Exploring etiologic contributions to the occurrence of external apical root resorption.

INTRODUCTION: External apical root resorption (EARR) is often an undesirable sequela of orthodontic treatment. Prior studies have suggested a substantial link between EARR and certain genetic components. Single nucleotide polymorphisms (SNPs) may play a role as predisposing factors. This study aimed to investigate the potential association between EARR and various SNPs. METHODS: The study included 218 orthodontic participants of all malocclusions who had available pretreatment and posttreatment panoramic radiographs. The most severely affected maxillary incisor on the radiograph was assessed for EARR using a 0-4 categorical scale. DNA was taken from the saliva samples of the participants, and the SNPs were analyzed using polymerase chain reaction and TaqMan chemistry. Statistical testing was performed to verify any associations with EARR (P <0.05). RESULTS: From all genes tested, the rs678397 SNP of ACT3N (P = 0.003) and the rs1051771 SNP of TSC2 (P = 0.03) were significantly associated with EARR. No association could be established between other polymorphisms and EARR. In addition, patients with Class III malocclusion and extended treatment times were at increased risk of developing EARR. CONCLUSIONS: Our results support the concept of gene polymorphisms as risk factors in EARR. In particular, a significant association was found between ACT3N and TSC2 and EARR. Clinically, predisposing risk factors for EARR should be assessed for each patient.

Family-based GWAS for dental class I malocclusion and clefts.

BACKGROUND: Individuals born with cleft lip and/or palate who receive corrective surgery regularly have abnormal growth in the midface region such that they exhibit premaxillary hypoplasia. However, there are also genetic contributions to craniofacial morphology in the midface region, so although these individuals appear to have Class III skeletal discrepancy, their molar relationship may be Class I. Past genome-wide association studies (GWASs) on skeletal Class II and III malocclusion suggested that multiple genetic markers contribute to these phenotypes via a multifactorial inheritance model, but research has yet to examine the genetic markers associated with dental Class I malocclusion. Thus, our goal was to conduct a family based GWAS to identify genes across the genome that are associated with Class I malocclusion, as defined by molar relations, in humans with and without clefts. METHODS: Our cohort consisted of 739 individuals from 47 Filipino families originally recruited in 2006 to investigate the genetic basis of orofacial clefts. All individuals supplied blood samples for DNA extraction and genotyping, and a 5,766 single nucleotide polymorphism (SNP) custom panel was used for the analyses. We performed a transmission disequilibrium test for participants with and without clefts to identify genetic contributors potentially involved with Class I malocclusion. RESULTS: In the total cohort, 13 SNPs had associations that reached the genomic control threshold (p < 0.005), while five SNPs were associated with Class I in the cohort of participants without clefts, including four associations that were identified in the total cohort. The associations for the SNPs ABCA4 rs952499, SOX1-OT rs726455, and RORA rs877228 are of particular interest, as past research found associations between these genes and various craniofacial phenotypes, including cleft lip and/or palate. CONCLUSIONS: These findings support the multifactorial inheritance model for dental Class I malocclusion and suggest a common genetic basis for different aspects of craniofacial development.

Potential involvement of beta-lactamase homologous proteins in resistance to beta-lactam antibiotics in gram-negative bacteria of the ESKAPEE group.

BACKGROUND: Enzymatic degradation mediated by beta-lactamases constitutes one of the primary mechanisms of resistance to beta-lactam antibiotics in gram-negative bacteria. This enzyme family comprises four molecular classes, categorized into serine beta-lactamases (Classes A, C, and D) and zinc-dependent metallo-beta-lactamases (Class B). Gram-negative bacteria producing beta-lactamase are of significant concern, particularly due to their prevalence in nosocomial infections. A comprehensive understanding of the evolution and dissemination of this enzyme family is essential for effective control of these pathogens. In this study, we conducted the prospecting, phylogenetic analysis, and in silico analysis of beta-lactamases and homologous proteins identified in 1827 bacterial genomes with phenotypic data on beta-lactam resistance. These genomes were distributed among Klebsiella pneumoniae (45%), Acinetobacter baumannii (31%), Pseudomonas aeruginosa (14%), Escherichia coli (6%), and Enterobacter spp. (4%). Using an HMM profile and searching for conserved domains, we mined 2514, 8733, 5424, and 2957 proteins for molecular classes A, B, C, and D, respectively. This set of proteins encompasses canonical subfamilies of beta-lactamases as well as hypothetical proteins and other functional groups. Canonical beta-lactamases were found to be phylogenetically distant from hypothetical proteins, which, in turn, are closer to other representatives of the penicillin-binding-protein (PBP-like) and metallo-beta-lactamase (MBL) families. The catalytic amino acid residues characteristic of beta-lactamases were identified from the sequence alignment and revealed that motifs are less conserved in homologous groups than in beta-lactamases. After comparing the frequency of protein groups in genomes of resistant strains with those of sensitive ones applying Fisher's exact test and relative risk, it was observed that some groups of homologous proteins to classes B and C are more common in the genomes of resistant strains, particularly to carbapenems. We identified the beta-lactamase-like domain widely distributed in gram-negative species of the ESKAPEE group, which highlights its importance in the context of beta-lactam resistance. Some hypothetical homologous proteins have been shown to potentially possess promiscuous activity against beta-lactam antibiotics, however, they do not appear to expressly determine the resistance phenotype. The selective pressure due to the widespread use of antibiotics may favor the optimization of these functions for specialized resistance enzymes.

Erosive Tooth Wear, Wine Intake, and Genetic Variation in COMT and MMP2.

INTRODUCTION: Erosive tooth wear (ETW) is a multifactorial condition of increasing prevalence in the younger population. This study aimed to explore the association between different ETW phenotypes with MMP2 and COMT single-nucleotide variants, and selected environmental factors. METHODS: Saliva samples, erosive wear and dental caries experience data, and dietary/behavioral information from 16-18-year-old patients (n= 747) were used. Genotypes were obtained and phenotypes were further analyzed considering diet and behavioral data, using logistic regression as implemented in PLINK, with an alpha of 0.05. RESULTS: When comparing individuals' ETW-free with those with mild ETW, an association was found with COMT rs6269 (p = 0.02). The comparison between ETW-free individuals with individuals with severe ETW also showed an association with COMT rs6269 under the recessive model (p = 0.03). Logistic regression showed that in the presence of less common alleles of MMP2 rs9923304 and COMT rs6269, ETW were more likely to occur when individuals drank wine. The GG genotype of COMT rs6269 was associated with the presence of lower (p = 0.02) and higher (p = 0.02) caries experience when individuals with ETW only in enamel were compared with individuals with ETW involving dentin. CONCLUSION: The results support a role of genes in ETW, with wine consumption being identified as a significant modulator, suggesting that gene-environment interactions may contribute to the development of erosive tooth wear.

Study of the antibacterial and cytotoxic activity of chitosan and its derivatives chemically modified with phthalic anhydride and ethylenediamine.

The insertion of hydrophobic and hydrophilic chains in the chitosan molecule can improve its antibacterial activity, expanding its range of application in several areas of medical-pharmaceutical sciences. Thus, this work aimed to increase the antibacterial activity of chitosan through the modification reaction with phthalic anhydride (QF) and subsequent reaction with ethylenediamine (QFE). The chitosan and derivatives obtained were characterized by elemental analysis, 13C Nuclear Magnetic Resonance (13C NMR), X-Ray Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR) and Thermogravimetric Analysis (TG), where it was possible to prove the chemical modification. Both materials showed a greater antibacterial inhibitory effect against Gram-positive bacteria, Staphylococcus aureus, emphasizing antibacterial activity against Gram-negative bacteria, Escherichia coli, with values above 70 % of the inhibitory effect, which is a promising result. Assays with human fibroblast cells by the [3-(4,5-dimethylthiazolyl)-2,5-diphenyl tetrazolium (MTT)] bromide reduction test did not indicate toxicity in the materials. Thus, the derived materials showed promise for biomedical applications since they combined excellent antibacterial activity against gram-positive and gram-negative strains and did not show cytotoxicity.

The salivary microbiota of patients with acute lower respiratory tract infection-A multicenter cohort study.

The human microbiome contributes to health and disease, but the oral microbiota is understudied relative to the gut microbiota. The salivary microbiota is easily accessible, underexplored, and may provide insight into response to infections. We sought to determine the composition, association with clinical features, and heterogeneity of the salivary microbiota in patients with acute lower respiratory tract infection (LRTI). We conducted a multicenter prospective cohort study of 147 adults with acute LRTI presenting to the emergency department of seven hospitals in three states (Pennsylvania, Michigan, and Ohio) between May 2017 and November 2018. Salivary samples were collected in the emergency department, at days 2-5 if hospitalized, and at day 30, as well as fecal samples if patients were willing. We compared salivary microbiota profiles from patients to those of healthy adult volunteers by sequencing and analyzing bacterial 16-rRNA. Compared to healthy volunteers, the salivary microbiota of patients with LRTI was highly distinct and strongly enriched with intestinal anaerobes such as Bacteroidaceae, Ruminococcaceae, and Lachnospiraceae (e.g., mean 10% relative abundance of Bacteroides vs < 1% in healthy volunteers). Within the LRTI population, COPD exacerbation was associated with altered salivary microbiota composition compared to other LRTI conditions. The largest determinant of microbiota variation within the LRTI population was geography (city in which the hospital was located).

Genetic and environmental contributions for the relationship between tooth loss and oral potentially malignant disorders and oral squamous cell carcinoma.

BACKGROUND: To investigate the association between tooth loss and oral potentially malignant disorders and oral squamous cell carcinoma, focusing on epidemiological factors and genetic variants. METHODS: Case-control study, including histologically confirmed oral potentially malignant disorders and oral squamous cell carcinoma cases and healthy controls. Unadjusted and adjusted odds ratios for this association were calculated. Single-nucleotides polymorphisms were tested for individuals with and without missing teeth. RESULTS: Case individuals were more edentulous while controls had fewer missing teeth (p = 0.006). There was an increased risk for the outcomes associated with edentulism (OR = 6.95, p = 0.000), even after adjustments for educational level (OR = 4.7, p = 0.034) and smoking habits (OR = 5.01, p = 0.022). Among individuals with tooth loss, rs1533767 (WNT11), rs3923087, and rs11867417 (AXIN2) were associated with the outcomes (OR = 1.67, p = 0.03, OR = 0.53, p = 0.05, and OR = 0.42, p = 0.00, respectively). CONCLUSIONS: Tooth loss could increase the risk for oral potentially malignant disorders and oral squamous cell carcinoma.

Association between molar hypomineralization, genes involved in enamel development, and medication in early childhood: A preliminary study.

BACKGROUND: Molar hypomineralization (MH) is defined as a multifactorial condition, and thus, its presence may be defined by interactions between environmental and genetic factors. AIM: To evaluate the association between MH, genes involved in enamel development, and the use of medication during pregnancy in early childhood. DESIGN: One hundred and eighteen children, 54 with and 64 without MH, were studied. The data collected included demographics, socioeconomic data, and the medical history of mothers and children. Genomic DNA was collected from saliva. Genetic polymorphisms in ameloblastin (AMBN; rs4694075), enamelin (ENAM; rs3796704, rs7664896), and kallikrein (KLK4; rs2235091) were evaluated. These genes were analyzed by real-time polymerase chain reaction using TaqMan chemistry. The software PLINK was used to compare allele and genotype distributions of the groups and to assess the interaction between environmental variables and genotypes (p < .05). RESULTS: The variant allele KLK4 rs2235091 was associated with MH in some children (odds ratio [OR]: 3.75; 95% confidence interval [CI] = 1.65-7.81; p = .001). Taking medications in the first 4 years of life was also associated with MH (OR: 2.94; 95% CI = 1.02-6.04; p = .041) and specifically in association with polymorphisms in ENAM, AMBN, and KLK4 (p < .05). The use of medications during pregnancy was not associated with MH (OR: 1.37; 95% CI = 0.593-3.18; p = .458). CONCLUSION: The results of this study suggest that taking medication in the postnatal period appears to contribute to the etiology of MH in some evaluated children. There may be a possible genetic influence of polymorphisms in the KLK4 gene with this condition.

Drug Hypersensitivity Associated with Dental Treatments

ABSTRACT Objective: To characterize drug hypersensitivity associated with dental treatments. Material and Methods: Data from 5,302 dental patients extracted from the Faculty of Dental Medicine were used to investigate drug use history, drug hypersensitivity, and associations with oral health outcomes. The chi-square test was used, and values of p ≤ 0.05 were considered statistically significant. Results: The frequency of patients' self-reported drug hypersensitivity was 26.42% (n = 1,401). The highest frequencies were for opioid/narcotic analgesics (20.84%, n = 292), antibiotics (18.13%, n = 961), and non-steroidal anti-inflammatory drugs (10.46%, n = 141). Most of the patients (68.65%, n = 3,640) reported using medications, mostly for cardiovascular disease (43.1%, n = 1,569), for psychiatric/neurological disorders (39.75%, n = 1,447), drugs that affect the endocrine system (32.55%, n= 1,185), and drugs for pain (24.92%, n = 907). Higher drug hypersensitivity frequencies were associated with older White female subjects (p<0.0001). Associations were also identified between drug hypersensitivity and history of the following dental procedures: tooth extractions (p=0.003), root canal treatment (p=0.0004), prosthodontic treatments (p<0.0001), and orthodontic treatments (p=0.007). Conclusion: A high frequency of self-reported drug hypersensitivity in dental patients was found, with a higher occurrence in older White women and those with a history of more extensive and invasive dental care.

Factors associated with the lifestyle of state basic education teachers of state during the pandemic.

OBJECTIVE: To analyze the prevalence and factors associated with the lifestyle profile of public basic education teachers in Minas Gerais during the COVID-19 pandemic. METHOD: Epidemiological websurvey carried out with public basic education teachers in Minas Gerais. Data collection took place from August to September2020 via digital form. Anthropometric, sociodemographic, work, and lifestyle characteristics were evaluated. Poisson Regression was used. RESULTS: 15,641 teachers participated and 31.1% had inadequate health habits. There was a higher prevalence among men (PR=1.38; 95%CI:1.31;1.45), older age (PR=1.20; 95%CI: 1.07;1.34), greater weekly workload (RP=1.10; 95%CI:1.03;1.17) and those dissatisfied with work (RP=1.21; 95%CI:1.15;1.27). As a protective factor, professors with longer teaching experience (RP=0.92; 95%CI:0.87;0.98) and those hired or appointed (PR=0.89; 95%CI:0.85) ;0.94). CONCLUSION: Lifestyle inadequacy was found among older male teachers, with longer working hours and job dissatisfaction.

Polymorphisms associated with oral clefts as potential markers for oral pre and malignant disorders.

OBJECTIVE: To investigate whether genes in the Wnt pathway, which have been previously associated with both oral clefts and oral squamous cell carcinoma, are also associated with oral potentially malignant disorders (leukoplakia, erythroplakia and lichen planus). MATERIALS AND METHODS: Case-control study: Dataset consisted of clinical information linked to DNA samples from affected subjects diagnosed with oral potential malignant disorders and oral cancer and their matched controls. Individual samples, clinical history, and potential risk factors were obtained through the Dental Registry and DNA Repository project of the School of Dental Medicine, University of Pittsburgh. The rs1533767 (WNT11), rs9879992 (GSK3B), and rs3923087 (AXIN2) were tested. After genomic DNA had been extracted, genotyping was performed blindly to clinical diagnosis status. Representation of genotypes and alleles in affected subjects in comparison to the unaffected individuals was determined using PLINK. Additional analysis was performed to investigate associations between environmental (socioeconomic/lifestyle) risk factors and the oral pathologies studied using STATA. RESULTS: Two of the SNPs tested (rs9879992 in GSK3B and rs3923087 in AXIN2) were statistically, significantly associated with the pathologies studied (p = 0.039 and 0.038, respectively). CONCLUSION: Single-nucleotide polymorphisms in genes in the Wnt pathway were associated with oral potentially malignant disorders.

Coast-or Inland Residence and Differences in the Occurrence of Cleft Lip and Cleft Palate.

OBJETIVE: To analyze if differences in lifestyle and environment between coastal and inland areas are associated with differences in frequency of orofacial cleft types. DESIGN: Populational cross-sectional study. SETTING: All live borns with orofacial cleft registered at Brazilian Live Birth Information System between 1999 and 2020. PARTICIPANTS: 33,699 live borns with orofacial cleft. INTERVENTION: Data from borns with orofacial cleft were collected at Brazilian Live Birth Information System. MAIN OUTCOME MEASURE: Differences in frequencies between the cleft types and covariates were determined using chi-square. Bivariate analysis was done to obtain the prevalence ratio of types of clefts by geographic origin. Multiple logistic regression analysis was used to determine adjusted odds ratios, controlling for covariates, establishing a significance level of p value <0.05. RESULTS: The frequency of cleft types was statistically significant different according to geographic origin (inland x coast). For syndromic clefts, the prevalence ratio for cleft lip with/without palate was 3.6 times higher inland (p value = 0.000). Regarding non-syndromics, the prevalence ratio for cleft lip with/without palate was two times higher inland (p value = 0.000). Logistic regression suggested cleft lip with/without palate was 6.33 more likely to occur in inland regions (p value = 0.000). CONCLUSION: Geographic origin was associated with the type of cleft in Brazil, with a higher prevalence of cleft lip with/without palate in inland areas, compared to cleft palate, which was higher in the coast.

CLEFT RR- New app to Calculate Recurrence Risk in Cleft lip and Palate.

OBJECTIVE: To describe the Cleft Recurrence Risk (Cleft RR) App, designed to be used on genetic counseling for cleft lip and/ or palate. DESIGN: A validation study, single cohort. SETTING: Tertiary care children's Hospital. PATIENTS, PARTICIPANTS: The manual obtained the results of 100 cases undergoing genetic counseling at the cleft lip and palate treatment center. INTERVENTIONS: The application for genetic counseling for cleft lip and/ or palate is designed to calculate quickly the recurrence risk considering the ancestry, cleft type, sex, and family history and thus encourage the implementation of genetic counseling in cleft lip and palate centers around the world. MAIN OUTCOME MEASURE(S): The data were submitted to the Bland-Altman statistics. RESULTS: After defining parameters the application development follows the steps: development, prototyping, and documentation. The validation of the calculated data was performed by comparing the results of 100 cases undergoing genetic counseling at the cleft lip and palate treatment center obtained by the manual method with the results obtained by the mobile app method; the data were submitted to the Bland-Altman statistics and a high concordance was found. CONCLUSIONS: The mobile app for use by healthcare professionals proved to be simple to use, easy to apply, and provided accurate results. Cleft Recurrence Risk is an application for smartphones developed for genetic counseling in cleft lip and palate, supplementary use by health professionals, and should not replace professional performance.

Molar-incisor hypomineralization in a cohort of individuals born with cleft lip and palate.

OBJECTIVE: This study aimed to investigate the frequency of molar-incisor hypomineralization (MIH) in individuals born with cleft lip and or cleft palate. SETTINGS AND SAMPLE: Three hundred eighty-six individuals born with cleft lip and/or palate before orthodontic treatment. METHODS: All the individuals were submitted to a clinical examination and intraoral standardized photos. The registration of MIH was taken by two orthodontists and analysed in association with the cleft type and laterality. The Kruskal-Wallis test and the regression test were used to compare the frequency of molars and incisors affected according to cleft type and laterality, sex and age. RESULTS: We found a frequency of 67.87% of MIH in the studied sample. The frequency varied from 25% (in individuals born with cleft palate) to 77% in individuals born with bilateral cleft lip and palate). The number of affected molars was statistically different depending on cleft type and laterality (P < .001- Kruskal-Wallis test). Differences were found between individuals born with unilateral cleft lip and palate and unilateral cleft lip and alveolus (P = .03), and with isolated cleft palate (P = .03), and between individuals born with bilateral cleft lip and palate and born with unilateral cleft lip and alveolus (P = .01), and cleft palate (P = .01). Sex (P = .21) and age (P = .36) had no influence on the frequency of MIH. A positive correlation was found between the number of molars affected and incisors affected (P < .001). CONCLUSION: Individuals born with cleft lip and palate have a higher frequency of MIH, and the complexity of cleft type was associated with the number of affected molars.

Patients Air Medical Transport During the COVID-19 Pandemic: A Retrospective Cohort Study.

INTRODUCTION: Air medical transport during the coronavirus disease 2019 pandemic was essential for transferring critically ill patients. This study aimed to comparatively analyze air-transported patients with and without coronavirus disease 2019 according to their clinical condition and complications that occurred during the flight. METHODS: This was a retrospective cohort study that analyzed the digital records of adult patients transported by fixed-wing aircraft from the interior of the state of Amazonas to the state capital Manaus, Brazil, from June 2019 to May 2021. Pearson's chi-squared, Fisher exact, and Wilcoxon-Mann-Whitney tests were applied (significance level of P < .05). RESULTS: The sample consisted of 741 patients (60.59% men, median age 54 years). The incidence of complications during the flight was 7.28%, with emphasis on dyspnea, psychomotor agitation, and pain. There was a significant difference between patients with (n = 466) and without coronavirus disease 2019 (n = 275) regarding the variables age (P < .001), comorbidities (P < .001), body mass index (P < .001), impact (P < .001) and priority (P = .002) of the transfer, physiological severity (P < .001), use of vasoactive drugs when boarding the aircraft (P = .033), and occurrence of respiratory complications during air medical transport (P = .003). DISCUSSION: Patients with coronavirus disease 2019 were older, had more comorbidities and were severely ill, and had higher body mass index, frequency of vasoactive drug use, and respiratory complications. Although there are minimal differences among these patients, the role that interhospital transfer plays in reducing burden on local, less well-equipped hospitals is a primary role of medical transport, particularly during pandemics.

Genome-wide Association Study Identifies Novel Risk Loci for Apical Periodontitis.

INTRODUCTION: Apical periodontitis (AP) is a common consequence of root canal infection leading to periapical bone resorption. Microbial and host genetic factors and their interactions have been shown to play a role in AP development and progression. Variations in a few genes have been reported in association with AP; however, the lack of genome-wide studies has hindered progress in understanding the molecular mechanisms involved. Here, we report the first genome-wide association study of AP in a large and well-characterized population. METHODS: Male and female adults (n = 932) presenting with deep caries and AP (cases), or deep caries without AP (controls) were included. Genotyping was performed using the Illumina Expanded Multi-Ethnic Genotyping Array (MEGA). Single-variant association testing was performed adjusting for sex and 5 principal components. Subphenotype association testing, analyses of genetically regulated gene expression, polygenic risk score, and phenome-wide association (PheWAS) analyses were also conducted. RESULTS: Eight loci reached near genome-wide significant association with AP (P < 5 × 10-6); gene-focused analyses replicated 3 previously reported associations (P < 8.9 × 10-5). Sex-specific and subphenotype-specific analyses revealed additional significant associations with variants genome-wide. Functionally oriented gene-based analyses revealed 8 genes significantly associated with AP (P < 5 × 10-5), and PheWAS analysis revealed 33 phecodes associated with AP risk score (P < 3.08 × 10-5). CONCLUSIONS: This study identified novel genes/loci contributing to AP and specific contributions to AP risk in men and women. Importantly, we identified additional systemic conditions significantly associated with AP risk. Our findings provide strong evidence for host-mediated effects on AP susceptibility.

Chapter 4: Development Defects of Enamel and Dentine and Coronal Caries.

The development of the human dentition is prone to disruption due to its delicate and complex nature - including variations in tooth number and anatomical form and in the characteristics of enamel, dentine, and cementum. This chapter will focus on developmental defects of dental enamel (DDE) and dentine (DDD), which can be associated with considerable treatment burden on an individual, often related to the change in dental hard tissue characteristics in those at increased caries risk. DDE are prevalent and can be related to genetic conditions such as amelogenesis imperfecta and environmental challenges such as direct physical trauma to the developing tooth or systemic insults during the different phases of amelogenesis. Phenotypical variability can be great, making diagnosis difficult in many cases. There are two major enamel defects - the quantitative defect of hypoplasia and the qualitative defect of hypomineralization. DDDs are less prevalent than DDEs, with two major DDD types: dentinogenesis imperfecta and dentine dysplasia. The main features of the DDDs are enamel fracture exposing the dentine and subsequent wear, with enlarged pulp spaces in some variants. The appearance may be affected, with bulbous teeth and grey-blue to brown opalescent colouring. With respect to dental caries, developmental defects of the teeth, in themselves, do not cause caries risk; however, they can change the manifestation of the disease due to creating niches for biofilm accumulation and thereby increasing cleaning difficulty and changing the physical and chemical characteristics of dental hard tissues and how they react to cariogenic challenges.

Polymorphism in epigenetic regulating genes in relation to periodontitis, number of teeth, and levels of high-sensitivity C-reactive protein and glycated hemoglobin: The Tromsø Study 2015-2016.

BACKGROUND: The aim of this study was to investigate the association between periodontitis and four single nucleotide polymorphisms (SNPs) in genes involved in epigenetic regulation of DNA, and between these same SNPs and tooth loss, high-sensitivity C-reactive protein (hs-CRP), and glycated hemoglobin (HbA1c) levels. METHODS: We included participants with periodontal examination (n = 3633, aged: 40-93 years) from the Tromsø Study seventh survey (2015-2016), Norway. Periodontitis was defined according to the 2017 AAP/EFP classification system as no periodontitis, grades A, B, or C. Salivary DNA was extracted and genotyping was performed to investigate four SNPs (rs2288349, rs35474715, rs34023346, and rs10010325) in the sequence of the genes DNMT1, IDH2, TET1, and TET2. Association between SNPs and periodontitis was analyzed by logistic regression adjusted for age, sex, and smoking. Subgroup analyses on participants aged 40-49 years were performed. RESULTS: In participants aged 40-49 years, homozygous carriage of minor A-allele of rs2288349 (DNMT1) was associated with decreased susceptibility to periodontitis (grade A: odds ratio [OR] 0.55; p = 0.014: grade B/C OR 0.48; p = 0.004). The minor A-allele of rs10010325 (TET2) was associated with increased susceptibility to periodontitis (grade A OR 1.69; p = 0.035: grade B/C OR 1.90; p = 0.014). In the entire sample, homozygous carriage of the G-allele of rs35474715 (IDH2) was associated with having ≤24 teeth (OR 1.31; p = 0.018). Homozygous carriage of the A-allele of TET2 was associated with hs-CRP≥3 mg/L (OR 1.37; p = 0.025) and HbA1c≥6.5% (OR 1.62; p = 0.028). CONCLUSIONS: In this Norwegian population, there were associations between polymorphism in genes related to DNA methylation and periodontitis, tooth loss, low-grade inflammation, and hyperglycemia.

TgKDAC4: A Unique Deacetylase of Toxoplasma's Apicoplast.

Toxoplasma gondii is an obligate intracellular parasite of the phylum Apicomplexa and causes toxoplasmosis infections, a disease that affects a quarter of the world's population and has no effective cure. Epigenetic regulation is one of the mechanisms controlling gene expression and plays an essential role in all organisms. Lysine deacetylases (KDACs) act as epigenetic regulators affecting gene silencing in many eukaryotes. Here, we focus on TgKDAC4, an enzyme unique to apicomplexan parasites, and a class IV KDAC, the least-studied class of deacetylases so far. This enzyme shares only a portion of the specific KDAC domain with other organisms. Phylogenetic analysis from the TgKDAC4 domain shows a putative prokaryotic origin. Surprisingly, TgKDAC4 is located in the apicoplast, making it the only KDAC found in this organelle to date. Transmission electron microscopy assays confirmed the presence of TgKDAC4 in the periphery of the apicoplast. We identified possible targets or/and partners of TgKDAC4 by immunoprecipitation assays followed by mass spectrometry analysis, including TgCPN60 and TgGAPDH2, both located at the apicoplast and containing acetylation sites. Understanding how the protein works could provide new insights into the metabolism of the apicoplast, an essential organelle for parasite survival.

Heterozygous Variants in FREM2 Are Associated with Mesiodens, Supernumerary Teeth, Oral Exostoses, and Odontomas.

BACKGROUND: Supernumerary teeth refer to extra teeth that exceed the usual number of dentitions. A mesiodens is a particular form of supernumerary tooth, which is located in the premaxilla region. The objective of the study was to investigate the genetic etiology of extra tooth phenotypes, including mesiodens and isolated supernumerary teeth. METHODS: Oral and radiographic examinations and whole-exome sequencing were performed on every patient in our cohort of 122 patients, including 27 patients with isolated supernumerary teeth and 94 patients with mesiodens. A patient who had multiple supernumerary teeth also had odontomas. RESULTS: We identified a novel (c.8498A>G; p.Asn2833Ser) and six recurrent (c.1603C>T; p.Arg535Cys, c.5852G>A; p.Arg1951His, c.6949A>T; p.Thr2317Ser; c.1549G>A; p.Val517Met, c.1921A>G; p.Thr641Ala, and c.850G>C; p.Val284Leu) heterozygous missense variants in FREM2 in eight patients with extra tooth phenotypes. CONCLUSIONS: Biallelic variants in FREM2 are implicated in autosomal recessive Fraser syndrome with or without dental anomalies. Here, we report for the first time that heterozygous carriers of FREM2 variants have phenotypes including oral exostoses, mesiodens, and isolated supernumerary teeth.