Prediction of Interactomic HUB Genes in Periodontitis With Acute Myocardial Infarction.

BACKGROUND: Acute myocardial infarction (AMI) risk correlates with C-reactive protein (CRP) levels, suggesting systemic inflammation is present well before AMI. Studying different types of periodontal disease (PD), extremely common in individuals at risk for AMI, has been one important research topic. According to recent research, AMI and PD interact via the systemic production of certain proinflammatory and anti-inflammatory cytokines, small signal molecules, and enzymes that control the onset and development of both disorders' chronic inflammatory reactions. This study uses machine learning to identify the interactome hub biomarker genes in acute myocardial infarction and periodontitis. METHODS: GSE208194 and GSE222883 were chosen for our research after a thorough search using keywords related to the study's goal from the gene expression omnibus (GEO) datasets. DEGs were identified from the GEOR tool, and the hub gene was identified using Cytoscape-cytohubba. Using expression values, Random Forest, Adaptive Boosting, and Naive Bayes, widgets-generated transcriptomics data, were labelled, and divided into 80/20 training and testing data with cross-validation. ROC curve, confusion matrix, and AUC were determined. In addition, Functional Enrichment Analysis of Differentially Expressed Gene analysis was performed. RESULTS: Random Forest, AdaBoost, and Naive Bayes models with 99%, 100%, and 75% AUC, respectively. Compared to RF, AdaBoost, and NB classification models, AdaBoost had the highest AUC. Categorization algorithms may be better predictors than important biomarkers. CONCLUSIONS: Machine learning model predicts hub and non-hub genes from genomic datasets with periodontitis and acute myocardial infarction.

The association between polyunsaturated fatty acids and periodontitis: NHANES 2011-2014 and Mendelian randomisation analysis.

BACKGROUND: We aimed to explore the association and potential causality between polyunsaturated fatty acids concentrations and the risk of periodontal disease. MATERIALS AND METHODS: Data were collected from the 2011-2014 National Health and Nutrition Examination Survey (NHANES). Weighted logistic regression analysis and restricted cubic spline (RCS) analysis were used to analyse the associations of the concentrations of omega-3 and omega-6 fatty acids and the omega-6/omega-3 fatty acids ratio with the risk of periodontitis. E-value and propensity score matching (PSM) analyses were used for sensitivity analyses. In addition, two-sample Mendelian randomisation (MR) analyses were performed to assess the potential causal impact of the concentrations of those fatty acids on periodontitis risk. RESULTS: A total of 2462 participants from the NHANES were included. Logistic regression analysis revealed that high omega-3 fatty acids levels were negatively associated with the risk of developing periodontitis (P < 0.05), while the omega-6/omega-3 fatty acids ratio was positively associated with the risk of developing periodontitis (P < 0.05). There was no significant association between omega-6 concentrations and the risk of periodontitis. The findings mentioned above were confirmed by analysis following a 1:1 PSM. Furthermore, MR examination of the two samples indicated no possible causal link between the risk of periodontitis and the concentrations of omega-3 or omega-6 fatty acids or the ratio of omega-6 to omega-3 fatty acids (P > 0.05). CONCLUSION: Although omega-3 fatty acids and the omega-6/omega-3 fatty acids ratio were associated with the risk of periodontitis in cross-sectional studies, the MR results did not support a causal relationship between them. Therefore, there is no indication that an increase in the omega-3 fatty acids concentration or a decrease in the omega-6/omega-3 fatty acids ratio may be beneficial for preventing periodontitis.

Deciphering the molecular nexus of BTG2 in periodontitis and diabetic kidney disease.

OBJECTIVE: To investigate the role of BTG2 in periodontitis and diabetic kidney disease (DKD) and its potential underlying mechanism. METHODS: Gene expression data for periodontitis and DKD were acquired from the Gene Expression Omnibus (GEO) database. Differential expression analysis identified co-expressed genes between these conditions. The Nephroseq V5 online nephropathy database validated the role of these genes in DKD. Pearson correlation analysis identified genes associated with our target gene. We employed Gene Set Enrichment Analysis (GSEA) and Protein-Protein Interaction (PPI) networks to elucidate potential mechanisms. Expression levels of BTG2 mRNA were examined using quantitative polymerase Chain Reaction (qPCR) and immunofluorescence assays. Western blotting quantified proteins involved in epithelial-to-mesenchymal transition (EMT), apoptosis, mTORC1 signaling, and autophagy. Additionally, wound healing and flow cytometric apoptosis assays evaluated podocyte migration and apoptosis, respectively. RESULTS: Analysis of GEO database data revealed BTG2 as a commonly differentially expressed gene in both DKD and periodontitis. BTG2 expression was reduced in DKD compared to normal conditions and correlated with proteinuria. GSEA indicated enrichment of BTG2 in the EMT and mTORC1 signaling pathways. The PPI network highlighted BTG2's relevance to S100A9, S100A12, and FPR1. Immunofluorescence assays demonstrated significantly lower BTG2 expression in podocytes under high glucose (HG) conditions. Reduced BTG2 expression in HG-treated podocytes led to increased levels of EMT markers (α-SMA, vimentin) and the apoptotic protein Bim, alongside a decrease in nephrin. Lower BTG2 levels were associated with increased podocyte mobility and apoptosis, as well as elevated RPS6KB1 and mTOR levels, but reduced autophagy marker LC3. CONCLUSION: Our findings suggest that BTG2 is a crucial intermediary gene linking DKD and periodontitis. Modulating autophagy via inhibition of the mTORC1 signaling pathway, and consequently suppressing EMT, may be pivotal in the interplay between periodontitis and DKD.

No genetic causal association between periodontitis and ankylosing spondylitis: a bidirectional two-sample mendelian randomization analysis.

BACKGROUND: Observational studies that reveal an association between periodontitis (PD) and ankylosing spondylitis (AS) exist. However, observational research is prone to reverse causality and confounding factors, which make it challenging to infer cause-and-effect relationships. We conducted a two-sample Mendelian randomization (MR) study to examine the causal relationship between the genetic prediction of PD and AS. METHODS: In our study, single-nucleotide polymorphisms (SNPs) were defined as instrumental variables (IVs). The genetic association with PD came from the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) consortium, wherein 17353 cases of European ancestry and 28210 controls of European ancestry were included in this study. The genetic association with AS from the Neale Laboratory Consortium included 337,159 individuals from the United Kingdom, with 968 cases and 336,191 controls. MR analysis was mainly performed using the inverse-variance weighted (IVW) method. In addition, the robustness of the study findings was assessed using sensitivity, pleiotropy, and heterogeneity analyses. RESULTS: Eighteen independent SNPs with P-values significantly smaller than 1 × 10- 5 were used as IV SNPs for PD, while 39 independent SNPs with P-values significantly smaller than 1 × 10- 5 were used as IV SNPs for AS. The results of the IVW method revealed no causal association between PD and AS (odds ratio = 1.00, 95% confidence interval: 0.99953 to 1.00067, P = 0.72). The MR-Egger method did not support the causal association between PD and AS. It is unlikely that horizontal pleiotropy distorts causal estimates based on sensitivity analysis. No significant heterogeneity was observed in the Q test. The ''leave-one-out'' analysis demonstrated that the robustness of our results was unaffected by eliminating any of the IVs. Likewise, no significant causative effect for AS on PD was observed in the inverse MR analysis. CONCLUSIONS: The study results do not support shared heritability or a causal association between PD and AS.

Association between biological aging and periodontitis using NHANES 2009-2014 and mendelian randomization.

Aging is a recognized risk factor for periodontitis, while biological aging could provide more accurate insights into an individual's functional status. This study aimed to investigate the potential association between biological aging and periodontitis. Epidemiological data from 9803 participants in the 2009-2014 National Health and Nutrition Examination Survey were analyzed at a cross-sectional level to assess this link. Three biological ages [Klemera-Doubal method (KDM), PhenoAge, and homeostatic dysregulation (HD)] and two measures of accelerated biological aging (BioAgeAccel and PhenoAgeAccel) were set as primary exposure and were calculated. Logistic regression and restricted cubic spline regression were employed to examine the relationship between biological aging and periodontitis. Additionally, Mendelian randomization analysis was conducted to explore the causal connection between accelerated biological aging and periodontitis. After adjusting for age, gender, race, educational level, marital status, ratio of family income, and disease conditions, this study, found a significant association between subjects with older higher biological ages, accelerated biological aging, and periodontitis. Specifically, for a per year increase in the three biological ages (HD, KDM, and PhenoAge), the risk of periodontitis increases by 15%, 3%, and 4% respectively. Individuals who had positive BioAgeAccel or PhenoAgeAccel were 20% or 37% more likely to develop periodontitis compared with those who had negative BioAgeAccel or PhenoAgeAccel. Furthermore, a significant non-linear positive relationship was observed between the three biological ages, accelerated biological aging, and periodontitis. However, the Mendelian randomization analysis indicated no causal effect of accelerated biological aging on periodontitis. Our findings suggest that biological aging may contribute to the risk of periodontitis, highlighting the potential utility of preventive strategies targeting aging-related pathways in reducing periodontitis risk among older adults.

Periodontal disease increases the severity of chronic obstructive pulmonary disease: a Mendelian randomization study.

BACKGROUND: Recent research suggests that periodontitis can increase the risk of chronic obstructive pulmonary disease (COPD). In this study, we performed two-sample Mendelian randomization (MR) and investigated the causal effect of periodontitis (PD) on the genetic prediction of COPD. The study aimed to estimate how exposures affected outcomes. METHODS: Published data from the Gene-Lifestyle Interaction in the Dental Endpoints (GLIDE) Consortium's genome-wide association studies (GWAS) for periodontitis (17,353 cases and 28,210 controls) and COPD (16,488 cases and 169,688 controls) from European ancestry were utilized. This study employed a two-sample MR analysis approach and applied several complementary methods, including weighted median, inverse variance weighted (IVW), and MR-Egger regression. Multivariable Mendelian randomization (MVMR) analysis was further conducted to mitigate the influence of smoking on COPD. RESULTS: We chose five single-nucleotide polymorphisms (SNPs) as instrumental variables for periodontitis. A strong genetically predicted causal link between periodontitis and COPD, that is, periodontitis as an independent risk factor for COPD was detected. PD (OR = 1.102951, 95% CI: 1.005-1.211, p = 0.039) MR-Egger regression and weighted median analysis results were coincident with those of the IVW method. According to the sensitivity analysis, horizontal pleiotropy's effect on causal estimations seemed unlikely. However, reverse MR analysis revealed no significant genetic causal association between COPD and periodontitis. IVW (OR = 1.048 > 1, 95%CI: 0.973-1.128, p = 0.2082) MR Egger (OR = 0.826, 95%CI:0.658-1.037, p = 0.1104) and weighted median (OR = 1.043, 95%CI: 0.941-1.156, p = 0.4239). The results of multivariable Mendelian randomization (MVMR) analysis, after adjusting for the confounding effect of smoking, suggest a potential causal relationship between periodontitis and COPD (P = 0.035). CONCLUSION: In this study, periodontitis was found to be independent of COPD and a significant risk factor, providing new insights into periodontitis-mediated mechanisms underlying COPD development.

Exploring the molecular mechanisms of ferroptosis-related genes in periodontitis: a multi-dataset analysis.

PURPOSE: This study aims to elucidate the biological functions of ferroptosis-related genes in periodontitis, along with their correlation to tumor microenvironment (TME) features such as immune infiltration. It aims to provide potential diagnostic markers of ferroptosis for clinical management of periodontitis. METHODS: Utilizing the periodontitis-related microarray dataset GSE16134 from the Gene Expression Omnibus (GEO) and a set of 528 ferroptosis-related genes identified in prior studies, this research unveils differentially expressed ferroptosis-related genes in periodontitis. Subsequently, a protein-protein interaction network was constructed. Subtyping of periodontitis was explored, followed by validation through immune cell infiltration and gene set enrichment analyses. Two algorithms, randomForest and SVM(Support Vector Machine), were employed to reveal potential ferroptosis diagnostic markers for periodontitis. The diagnostic efficacy, immune correlation, and potential transcriptional regulatory networks of these markers were further assessed. Finally, potential targeted drugs for differentially expressed ferroptosis markers in periodontitis were predicted. RESULTS: A total of 36 ferroptosis-related genes (30 upregulated, 6 downregulated) were identified from 829 differentially expressed genes between 9 periodontitis samples and the control group. Subsequent machine learning algorithm screening highlighted 4 key genes: SLC1A5(Solute Carrier Family 1 Member 5), SLC2A14(Solute Carrier Family 1 Member 14), LURAP1L(Leucine Rich Adaptor Protein 1 Like), and HERPUD1(Homocysteine Inducible ER Protein With Ubiquitin Like Domain 1). Exploration of these 4 key genes, supported by time-correlated ROC analysis, demonstrated reliability, while immune infiltration results indicated a strong correlation between key genes and immune factors. Furthermore, Gene Set Enrichment Analysis (GSEA) was conducted for the four key genes, revealing enrichment in GO/KEGG pathways that have a significant impact on periodontitis. Finally, the study predicted potential transcriptional regulatory networks and targeted drugs associated with these key genes in periodontitis. CONCLUSIONS: The ferroptosis-related genes identified in this study, including SLC1A5, SLC2A14, LURAP1L, and HERPUD1, may serve as novel diagnostic and therapeutic targets for periodontitis. They are likely involved in the occurrence and development of periodontitis through mechanisms such as immune infiltration, cellular metabolism, and inflammatory chemotaxis, potentially linking the ferroptosis pathway to the progression of periodontitis. Targeted drugs such as flurofamide, L-733060, memantine, tetrabenazine, and WAY-213613 hold promise for potential therapeutic interventions in periodontitis associated with these ferroptosis-related genes.

No genetic causal associations between periodontitis and brain atrophy or cognitive impairment: evidence from a comprehensive bidirectional Mendelian randomization study.

BACKGROUND: Observational studies have explored the relationships of periodontitis with brain atrophy and cognitive impairment, but these findings are limited by reverse causation, confounders and have reported conflicting results. Our study aimed to investigate the causal associations of periodontitis with brain atrophy and cognitive impairment through a comprehensive bidirectional Mendelian randomization (MR) research. METHODS: We incorporated two distinct genome-wide association study (GWAS) summary datasets as an exploration cohort and a replication cohort for periodontitis. Four and eight metrics were selected for the insightful evaluation of brain atrophy and cognitive impairment, respectively. The former involved cortical thickness and surface area, left and right hippocampal volumes, with the latter covering assessments of cognitive performance, fluid intelligence scores, prospective memory, and reaction time for mild cognitive impairment to Alzheimer's disease (AD), Lewy body dementia, vascular dementia and frontotemporal dementia for severe situations. Furthermore, supplementary analyses were conducted to examine the associations between the longitudinal rates of change in brain atrophy and cognitive function metrics with periodontitis. The main analysis utilized the inverse variance weighting (IVW) method and evaluated the robustness of the results through a series of sensitivity analyses. For multiple tests, associations with p-values < 0.0021 were considered statistically significant, while p-values ≥ 0.0021 and < 0.05 were regarded as suggestive of significance. RESULTS: In the exploration cohort, forward and reverse MR results revealed no causal associations between periodontitis and brain atrophy or cognitive impairment, and only a potential causal association was found between AD and periodontitis (IVW: OR = 0.917, 95% CI from 0.845 to 0.995, P = 0.038). Results from the replication cohort similarly corroborated the absence of a causal relationship. In the supplementary analyses, the longitudinal rates of change in brain atrophy and cognitive function were also not found to have causal relationships with periodontitis. CONCLUSIONS: The MR analyses indicated a lack of substantial evidence for a causal connection between periodontitis and both brain atrophy and cognitive impairment.

Bioinformatics investigation of adaptive immune-related genes in peri-implantitis and periodontitis: Characteristics and diagnostic values.

BACKGROUND: Peri-implantitis and periodontitis have similar immunological bioprocesses and inflammatory phenotypes. In the inflammatory process, the adaptive immune cells can drive the development of disease. This research investigated the differences and diagnostic significance of peri-implantitis and periodontitis in adaptive immune responses. METHODS: We acquired four GEO datasets of gene expressions in surrounding tissues in healthy person, healthy implant, periodontitis, and peri-implantitis patients. The structural characteristics and enrichment analyses of differential expression genes were examined. The adaptive immune landscapes in peri-implantitis and periodontitis were then evaluated using single sample gene set enrichment analysis. The STRING database and Cytoscape were used to identify adaptive hub genes, and the ROC curve was used to verify them. Finally, qRT-PCR method was used to verify the expression level of Hub gene in activated T cells on the titanium-containing or titanium-free culture plates. RESULTS: At the transcriptome level, the data of healthy implant, peri-implantitis and periodontitis were highly dissimilar. The peri-implantitis and periodontitis both exhibited adaptive immune response. Except for the activated CD4+T cells, there was no significant difference in other adaptive immune cells between peri-implantitis and periodontitis. In addition, correlation analysis showed that CD53, CYBB, and PLEK were significantly positively linked with activated CD4+T cells in the immune microenvironment of peri-implantitis, making them effective biomarkers to differentiate it from periodontitis. CONCLUSIONS: Peri-implantitis has a uniquely immunogenomic landscape that differs from periodontitis. This study provides new insights and ideas into the activated CD4+T cells and hub genes that underpin the immunological bioprocess of peri-implantitis.

Impact of periodontitis on type 2 diabetes: a bioinformatic analysis.

BACKGROUND: Periodontitis is strongly associated with type 2 diabetes (T2D) that results in serious complications and mortality. However, the pathogenic role of periodontitis in the development of T2D and the underlain mechanism have not been fully elucidated. METHODS: A Mendelian randomization (MR) was performed to estimate the causality between two diseases. Bioinformatics tools, including gene ontology and pathway enrichment analyses, were employed to analyze the common differentially expressed genes (DEGs) in periodontitis and T2D. MR and colocalization analyses were then utilized to investigate the causal associations between potential pathogenic gene expression and the risk of T2D. Single cell-type expression analysis was further performed to detect the cellular localization of these genes. RESULTS: Genetically predicted periodontitis was associated with a higher risk of T2D (OR, 1.469; 95% CI, 1.117-1.930; P = 0.006) and insulin resistance (OR 1.034; 95%CI 1.001-1.068; P = 0.041). 79 common DEGs associated with periodontitis and T2D were then identified and demonstrated enrichment mainly in CXC receptor chemokine receptor binding and interleutin-17 signaling pathway. The integration of GWAS with the expression quantitative trait locis of these genes from the peripheral blood genetically prioritized 6 candidate genes, including 2 risk genes (RAP2A, MCUR1) and 4 protective genes (WNK1, NFIX, FOS, PANX1) in periodontitis-related T2D. Enriched in natural killer cells, RAP2A (OR 4.909; 95% CI 1.849-13.039; P = 0.001) demonstrated high risk influence on T2D, and exhibited strong genetic evidence of colocalization (coloc.abf-PPH4 = 0.632). CONCLUSIONS: This study used a multi-omics integration method to explore causality between periodontitis and T2D, and revealed molecular mechanisms using bioinformatics tools. Periodontitis was associated with a higher risk of T2D. MCUR1, RAP2A, FOS, PANX1, NFIX and WNK1 may play important roles in the pathogenesis of periodontitis-related T2D, shedding light on the development of potential drug targets.

MicroRNA-671-5p regulates the inflammatory response of periodontal ligament stem cells via the DUSP8/p38 MAPK pathway.

BACKGROUND: MicroRNAs are differentially expressed in periodontitis tissues. They are involved in cellular responses to inflammation and can be used as markers for diagnosing periodontitis. Microarray analysis showed that the expression level of microRNA-671-5p in periodontal tissues of patients with periodontitis was increased. In this study, we investigated the mechanism of action of microRNA-671-5p in human periodontal ligament stem cells (hPDLSCs) under inflammatory conditions. METHODS AND RESULTS: HPDLSCs were treated with lipopolysaccharide (LPS) to establish an inflammation model. The cell survival rate was determined using the cell counting kit-8 (CCK8). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analyses were used to detect the expression of microRNA-671-5p and dual-specificity phosphatase (DUSP) 8 proteins, respectively, Interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α were detected using qRT-PCR and Enzyme-linked immunosorbent assay (ELISA). A dual-luciferase reporter system was employed to determine the relationship between micoRNA-671-5p and DUSP8 expression. Activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway was confirmed using western blot analysis. Following the treatment of hPDLSCs with LPS, the expression levels of microRNA-671-5p in hPDLSCs were increased, cell viability decreased, and the expression of inflammatory factors displayed an increasing trend. MicroRNA-671-5p targets and binds to DUSP8. Silencing microRNA-671-5p or overexpressing DUSP8 can improve cell survival rate and reduce inflammatory responses. When DUSP8 was overexpressed, the expression of p-p38 was reduced. CONCLUSIONS: microRNA-671-5p targets DUSP8/p38 MAPK pathway to regulate LPS-induced proliferation and inflammation in hPDLSCs.

Linking periodontitis with 20 cancers, emphasis on oropharyngeal cancer: a Mendelian randomization analysis.

While associations between periodontitis and an elevated risk of cancer have been suggested, the results of existing observational studies have been inconsistent, also leaving room for further investigation into the underlying mechanisms. This study was designed to delve into the possible causal link between periodontitis and 20 standard cancers while concurrently identifying potential mediators. We initiated a Mendelian randomization analysis that drew from either publicly accessible or personally obtained genome-wide association study (GWAS) datasets. The inverse variance weighting (IVW) method served as our primary tool for analysis. To ensure the strength and consistency of our results, we implemented additional strategies, including weighted median, weighted mode, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO), bolstered by funnel plots. Our analysis unveiled an elevated risk of head and neck cancer concomitant with periodontitis (p = 0.041, OR 0.999, 95% CI 0.999-1.000), specifically a heightened risk of oropharyngeal cancer (p = 0.022, OR 0.999, 95% CI 0.999-1.000). As a result of probing into potential mediators, Fusobacterium nucleatum emerged as a likely intermediary in the promoting effect of periodontitis on oropharyngeal cancer (p = 0.021, OR 0.999, 95% CI 0.998-1.000). Inversely, basal cell carcinoma and endometrial cancer demonstrated an association with an increased incidence of periodontitis (basal cell carcinoma: p = 0.020, OR 0.987, 95% CI 0.976-0.998; endometrial cancer: p = 0.027, OR 0.984, 95% CI 0.970-0.998). However, periodontitis exerted no significant causal impact on the 19 other common cancers or the three subtypes of head and neck cancer. To conclude, our results support the theory that periodontitis contributes to an enhanced risk of head and neck cancer, particularly oropharyngeal cancer, with Fusobacterium nucleatum functioning as a potential intermediary.

Assessing Causal Relationships Between Periodontitis and Non-alcoholic Fatty Liver Disease: A Two-Sample Bidirectional Mendelian Randomisation Study.

PURPOSE: To investigate the causality between periodontitis and non-alcoholic fatty liver disease (NAFLD) using a two-sample bidirectional Mendelian randomisation (MR) analysis. MATERIALS AND METHODS: Genetic variations in periodontitis and NAFLD were acquired from genome-wide association studies (GWAS) using the Gene-Lifestyle Interaction in Dental Endpoints, a large-scale meta-analysis, and FinnGen consortia. Data from the first two databases were used to explore the causal relationship between periodontitis and NAFLD ("discovery stage"), and the data from FinnGen was used to validate our results ("validation stage"). We initially performed MR analysis using 5 single nucleotide polymorphisms (SNPs) in the discovery samples and 18 in the replicate samples as genetic instruments for periodontitis to investigate the causative impact of periodontitis on NAFLD. We then conducted a reverse MR analysis using 6 SNPs in the discovery samples and 4 in the replicate samples as genetic instruments for NAFLD to assess the causative impact of NAFLD on periodontitis. We further implemented heterogeneity and sensitivity analyses to assess the reliability of the MR results. RESULTS: Periodontitis was not causally related to NAFLD (odds ratio [OR] = 1.036, 95% CI: 0.914-1.175, p = 0.578 in the discovery stage; OR = 1.070, 95% CI: 0.935-1.224, p = 0.327 in the validation stage), and NAFLD was not causally linked with periodontitis (OR = 1.059, 95% CI: 0.916-1.225, p = 0.439 in the discovery stage; OR = 0.993, 95% CI: 0.896-1.102, p = 0.901 in the validation stage). No heterogeneity was observed among the selected SNPs. Sensitivity analyses demonstrated the absence of pleiotropy and the reliability of our MR results. CONCLUSION: The present MR analysis showed no genetic evidence for a cause-and-effect relationship between periodontitis and NAFLD. Periodontitis may not directly influence the development of NAFLD and vice versa.

PYCARD gene polymorphisms and susceptibility to periodontal and coronary heart diseases.

Numerous studies have established a link between gene variants within the inflammasome complex and the incidence of periodontitis and cardiovascular illness across various ethnic groups. This study investigated the association between PYCARD gene polymorphism and susceptibility to periodontal disease and coronary heart disease (CHD) and their correlation with clinical periodontal indices. A total of 120 participants were enrolled, categorized into four groups: 30 healthy controls (C), 30 patients with generalized periodontitis (P), 30 patients with atherosclerotic CHD but clinically healthy periodontium (AS-C), and 30 patients with both atherosclerotic CHD and generalized periodontitis (AS-P). We recorded demographic data, collected blood samples, and measured periodontal indices, including plaque index, clinical attachment loss, bleeding on probing, and pocket depth. The genomic variant of the PYCARD gene was analyzed using a conventional polymerase reaction. A significant prevalence of T and G allele mutations and a higher distribution of CT and TT genotypes in PYCARD C/T (rs8056505) and the AG genotype in PYCARD A/G (rs372507365) were observed in groups P, AS-P, and AS-C. These single nucleotide polymorphisms (SNPs) were also positively correlated with the severity of clinical periodontitis indices. Our findings suggest that the increased frequency of T and G alleles and the distribution of CT, TT, and AG genotypes in PYCARD SNPs are significantly associated with an elevated risk for periodontal disease and CHD. These SNPs may participate in the pathogenesis of these conditions. The study reinforces the potential role of these genetic markers as risk factors for both diseases in the Iraqi population.

Association of IL-4 polymorphism with severe periodontitis in a sample of Iraqi population.

INTRODUCTION: Specific bacterial plaque and environmental factors cannot be considered the only cause of periodontitis. Still, several genetic factors affect the host response to the bacteria, like gene polymorphisms in anti-inflammatory cytokines. Several studies have reported that clones of T-helper 2 lymphocytes (TH2) are generated in response to dental plaque in periodontitis patients, while in healthy individuals, they are regulated by T-helper 1 (TH1) lymphocytes. Accordingly, such patients consistently produce more IL-4 (TH2) in response to bacterial stimulation, whereas healthy controls with intact periodontal tissues produce a significantly higher level of TH1.

Macrophage-enriched novel functional long noncoding RNAs LRRC75A-AS1 and GAPLINC regulate polarization and innate immune responses.

INTRODUCTION: Macrophages (Mφs) are functionally dynamic immune cells that bridge innate and adaptive immune responses; however, the underlying epigenetic mechanisms that control Mφ plasticity and innate immune functions are not well elucidated. OBJECTIVE: To identify novel functions of macrophage-enriched lncRNAs in regulating polarization and innate immune responses. METHODS: Total RNA isolated from differentiating monocyte-derived M1 and M2 Mφs was profiled for lncRNAs expression using RNAseq. Impact of LRRC75A-AS1, GAPLINC and AL139099.5 knockdown was examined on macrophage differentiation, polarization markers, phagocytosis, and antigen processing by flow cytometry and florescence microscopy. Cytokine profiles were examined by multiplex bead array and cytoskeletal signaling pathway genes were quantified by PCR-based array. Gingival biopsies were collected from periodontally healthy and diseased subjects to examine lncRNAs, M1/M2 marker expression. RESULTS: Transcriptome profiling of M1 and M2 Mφs identified thousands of differentially expressed known and novel lncRNAs. We characterized three Mφ-enriched lncRNAs LRRC75A-AS1, GAPLINC and AL139099.5 in polarization and innate immunity. Knockdown of LRRC75A-AS1 and GAPLINC downregulated the Mφ differentiation markers and skewed Mφ polarization by decreasing M1 markers without a significant impact on M2 markers. LRRC75A-AS1 and GAPLINC knockdown also attenuated bacterial phagocytosis, antigen processing and inflammatory cytokine secretion in Mφs, supporting their functional role in potentiating innate immune functions. Mechanistically, LRRC75A-AS1 and GAPLINC knockdown impaired Mφ migration by downregulating the expression of multiple cytoskeletal signaling pathways suggesting their critical role in regulating Mφ migration. Finally, we showed that LRRC75A-AS1 and GAPLINC were upregulated in periodontitis and their expression correlates with higher M1 markers suggesting their role in macrophage polarization in vivo. CONCLUSION: Our results show that polarized Mφs acquire a unique lncRNA repertoire and identified many previously unknown lncRNA sequences. LRRC75A-AS1 and GAPLINC, which are induced in periodontitis, regulate Mφ polarization and innate immune functions supporting their critical role in inflammation.

Regulatory role of PDK1 via integrated gene analysis of mitochondria-immune response in periodontitis.

AIMS: To investigate the association between mitochondrial events and immune response in periodontitis and related regulatory genes. MAIN METHODS: Gene expression profiles in gingival tissues were retrieved from the Gene Expression Omnibus. Mitochondria-immune response-related differentially expressed genes (MIR-DEGs) between the healthy and periodontitis samples were determined. WGCNA, GO, and KEGG were used to investigate the function and the enriched pathways of MIR-DEGs. The correlation between MIR-DEGs expression and clinical probing pocket depth was analyzed. The MIR-DEGs were further identified and verified in animal samples. A periodontitis model was established in C57BL/6 mice with silk ligation. Micro-computed tomography was used to assess alveolar bone loss. Western blot, quantitative real-time polymerase chain reaction, and immunohistochemical analyses further validated the differential expression of the MIR-DEGs. KEY FINDINGS: A total of ten MIR-DEGs (CYP24A1, PRDX4, GLDC, PDK1, BCL2A1, CBR3, ARMCX3, BNIP3, IFI27, and UNG) were identified, the expression of which could effectively distinguish patients with periodontitis from the healthy controls. Enhanced immune response was detected in the periodontitis group with that in the healthy controls, especially in B cells. PDK1 was a critical MIR-DEG correlated with B cell immune response and clinical periodontal probing pocket depth. Both animal and clinical periodontal samples presented higher gene and protein expression of PDK1 than the control samples. Additionally, PDK1 colocalized with B cells in both animal and clinical periodontal tissues. SIGNIFICANCE: Mitochondria participate in the regulation of the immune response in periodontitis. PDK1 may be the key mitochondria-related gene regulating B-cell immune response in periodontitis.

Bioinformatics analysis revealed the potential crosstalk genes and molecular mechanisms between intracranial aneurysms and periodontitis.

OBJECTIVES: The risk of intracranial aneurysms (IAs) development and rupture is significantly higher in patients with periodontitis (PD), suggesting an association between the two. However, the specific mechanisms of association between these two diseases have not been fully investigated. MATERIALS AND METHODS: In this study, we downloaded IAs and PD data from the Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified, and functional enrichment analysis was performed. The protein-protein interaction (PPI) network and weighted gene co-expression network analysis (WGCNA) was performed to identified key modules and key crosstalk genes. In addition, the immune cell landscape was assessed and the correlation of key crosstalk genes with each immune cell was calculated. Finally, transcription factors (TFs) regulating key crosstalk genes were explored. RESULTS: 127 overlapping DEGs were identified and functional enrichment analysis highlighted the important role of immune reflection in the pathogenesis of IAs and PD. We identified ITGAX and COL4A2 as key crosstalk genes. In addition, the expression of multiple immune cells was significantly elevated in PDs and IAs compared to controls, and both key crosstalk genes were significantly negatively associated with Macrophages M2. Finally, GATA2 was identified as a potential key transcription factor (TF), which regulates two key crosstalk gene. CONCLUSIONS: The present study identifies key crosstalk genes and TF in PD and IAs, providing new insights for further study of the co-pathogenesis of PD and IAs from an immune and inflammatory perspective. Also, this is the first study to report the above findings.

Periodontitis and Sjogren's syndrome: a bidirectional two-sample mendelian randomization study.

OBJECTIVES: Observational studies indicated a controversial relationship between periodontitis (PD) and Sjogren's syndrome (SS). To overcome restrictions in conventional observational studies, we conducted a two-sample Mendelian randomization (MR) analysis to assess the potential bidirectional relationship between PD and SS. METHODS: We utilized the largest available genome-wide association study (GWAS) of European ancestry on both PD (17,353 cases-28,210 controls) and SS (2495 cases-365,533 controls) for MR genetic instrument selection. The random-effect inverse-variance weighted (IVW) method complemented by Causal Analysis Using Summary Effect (CAUSE), weighted median, weighted mode, simple mode, MR-Egger regression, and MR-pleiotropy residual sum and outlier (MR-PRESSO) was used for MR analysis. Subsequent pleiotropy and heterogeneity tests were conducted. RESULTS: IVW analysis exhibited neither an effect of PD on SS (OR = 0.939, 95%CI = 0.525-1.677, P = 0.8304) nor that of SS on PD (OR = 1.007, 95%CI = 0.977-1.038, P = 0.6440). The other five complementary methods further recognized the null association with an effect size close to one. No significant pleiotropy was detected in the relationship between PD and SS (P > 0.05). Heterogeneity existed in the effect of PD on SS but not vice versa. CONCLUSIONS: No genetic causality between PD and SS or vice versa was supported by our results under MR assumptions and limitations. The study results provided new insights into the relationship between periodontal status and sjogren's syndrome, highlighting the need for a more prudent medical intervention.

Periodontitis and osteoporosis: a two-sample Mendelian randomization analysis.

The incidences of periodontitis and osteoporosis are rising worldwide. Observational studies have shown that periodontitis is associated with increased risk of osteoporosis. We performed a Mendelian randomization (MR) study to genetically investigate the causality of periodontitis on osteoporosis. We explored the causal effect of periodontitis on osteoporosis by MR analysis. A total of 9 single nucleotide polymorphisms (SNP) were related to periodontitis. The primary approach in this MR analysis was the inverse variance-weighted (IVW) method. Simple median, weighted median, and penalized weighted median were used to analyze sensitivity. The fixed-effect IVW model and random-effect IVW model showed no significant causal effect of genetically predicted periodontitis on the risk of osteoporosis (OR=1.032; 95%CI: 0.923-1.153; P=0.574; OR=1.032; 95%CI: 0.920-1.158; P=0.588, respectively). Similar results were observed in simple mode (OR=1.031; 95%CI: 0.780-1.361, P=0.835), weighted mode (OR=1.120; 95%CI: 0.944-1.328, P=0.229), simple median (OR=1.003; 95%CI: 0.839-1.197, P=0.977), weighted median (OR=1.078; 95%CI: 0.921-1.262, P=0.346), penalized weight median (OR 1.078; 95%CI: 0.919-1.264, P=0.351), and MR-Egger method (OR=1.360; 95%CI: 0.998-1.853, P=0.092). There was no heterogeneity in the IVW and MR-Egger analyses (Q=7.454, P=0.489 and Q=3.901, P=0.791, respectively). MR-Egger regression revealed no evidence of a pleiotropic influence through genetic variants (intercept: -0.004; P=0.101). The leave-one-out sensitivity analysis indicated no driven influence of any individual SNP on the association between periodontitis and osteoporosis. The Mendelian randomization analysis did not show a significant detrimental effect of periodontitis on the risk of osteoporosis.