Evidence Linking PPARG Genetic Variants with Periodontitis and Type 2 Diabetes Mellitus in a Brazilian Population.

The peroxisome proliferator-activated receptor gamma (PPARG) gene encodes a transcription factor involved in the regulation of complex metabolic and inflammatory diseases. We investigated whether single nucleotide polymorphisms (SNPs) and haplotypes of the PPARG gene could contribute with susceptibility to develop periodontitis alone or together with type 2 diabetes mellitus (T2DM). Moreover, we evaluated the gene-phenotype association by assessing the subjects' biochemical and periodontal parameters, and the expression of PPARG and other immune response-related genes. We examined 345 subjects with a healthy periodontium and without T2DM, 349 subjects with moderate or severe periodontitis but without T2DM, and 202 subjects with moderate or severe periodontitis and T2DM. PPARG SNPs rs12495364, rs1801282, rs1373640, and rs1151999 were investigated. Multiple logistic regressions adjusted for age, sex, and smoking status showed that individuals carrying rs1151999-GG had a 64% lower chance of developing periodontitis together with T2DM. The CCGT haplotype increased the risk of developing periodontitis together with T2DM. The rs1151999-GG and rs12495364-TC were associated with reduced risk of obesity, periodontitis, elevated triglycerides, and elevated glycated hemoglobin, but there was no association with gene expression. Polymorphisms of the PPARG gene were associated with developing periodontitis together with T2DM, and with obesity, lipid, glycemic, and periodontal characteristics.

Antepartum periodontitis treatment and risk of offspring screening positive for autism spectrum disorder.

BACKGROUND: To evaluate if treating maternal periodontal disease, a pro-inflammatory condition, during pregnancy (intervention) compared to after pregnancy (control) reduces the likelihood of offspring screening positive for autism spectrum disorder (ASD). METHODS: In a follow-up study to the MOTOR randomized trial, we compared rates of positive screens on the Modified Checklist for Autism in Toddlers (M-CHAT) among n = 306 two-year-old toddlers and correlated findings to maternal and cord blood pro-inflammatory interleukin-6 (IL-6). RESULTS: Toddlers in the intervention group had decreased risk of a positive M-CHAT screen (adjusted RR = 0.53, 95% CI 0.29-0.99). Toddlers screening positive compared to negative had higher mean IL-6 in cord blood (1.58 ± 1.14 vs. 1.09 ± 0.72 p = 0.001) and maternal IL-6 change from baseline (1.30 ± 0.61 vs 0.96 ± 0.62 p = 0.03). CONCLUSIONS: Treating periodontal disease during pregnancy reduced risk of a positive ASD screen. M-CHAT positivity was associated with increased IL-6 in maternal and cord blood. CLINICAL TRIAL: Trial Registration numbers: Clinicaltrials.gov NCT03423836.

Polymorphisms in risk genes of type 2 diabetes mellitus could be also markers of susceptibility to periodontitis.

OBJECTIVES: This study aimed to investigate polymorphisms in genes considered molecular biomarkers of type 2 diabetes mellitus (T2DM) to assess whether they are associated with periodontitis, and relating them to the periodontal status, glycemic and lipid profile of the subjects. DESIGN: We investigated individuals who underwent complete periodontal examination and biochemical evaluation. We categorized them into three groups: (i) periodontitis with T2DM (Periodontitis+T2DM group, n = 206); (ii) periodontitis without T2DM (Periodontitis group, n = 346); and (iii) healthy individuals without Periodontitis or T2DM (Healthy group, n = 345). We investigated three single nucleotide polymorphisms (SNPs) for AGER, RBMS1 and VEGFA genes. We applied multivariate logistic and multiple linear regression models for all groups and stratified the subjects by sex and smoking habits. RESULTS: Compared with RBMS1-rs7593730-CC+CT genotype carriers, RBMS1-rs7593730-TT carriers were more susceptible to periodontitis [odds ratio (OR) = 2.29; 95% confidence interval (CI) = 1.04-5.01; P-value = 0.033]. Among AGER-rs184003-CC carriers, never smokers had reduced risks of periodontitis and Periodontitis+T2DM than ever smokers. For either RBMS1-rs7593730-CC or VEGFA-rs9472138-CC carriers, never smokers had less susceptibility to develop periodontitis than ever smokers. Compared with AGER-rs184003-CC carriers, AGER-rs184003-AA carriers presented fewer remaining teeth. VEGFA-rs9472138-TT carriers showed a lower percentage of sites with characteristics of active periodontal disease (bleeding on pocket probing and interproximal clinical attachment level) compared with VEGFA-rs9472138-CC carriers. CONCLUSIONS: In the studied population, AGER rs184003, RBMS1 rs7593730, and VEGFA rs9472138, which are considered genetic markers for T2DM, were associated with periodontitis without T2DM or periodontitis together with T2DM.

Polymorphisms in Genes of Lipid Metabolism Are Associated with Type 2 Diabetes Mellitus and Periodontitis, as Comorbidities, and with the Subjects' Periodontal, Glycemic, and Lipid Profiles.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and periodontitis (P) commonly occur as comorbidities, but the commonalities in the genetic makeup of affected individuals is largely unknown. Since dyslipidemia is a frequent condition in these individuals, we investigate the association of genomic variations in genes involved in lipid metabolism with periodontal, glycemic, lipid profiles, and the association with periodontitis and T2DM (as comorbidities). METHODS: Based on clinical periodontal examination and biochemical evaluation, 893 subjects were divided into T2DM+P (T2DM subjects also affected by periodontitis, n = 205), periodontitis (n = 345), and healthy (n = 343). Fourteen single-nucleotide polymorphisms (SNPs) were investigated: LDLR gene (rs5925 and rs688), APOB (rs676210, rs1042031, and rs693), ABCC8 (rs6544718 and 6544713), LPL (rs28524, rs3735964, and rs1370225), HNF1A (rs2650000), APOE (rs429358 and rs7412), and HNF4A (rs1800961). Multiple linear and logistic regressions (adjusted for covariates) were made for all populations and stratified by sex and smoking habits. RESULTS: Individuals carrying APOB-rs1042031-CT (mainly women and never smokers) had a lower risk of developing periodontitis and T2DM (T2DM+P); altogether, this genotype was related with healthier glycemic, lipid, and periodontal parameters. Significant disease-phenotype associations with gene-sex interaction were also found for carriers of APOB-rs1676210-AG, HNF4A-rs1800961-CT, ABCC8-rs6544718-CT, LPL-rs13702-CC, and LPL-rs285-CT. CONCLUSIONS: Polymorphisms in lipid metabolism genes are associated with susceptibility to T2DM-periodontitis comorbidities, demonstrating gene-sex interaction. The APOB-rs1042031 was the most relevant gene marker related to glucose and lipid metabolism profiles, as well as with obesity and periodontitis.

Polymorphisms and haplotypes in the Interleukin 17 Alfa gene: potential effect of smoking habits in the association with periodontitis and type 2 diabetes mellitus.

Few studies evaluate interrelationships between periodontitis (P) and Type 2 Diabetes Mellitus (T2DM). The aim of this study is to investigate the genetic susceptibility to periodontitis alone, or concomitant with T2DM (as comorbidities), analyzing single nucleotide polymorphisms (SNPs) in the Interleukin 17 alpha (IL17A) gene, considering the biochemical profile and smoking habits on the subjects' periodontal status. We investigated 879 individuals divided into: T2DM subjects also affected by severe or moderate periodontitis (T2DM-P, n = 199); non-diabetics with severe or moderate periodontitis (PERIODONTITIS, n = 342); and healthy subjects (HEALTHY, n = 338). Subjects underwent complete periodontal examination, history of smoking habits, glycemic and lipid biochemical evaluation. DNA from buccal cells was utilized to genotype the SNPs rs2275913, rs3819024 and rs10484879. The impact of the subjects' biochemical profile was analyzed in their periodontal status. Each SNP was analyzed independently, and as haplotypes, by multiple logistic regressions, adjusted for covariates, and also stratifying the groups by age, sex and smoking habits. Independently of the periodontitis degree, poorly-controlled T2DM subjects showed worse glycemic and lipid profile. Multiple logistic regressions demonstrated that smokers and former-smokers carrying the GG genotype of rs3819024 seemed to have higher risk for T2DM-Periodontitis (OR = 6.33; 95% CI = 1.26-31.77, p = 0.02), and mainly for T2DM alone (OR = 5.11; 95% CI = 1.37-19.06, p = 0.01), than never smokers. We found the potential effect of smoking habits in the association of IL17A-rs3819024-GG with diseased phenotypes. Because the observed wide confidence intervals, further studies enrolling larger populations, and SNPs' functional evaluations are needed to better understand our findings.

Association of type 2 diabetes mellitus and periodontal disease susceptibility with genome-wide association-identified risk variants in a Southeastern Brazilian population.

OBJECTIVE: Genome-wide association studies (GWAS) and literature have identified polymorphisms in the KCNJ11, HNF1A, IRS1, TCF7L2, CDKAL1, CDKN2B, RPSAP52, GPR45 HHEX, IL18, and RUNX2 genes associated with type 2 diabetes mellitus (T2DM) and/or periodontitis (P) in diverse populations, and we sought to evaluate them as genetic risk variants for these diseases in the Brazilian population. MATERIAL AND METHODS: Periodontal, glycemic, and lipid data were obtained from 931 individuals divided into: control (n = 334), periodontitis (P; n = 358), and periodontitis associated with T2DM (P + T2DM; n = 239). After genotyping, associations between polymorphisms and pathologies were tested by multiple logistic and linear regressions, adjusting for age, sex, and smoking habits. RESULTS: Considering the studied subjects, the increased risk to develop periodontitis in the periodontitis P + T2DM group was found for HNF1A-rs7957197-TA, CDKAL1-rs7754840-CG, RPSAP52-rs1531343-GC, TCF7L2-rs7903146-TT, and CDKN2B-rs7018475-GG. The association of these genetic variants for TCF7L2 and CDKN2B was confirmed for female, never smokers, and poorly controlled P + T2DM. CDKN2B-rs7018475 was associated with worse glycemic condition and periodontal parameters. CONCLUSION: These five reported genetic variants were associated in the studied Southeastern Brazilian population as genetic risk variants of periodontitis and T2DM associated to periodontitis as comorbidity. Gene-phenotype associations with sex and smoking habits and the CDKN2B-rs7018475 with the poor glycemic control and more severe periodontal conditions should be further investigated. CLINICAL RELEVANCE: Polymorphisms in the CDKAL1-rs7754840, HNF1A-rs7957197, RPSAP52-rs1531343, TCF7L2-rs7903146, and CDKN2B-rs7018475 might predispose to periodontitis and T2DM associated with periodontitis. These findings may be useful in public health genomics and future advanced clinical practice, since genetic carriage can be measured before disease onset, being of potential great benefit for treatment planning and prognosis in early disease stages.

Validation in a Brazilian population of gene markers of periodontitis previously investigated by GWAS and bioinformatic studies.

BACKGROUND: Bioinformatic tools and genome-wide association studies (GWAS) have led to comprehensive identification of single nucleotide polymorphisms (SNPs) associated with periodontitis in diverse populations. Here we aimed to detect and validate the association of seven SNPs as genetic markers of susceptibility to periodontitis in a Brazilian population. METHODS: This case-control study assessed complete periodontal parameters of 714 subjects with periodontal status classified as healthy/mild periodontitis (n = 356) and moderate/severe periodontitis (n = 358). Genotyping for rs187238, rs352140, rs1360573, rs2521634, rs3811046, rs3826782, and rs7762544 SNPs were evaluated. Genetic-phenotype associations, and sex or smoking effects of SNPs on periodontitis were tested using multiple logistic regressions adjusted for covariates. RESULTS: The rs2521634-AA (close to NPY gene) presented increased risk for severe periodontitis (OR = 2.34; 95% CI = 1.19-4.59). The rs3811046-GG (IL37 gene) demonstrated increased risk for moderate periodontitis (OR = 2.58; 95% CI = 1.28-5.18). Higher risk for moderate periodontitis was found in male with rs7762544-AG close to NCR2 gene. The rs352140-TT in the TLR9 gene proved to be associated with lower risk to severe periodontitis in men. The rs2521634-AA was associated with higher percentage of interproximal probing pocket depth (P = .004). CONCLUSIONS: This is the first evidence of validation in a Brazilian population of genetic markers of periodontitis previously investigated by GWAS and bioinformatics studies. SNPs in the NPY, IL37, and NCR2 genes were associated with susceptibility to moderate or severe periodontitis; whereas the TLR9 marker was associated with lower chance to develop severe periodontitis. Those SNPs had sex- and smoking-habit-specific effects on periodontitis; reinforcing the genetic profile predisposing to periodontitis.

Functional haplotype in the Interleukin8 (CXCL8) gene is associated with type 2 Diabetes Mellitus and Periodontitis in Brazilian population.

BACKGROUND AND AIM: Type 2 Diabetes Mellitus (T2DM) and Periodontitis (P) are prevalent multifactorial disorders worldwide, sharing a bidirectional relationship influenced by the genetic susceptibility of the host immune system. We investigated whether SNPs in the Interleukin 8 (IL8, alias CXCL8) gene could be associated with T2DM and Periodontitis. METHODS: Genomic DNA was obtained from 874 Brazilian individuals divided into: Healthy group (n = 307), Periodontitis group (n = 334), and individuals affected by both T2DM and Periodontitis (T2DM_P) group (n = 233). The SNPs -251(T>A) rs4073, +396(T>G) rs2227307 and +781(C>T) rs2227306 were genotyped by TaqMan®. Multiple logistic regressions were used to determine the degree of association between polymorphisms (and haplotypes) with periodontitis and T2DM adjusted for known confounders. RESULTS: The additive model revealed that the heterozygous AT(-251), GT(+396) and CT(+781) genotypes showed a lower risk for the diseased phenotypes, and carriers of the TTC/TTC haplotype were significantly susceptible to T2DM and Periodontitis concomitantly, as well to isolated Periodontitis (mainly the severe form). CONCLUSIONS: We concluded, for the first time, that these functional CXCL8 SNPs, and the homozygous TTC haplotype are relevant genetic factors for T2DM and Periodontitis as comorbidities, as well as for severe Periodontitis susceptibility in Brazilian population.

Genetic polymorphisms in the Interleukins IL1B, IL4, and IL6 are associated with concomitant periodontitis and type 2 diabetes mellitus in Brazilian patients.

OBJECTIVE: To assess whether single nucleotide polymorphisms (SNPs) in the IL10, IL1A, IL1B, IL4, TNFA, IL6, OPG, RANK, and RANKL genes, "classically" related with periodontitis, could be associated with susceptibility to T2DM, and also with both diseases concomitantly. BACKGROUND: There are common pathogenic mechanisms in type 2 diabetes mellitus (T2DM) and periodontitis, but the knowledge of the genetic aspect of this is limited. In patients affected by concomitant T2DM and periodontitis, whose incidence is increasing, there is scarce information regarding the gene-phenotype association, including whether there are genes able to influence both diseases as comorbidities. METHODS: Periodontal clinical parameters and biochemical profile (Insulin, Fasting Glycemia, HbA1c, Triglycerides, Total Cholesterol, HDL-cholesterol, and LDL-cholesterol) data were obtained from 894 individuals divided into following three groups: Healthy (H; n = 347), Periodontitis (P; n = 348), and Periodontitis + T2DM (P + T2DM; n = 199). DNA from oral epithelial cells was collected for genotyping. Associations between SNPs and pathologies were tested by multiple logistic regression models, adjusting for age, sex, and smoking habits. We also investigated whether there are sex or smoking effects of each SNP in these phenotypes. RESULTS: The rs1143634-GA (IL1B) SNP showed significantly less likely to develop P + T2DM for all population and mainly for women (adjusted OR = 0.37, 95% CI = 0.16-0.88), while women carrying the rs224320 CT (IL4) were more susceptible to develop P + T2DM (adjusted OR = 1.81, 95% CI = 1.04-3.15). Men carrying the rs1800795-CC (IL6) genotype were less likely to develop T2DM (adjusted OR = 0.12, 95% CI = 0.02-0.70, P = .01). CONCLUSIONS: Some SNPs in the IL1B, IL4, and IL6 genes demonstrated sex-influenced association with concomitant periodontitis and T2DM, increasing the evidence of a common genetic component between these diseases and contributing with the understanding of their common pathogenic mechanisms.

Maintaining barrier function of infected gingival epithelial cells by inhibition of DNA methylation.

BACKGROUND: Infection and inflammation induce epigenetic changes that alter gene expression. In periodontal disease, inflammation, and microbial dysbiosis occur, which can lead to compromised barrier function of the gingival epithelia. Here, we tested the hypotheses that infection of cultured human gingival epithelial (HGEp) cells with Porphyromonas gingivalis disrupts barrier function by inducing epigenetic alterations and that these effects can be blocked by inhibitors of DNA methylation. METHODS: Primary HGEp cells were infected with P. gingivalis either in the presence or absence of the non-nucleoside DNA methyltransferase (DNMT) inhibitors RG108, (-) epigallocatechin-3-gallate (EGCG), or curcumin. Barrier function was assessed as transepithelial electrical resistance (TEER). DNA methylation and mRNA abundance were quantified for genes encoding components of three cell-cell junction complexes, CDH1, PKP2, and TJP1. Cell morphology and the abundance of cell-cell junction proteins were evaluated by confocal microscopy. RESULTS: Compared to non-infected cells, P. gingivalis infection decreased TEER (P < 0.0001) of HGEp cells; increased methylation of the CDH1, PKP2, and TJP1 (P < 0.0001); and reduced their expression (mRNA abundance) (P < 0.005). Pretreatment with DNMT inhibitors prevented these infection-induced changes in HGEp cells, as well as the altered morphology associated with infection. CONCLUSION: Pathogenic infection induced changes in DNA methylation and impaired the barrier function of cultured primary gingival epithelial cells, which suggests a mechanism for systemic consequences of periodontal disease. Inhibition of these events by non-nucleoside DNMT inhibitors represents a potential strategy to treat periodontal disease.

Circulating lymphocytes and monocytes transcriptomic analysis of patients with type 2 diabetes mellitus, dyslipidemia and periodontitis.

Type 2 diabetes mellitus (T2DM), dyslipidemia and periodontitis are frequently associated pathologies; however, there are no studies showing the peripheral blood transcript profile of these combined diseases. Here we identified the differentially expressed genes (DEGs) of circulating lymphocytes and monocytes to reveal potential biomarkers that may be used as molecular targets for future diagnosis of each combination of these pathologies (compared to healthy patients) and give insights into the underlying molecular mechanisms of these diseases. Study participants (n = 150) were divided into groups: (H) systemically and periodontal healthy (control group); (P) with periodontitis, but systemically healthy; (DL-P) with dyslipidemia and periodontitis; (T2DMwell-DL-P) well-controlled type 2 diabetes mellitus with dyslipidemia and periodontitis; and (T2DMpoorly-DL-P) poorly-controlled type 2 diabetes mellitus with dyslipidemia and periodontitis. We preprocessed the microarray data using the Robust Multichip Average (RMA) strategy, followed by the RankProd method to identify candidates for DEGs. Furthermore, we performed functional enrichment analysis using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis. DEGs were submitted to pairwise comparisons, and selected DEGs were validated by quantitative polymerase chain reaction. Validated DEGs verified from T2DMpoorly-DL-P versus H were: TGFB1I1, VNN1, HLADRB4 and CXCL8; T2DMwell-DL-P versus H: FN1, BPTF and PDE3B; DL-P versus H: DAB2, CD47 and HLADRB4; P versus H: IGHDL-P, ITGB2 and HLADRB4. In conclusion, we identified that circulating lymphocytes and monocytes of individuals simultaneously affected by T2DM, dyslipidemia and periodontitis, showed an altered molecular profile mainly associated to inflammatory response, immune cell trafficking, and infectious disease pathways. Altogether, these results shed light on novel potential targets for future diagnosis, monitoring or development of targeted therapies for patients sharing these conditions.

Epigenetic reprogramming in periodontal disease: Dynamic crosstalk with potential impact in oncogenesis.

Periodontitis is a chronic multifactorial inflammatory disease associated with microbial dysbiosis and characterized by progressive destruction of the periodontal tissues. Such chronic infectious inflammatory disease is recognized as a major public health problem worldwide with measurable impact in systemic health. It has become evident that the periodontal disease phenotypes are not only determined by the microbiome effect, but the extent of the tissue response is also driven by the host genome and epigenome patterns responding to various environmental exposures. More recently there is mounting evidence indicating that epigenetic reprogramming in response to combined intrinsic and environmental exposures, might be particularly relevant due its plasticity and potential application towards precision health. The complex epigenetic crosstalk is reflected in the prognosis and progress of periodontal diseases and may also lead to a favorable landscape for cancer development. This review discusses epigenomics modifications focusing on the role of DNA methylation and pathways linking microbial infection and inflammatory pathways, which are also associated with carcinogenesis. There is a more clear vision whereas 'omics' technologies applied to unveil relevant epigenetic factors could play a significant role in the treatment of periodontal disease in a personalized mode, evidencing that public health approach should coexist with precision individualized treatment.

Differential Mucosal Gene Expression Patterns in Candida-Associated, Chronic Oral Denture Stomatitis.

PURPOSE: Denture stomatitis is a common condition manifested by inflammation of the oral mucous membrane beneath a denture. The objective of this study was to compare the transcriptome of human palatal mucosa with chronic oral stomatitis-associated Candida albicans infection to that of healthy oral mucosa. MATERIALS AND METHODS: Oral palatal biopsies were obtained from 17 healthy and 15 C. albicans-infected stomatitis subjects for whole transcriptome analyses. The presence of C. albicans was confirmed by cytology and cultivable methods. The clinical severity of the stomatitis was evaluated by the Newton Classification (Class II or III). For transcriptome analyses a false discovery rate (FDR) of <0.05 was used, and the effects of age, race, and gender were evaluated by principle component analysis (PCA). Specific differentially expressed genes identified by mRNA array data were confirmed by measurements of salivary protein expression using multiplex analyses. RESULTS: Microarray analysis of mRNA expression indicated that in C. albicans stomatitis there were 3034 genes-in-play that were differentially expressed and met the FDR < 0.05 criteria. Two hundred thirty five (235) genes were up-regulated >2-fold, and 71 genes were down-regulated >2-fold. Five of the 6 most significant gene ontology pathways involve inflammation and activation of the immune response with CD28 and CTLA signaling of T cells. There was strong up-regulation of TLR2, CD14, MYD88, IKKA, and NFKB as the dominant toll-like receptor-signaling pathway. The expression of several extracellularly expressed inflammatory protein genes was up-regulated in candidiasis, and 2 were confirmed as up-regulated within the saliva using protein multiplexing analyses. CONCLUSIONS: Neutrophil recruitment and activation, epithelial suppression, and T-cell activation appear as major pathways in chronic oral candidiasis. Tissue up-regulation of TLR2 pathways, as well as potential C. albicans binding proteins, was observed, whereas keratin and adhesion molecule synthesis were down-regulated. Several candidate biomarkers to potentially identify the presence of oral candidiasis were differentially expressed in tissues and saliva.

Targeting epigenetic mechanisms in periodontal diseases.

Epigenetic factors are heritable genome modifications that potentially impact gene transcription, contributing to disease states. Epigenetic marks play an important role in chronic inflammatory conditions, as observed in periodontal diseases, by allowing microbial persistence or by permitting microbial insult to play a role in the so-called 'hit-and-run' infectious mechanism, leading to lasting pathogen interference with the host genome. Epigenetics also affects the health sciences by providing a dynamic mechanistic framework to explain the way in which environmental and behavioral factors interact with the genome to alter disease risk. In this article we review current knowledge of epigenome regulation in light of the multifactorial nature of periodontal diseases. We discuss epigenetic tagging in identified genes, and consider the potential implications of epigenetic changes on host-microbiome dynamics in chronic inflammatory states and in response to environmental stressors. The most recent advances in genomic technologies have placed us in a position to analyze interaction effects (eg, between periodontal disease and type 2 diabetes mellitus), which can be investigated through epigenome-wide association analysis. Finally, because of the individualized traits of epigenetic biomarkers, pharmacoepigenomic perspectives are also considered as potentially novel therapeutic approaches for improving periodontal disease status.

GWAS for Interleukin-1ß levels in gingival crevicular fluid identifies IL37 variants in periodontal inflammation.

There is no agnostic GWAS evidence for the genetic control of IL-1ß expression in periodontal disease. Here we report a GWAS for "high" gingival crevicular fluid IL-1ß expression among 4910 European-American adults and identify association signals in the IL37 locus. rs3811046 at this locus (p = 3.3 × 10-22) is associated with severe chronic periodontitis (OR = 1.50; 95% CI = 1.12-2.00), 10-year incident tooth loss (≥3 teeth: RR = 1.33; 95% CI = 1.09-1.62) and aggressive periodontitis (OR = 1.12; 95% CI = 1.01-1.26) in an independent sample of 4927 German/Dutch adults. The minor allele at rs3811046 is associated with increased expression of IL-1ß in periodontal tissue. In RAW macrophages, PBMCs and transgenic mice, the IL37 variant increases expression of IL-1ß and IL-6, inducing more severe periodontal disease, while IL-37 protein production is impaired and shows reduced cleavage by caspase-1. A second variant in the IL37 locus (rs2708943, p = 4.2 × 10-7) associates with attenuated IL37 mRNA expression. Overall, we demonstrate that IL37 variants modulate the inflammatory cascade in periodontal disease.

Serum lipid levels in patients with periodontal disease: A meta-analysis and meta-regression.

AIM: Several papers have considered the potential relationship between periodontitis and lipid parameters. The present systematic review, meta-analysis and meta-regression studies focused on investigating whether serum lipid parameter levels were elevated in patients with periodontal disease (PD; without altered systemic conditions) in comparison with periodontally healthy subjects. MATERIALS AND METHODS: Eligible studies were those with data about serum lipid parameter levels in non-smoking subjects with and without chronic periodontitis, who are generally healthy and not taking any medication for dyslipidaemia. Mean differences and 95% confidence intervals for total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were obtained from all the selected studies. RESULTS: A total of 19 publications were included for meta-analysis. Participants with chronic periodontitis presented significantly higher serum levels of LDL and triglycerides (p = .003 and p < .0001, respectively). The total cholesterol was higher in the PD group, but without significant difference in comparison with healthy participants. Significantly (p = .0005) lower HDL serum levels were found in patients with chronic periodontitis than in healthy subjects. CONCLUSIONS: Even considering the limitations of this meta-analysis, it is suggested that PD is significantly associated with reduction in HDL and elevation of LDL and triglyceride concentrations. This analysis supports the rationale that periodontal disease is associated with lipid metabolic control.

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-1ß) 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-1ß 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.

Gingival crevicular fluid as a source of biomarkers for periodontitis.

In evaluating the pathogenesis of periodontal diseases, the diagnostic potential of gingival crevicular fluid has been extensively explored during the last twenty years, from initially just confirming health and disease states to more recently investigating it as a potential prognostic tool. As host susceptibility is a critical determinant in periodontal disease pathogenesis, the inflammatory mediator levels present in gingival crevicular fluid represent relevant risk indicators for disease activity. Considerable work has been carried out to identify the many different cytokine inflammatory pathways and microbial stimuli that are associated with periodontal disease pathogenesis. Now, 'omics' approaches aim to summarize how these pathways interact and probably converge to create critical inflammatory networks. More recently, gingival crevicular fluid metabolomics appears promising as an additional diagnostic method. Biofilm structure and the host inflammatory response to the microbial challenge may induce specific inflammatory signatures. Host genetics and epigenetics may also modulate microbial colonization, adding to the multiplicity of potential causal pathways. Omics analyses of gingival crevicular fluid, measuring microbial and host interactions in association with the onset and progression of periodontal diseases, still show the potential to expand the landscape for the discovery of diagnostic, prognostic and therapeutic markers.

Microbial Profiling in Experimentally Induced Biofilm Overgrowth Among Patients With Various Periodontal States.

BACKGROUND: This study measures microbial composition changes during biofilm overgrowth and subsequent removal among patients with various states of periodontal disease. METHODS: In this prospective cohort study, 175 participants with various periodontal states (five biofilm-gingival interface [BGI] groups) abstained from oral hygiene while using an acrylic stent. At day 21, participants reinstituted oral hygiene and were followed for 4 weeks. Clinical parameters were recorded, and subgingival plaque samples were analyzed at baseline, peak of induction (day 21), and resolution using 16S rRNA probes (human oral microbe identification microarray [HOMIM]). Using the change score (peak at induction minus baseline) for bleeding on probing and probing depth (PD), the patients were separated into high and low clinical responders. RESULTS: At baseline, synergistetes were more abundant in moderate and severe periodontitis (BGI-P2 and -P3) compared to mild periodontitis (BGI-P1), health (BGI-H), and gingivitis (BGI-G) (P = 0.005). Overall, at day 21 there was an increase in HOMIM scores of firmicutes (P ≤0.001), fusobacteria (P = 0.003), proteobacteria (P ≤0.001), synergistetes (P = 0.04), and bacteroidetes (P ≤0.001). At resolution, these phyla returned to baseline, except for synergistetes. Levels of synergistetes were significantly higher at day 21 (P ≤0.0001) and resolution (P = 0.0002) for high clinical responders compared to low responders. CONCLUSION: The association of synergistetes as a baseline predictor of incident PD increase, as well as the higher levels at day 21, indicates a pathogenic role for these organisms in disease progression in addition to the previously characterized fusobacteria, proteobacteria, firmicutes, and bacteroidetes.

Using genetics to test the causal relationship of total adiposity and periodontitis: Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium.

BACKGROUND: The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body mass index (BMI). METHODS: We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49,066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17,672/31,394 with/without periodontitis); 68,761 participants with BMI and genotype data; and 57,871 participants (18,881/38,990 with/without periodontitis) with data on BMI and periodontitis. RESULTS: In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 [95% confidence interval (CI): 1.03, 1.24] per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI:1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data. CONCLUSIONS: Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals.