occur when there are disturbances during the mineralization or maturation stage of amelogenesis. Both genetic and environmental factors have been suggested to play roles in MIH’s development, but no conclusive risk factors have shown the source of the disease. During head and neck development, the interferon regulatory factor 6 (IRF6) gene is involved in the structure formation of the oral and maxillofacial regions, and the transforming growth factor alpha (TGFA) is an essential cell regulator, acting during proliferation, differentiation, migration and apoptosis. In this present study, it was hypothesized that these genes interact and contribute to predisposition of MIH. Environmental factors affecting children that were 3 years of age or older were also hypothesized to play a role in the disease etiology. Those factors included respiratory issues, malnutrition, food intolerance, infection of any sort and medication intake. A total of 1,065 salivary samples from four different cohorts were obtained, and DNA was extracted from each sample and genotyped for nine different single nucleotide polymorphisms. Association tests and logistic regression implemented in PLINK were used for analyses. A potential interaction betweenTGFArs930655 with all markers tested in the cohort from Turkey was identified. These interactions were not identified in the remaining cohorts. Associations (p<0.05) between the use of medication after three years of age and MIH were also found, suggesting that conditions acquired at the age children start to socialize might contribute to the development of MIH.

The purpose of this study was to address the hypothesis that extreme outcomes of dental caries, such as edentulism or prematurely losing permanent teeth are associated with genetic variation in enamel-formation genes. After scanning 6206 individuals, samples of 330 were selected for this study. Tested phenotypes included patients who were edentulous by age 30, patients with missing first molars by age 30, patients with missing second molars by age 30, and caries-free patients. Fourteen single nucleotide polymorphisms were genotyped by TaqMan chemistry. The analyses of each phenotype were performed using the software PLINK with an alpha of 0.05. Nominal associations were found between rs12640848 in enamelin (p = 0.05), rs1784418 in matrix metallopeptidase 20 (p = 0.02), and rs5997096 in the tuftelin interacting protein 11 and being caries-free at the age of 60. When combining patients that were missing both first mandibular molars and missing both second mandibular molars, no associations were found. Matrix metallopeptidase 20, and tuftelin interacting protein 11 also showed trends for association with being caries-free. Genetic variation in TFIP11, MMP20, and ENAM may have a protective effect increasing the chances of individuals preserving their teeth caries-free over a lifetime.

Cancer is a disease caused by a process that drives the transformation of normal cells into malignant cells. The late diagnosis of cancer has a negative impact on the health care system due to high treatment cost and decreased chances of favorable prognosis. Here, we aimed to identify orofacial conditions that can serve as potential risk markers for cancers by performing a phenome-wide scan (PheWAS). From a pool of 6,100 individuals, both genetic and epidemiological data of 1,671 individuals were selected: 350 because they were previously diagnosed with cancer and 1,321 to match to those individuals that had cancer, based on age, sex, and ethnicity serving as a comparison group. Results of this study showed that when analyzing the individuals affected by cancer separately, tooth loss/edentulism is associated with SNPs in AXIN2 (rs11867417 p = 0.02 and rs2240308 p = 0.02), and leukoplakia of oral mucosa is associated with both AXIN2 (rs2240308 p = 0.03) and RHEB (rs2374261 p = 0.03). These phenotypes did not show the same trends in patients that were not diagnosed with cancer, allowing for the conclusion that these phenotypes are unique to cases with higher cancer risk.