Association of P2RX7 functional variants with localized aggressive periodontitis.
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ABSTRACT: Objective
The purpose of this study was to investigate involvement of the P2X7 receptor in the rare condition, localized aggressive periodontitis.Material and methods
Peripheral blood from 220 African Americans (103 with localized aggressive periodontitis and 117 healthy unrelated controls) was stimulated with lipopolysaccharide from E coli and Porphyromonas gingivalis. P2RX7 single nucleotide polymorphisms rs208294 (H155Y), rs1718119 (T348A), rs2230911 (T357S) and rs3751143 (E496A) were genotyped in 103 localized aggressive periodontitis patients and 117 healthy unrelated subjects. We examined genetic association between four P2RX7 single nucleotide polymorphisms and localized aggressive periodontitis, and tested for correlations between the single nucleotide polymorphisms and inflammatory response to lipopolysaccharide in blood samples from these patients.Results
A significant association with localized aggressive periodontitis was observed with rs1718119 A (Thr) allele (P = 0.0063, odds ratio = 1.904) and with a haplotype containing this allele (P = 0.0075). Additionally, significant correlations with these data were found: the rs1718119 G allele correlated with greater production of IL-6, IL-2 and GM-CSF; the C (His) allele of rs208294 correlated with lower levels of IL-12p40; and the C (Thr) allele of rs2230911 correlated with greater levels of G-CSF.Conclusion
The data from these analyses support a possible biological relationship between P2RX7 genetic variants and inflammatory response in localized aggressive periodontitis patients.
SUBMITTER: Harris TH
PROVIDER: S-EPMC8018522 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimThe purpose of this study was to test for the role of the P2X7 receptor in localized aggressive periodontitis (LAP).MethodsPeripheral blood was obtained from 95 subjects with LAP and 76 healthy unrelated controls (HUCs). Three P2RX7 single-nucleotide polymorphisms (rs1718119, rs2230911, and rs3751143) were genotyped from these subjects, and their peripheral blood samples were stimulated with lipopolysaccharide (LPS) from Escherichia coli and tested for inflammatory markers. The 3 P2RX7 single-nucleotide polymorphisms were in found to be in perfect linkage disequilibrium, and a total of 4 haplotypes and 9 diplotypes were identified among all subjects. For both subject populations, the 9 diplotypes were grouped into 4 functional groups and tested for association with subject inflammatory response. To specifically study the effects of extrinsic activation of the P2X7 receptor in LAP, peripheral blood samples from were stimulated under 3 treatments: LPS, LPS + ATP, and LPS +ATP+ P2X7 selective inhibitor. The effects of these treatments on P2X7 receptor activity were measured through Luminex protein assay. Last, to test whether receptor stimulation was related to P2RX7 expression, relative mRNA levels of P2RX7 were quantified with real-time quantitative polymerase chain reaction.ResultsSeveral associations between the P2RX7 diplotypes and LPS-stimulated blood chemokine/cytokine levels were found between the LAP and HUC populations (P < 0.05). P2X7 activation resulted in statistically significant differences in IL-1β and IL-12p40 concentrations for both subject populations. The relative P2RX7 mRNA levels increased significantly after addition of its inhibitor for both LAP and HUC populations.ConclusionsThis study detected an association between P2RX7 functional diplotypes and in vitro immune response of whole blood from subjects with LAP. In addition, we found that inhibition of the activated P2X7 receptor leads to increased P2RX7 mRNA levels, suggesting a feedback loop ( ClinicalTrials.gov NCT01330719).Knowledge transfer statementThe results of this study suggest that P2RX7 functional diplotypes are associated with LAP and their in vitro immune response to bacteria. Ongoing studies to uncover the mechanistic link between P2RX7 and LAP phenotypes could lead to the development of preventive approaches for susceptible subjects.
| S-EPMC6749795 | biostudies-literature
Project description:We previously reported a systemic hyperinflammatory response to bacterial lipopolysaccharide (LPS) in children with localized aggressive periodontitis (LAP). Additionally, different levels of this response were observed within the LAP group. It is unknown whether this hyperinflammatory response influences the clinical response to periodontal treatment in these children. Therefore, the goal of this study was to evaluate the influence of LPS responsiveness present prior to treatment on the clinical response to treatment within the LAP cohort. Prior to treatment, peripheral blood was collected from 60 African American participants aged 5 to 21 y, free of systemic diseases, and diagnosed with LAP. Blood was stimulated with ultrapure LPS from Escherichia coli, and Luminex assays were performed to quantify 14 cytokine/chemokine levels. Principal component and cluster analyses were used to find patterns of cytokine/chemokine expression among participants and subdivide them into clusters. Three distinct clusters emerged among LAP participants: a high responder group (high level of response for INFg, IL6, and IL12p40), a mixed responder group (low for some and high for other cytokines/chemokines), and a low responder group (low overall cytokine/chemokine response). Periodontal clinical parameters were compared among these groups prior to and 3, 6, and 12 mo following treatment with mechanical debridement and systemic antibiotics. High responders presented the lowest reductions in clinical parameters after treatment, whereas the low responders presented the highest reductions. In our LAP participants, distinct patterns of LPS response were significantly predictive of changes in clinical parameters after treatment. Future studies are needed to evaluate the underlying mechanisms predicting the heterogeneity of LAP activity, severity, and response to treatment (ClinicalTrials.gov NCT01330719).
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Project description:We have previously demonstrated a Toll-like receptor (TLR)-mediated hyper-responsive phenotype in our cohort of localized aggressive periodontitis (LAP) individuals. However, mechanisms related to this phenotype are still not clear in the literature. The objective of this cross-sectional study is to examine the role of epigenetic regulation, specifically DNA methylation status of genes in the TLR pathway in this cohort. Peripheral blood was collected from 20 LAP patients and 20 healthy unrelated controls. Whole blood was stimulated with 1 ?l (100 ng/?l) of purified Escherichia coli lipopolysaccharide (LPS) for 24 h and cyto/chemokines in the supernatants analyzed by Luminex multiplex assays. Genomic DNA extracted from buffy coats prepared from a second tube of whole blood was used for DNA methylation analysis by pyrosequencing of seven TLR signaling genes (FADD, MAP3K7, MYD88, IL6R, PPARA, IRAK1BP1, RIPK2).Significant differences in the methylation status were observed at specific CpG positions in LAP patients compared to healthy controls and interestingly also between severe and moderate LAP. Specifically, subjects with moderate LAP presented hypermethylation of both the upregulating (MAP3K7, MYD88, IL6R, and RIPK2) and downregulating (FADD, IRAK, and PPARA) genes, while severe LAP presented hypomethylation of these genes. Further analysis on CpG sites with significant differences in methylation status correlates with an increased pro-inflammatory cytokine profile for LAP patients.Our findings suggest that epigenetic modifications of genes in the TLR pathway may orchestrate the thresholds for balancing induction and prevention of tissue destruction during the course of disease, and thus differ significantly at different stages of the disease, where moderate LAP shows hypermethylation and severe LAP shows hypomethylation of several genes.https://clinicaltrials.gov, NCT01330719.
| S-EPMC5581417 | biostudies-literature
Project description:Localized aggressive periodontitis (LAP) patients possess a systemic hyperinflammatory response after lipopolysaccharide stimulation. However, the levels of inflammatory and bone biomarkers in plasma, as well as possible associations between local and plasma biomarkers, are unknown in LAP. This cross-sectional study aimed to characterize gingival crevicular fluid (GCF) and plasma biomarker profiles in LAP patients, their healthy siblings (HS), and healthy unrelated controls (HC). Fifty-eight LAP subjects, 33 HS, and 49 HC (African Americans, aged 5 to 25 y) were included. Following collection of clinical parameters with GCF and plasma samples, levels of 16 inflammatory and bone resorption biomarkers were determined with Milliplex. Univariate and correlation analyses were performed among all clinical and laboratorial parameters. Discriminant analyses were used to investigate groups of biomarkers discriminating LAP from HS and HC in GCF and plasma. GCF levels of multiple cytokines and chemokines and RANKL:OPG ratio (receptor activator of nuclear factor kappa-B ligand:osteoprotegerin) were higher in LAP disease, most of which positively correlated with probing depth and attachment loss of sampled sites. A group of IL-12p40, IL-6, IL-12p70, IL-2, and MIP-1? discriminated LAP diseased sites from twheir healthy sites, as well as from HS and HC healthy sites. In plasma, only RANKL levels were increased in LAP versus controls, which positively correlated with the percentage of affected sites and deep/bleeding sites. A plasma inflammatory profile including MIP-1?, IL-8, IL-10, and INF-? could significantly discriminate LAP patients from HS and HC. No correlations were found between GCF and plasma levels of biomarkers. In conclusion, an inflammatory profile including groups of specific biomarkers in GCF and plasma may significantly discriminate LAP from healthy individuals. The hyperinflammatory response previously found in the peripheral blood of LAP patients is dependent on lipopolysaccharide stimulation, apparently resulting mostly in local tissue destruction and changes in biomarker profile, with a slight influence in the systemic inflammatory profile (ClinicalTrials.gov NCT01330719). Knowledge Transfer Statement: The results of this study can be possibly used by clinicians in the future as diagnostic tools for localized aggressive periodontitis. Thus, in the future, with proper consideration of cost, patient preference, chair-side feasibility and ultimately further studies validating the role of GCF markers for disease progression and response to treatment, this information could lead to more appropriate therapeutic decisions and the development of preventive approaches for susceptible patients.
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Project description:Due to the low prevalence of localized aggressive periodontitis (LAP), clinical characteristics of LAP in primary dentition are derived from a few case reports/series in the literature. The goal of this study was to determine common clinical characteristics such as bone and root resorption patterns, in a series of cases with LAP in primary dentition. We hypothesize these cases present aggressive periodontal bone destruction starting mostly around first primary molars and atypical root resorption patterns.We have evaluated 33 LAP cases in primary dentition for pattern of bone destruction, root resorption and early exfoliation.Cases evaluated were aged 5-12 (mean=8.7 years). Thirty cases presented more severe bone loss on first than second molars, with relatively fast progression to second molars, altered pattern of root resorption, mostly external (n=16) and early exfoliation of primary teeth due to periodontal bone loss, rather than physiologic root resorption (n=11).This study showed common clinical characteristics found in LAP in primary molars, including possible initiation on first primary molars and abnormal root resorption patterns. These characteristics are important to be early identified and treated in order to prevent possible progression into the permanent dentition.
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Project description:Matrix metalloproteinases (MMPs) are a family of host-derived proteinases reported to mediate multiple functions associated with periodontal breakdown and inflammation. High MMP levels in African-American children with localized aggressive periodontitis (LAgP) have been reported previously by the present authors. However, little is known about MMP reductions in gingival crevicular fluid (GCF) after therapy. This study aims to evaluate MMP levels in the GCF after treatment of LAgP and to correlate these levels with clinical response.GCF samples were collected from 29 African-American individuals diagnosed with LAgP. GCF was collected from one diseased site (probing depth [PD] >4 mm, bleeding on probing [BOP], and clinical attachment level ? 2 mm) and one healthy site (PD ? 3 mm, no BOP) from each individual at baseline and 3 and 6 months after periodontal treatment, which consisted of full-mouth scaling and root planing (SRP) and systemic antibiotics. The volume of GCF was controlled using a calibrated gingival fluid meter, and levels of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-12, and MMP-13 were assessed using fluorometric kits.MMP-1, MMP-8, MMP-9, MMP-12, and MMP-13 levels were reduced significantly up to 6 months, comparable to healthy sites at the same point. Significant correlations were noted between MMP-2, MMP-3, MMP-8, MMP-9, MMP-12, and MMP-13 levels and percentage of sites with PD >4 mm. MMP-3, MMP-12, and MMP-13 levels also correlated with mean PD of affected sites.Treatment of LAgP with SRP and systemic antibiotics was effective in reducing local levels of specific MMPs in African-American individuals, which correlated positively with some clinical parameters.
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Project description:The comparative treatment response of children and young adults with localized aggressive periodontitis treatment (LAgP) affecting primary and permanent dentition is unknown. The objective of this study is to evaluate the influence of non-surgical periodontal therapy with adjunctive systemic antibiotics on the clinical outcome of children and young adults with primary versus permanent dentition affected by LAgP.A cohort of 97 African American participants aged 5 to 21 years (30 males and 67 females; 22 primary and 75 permanent dentitions affected) diagnosed with LAgP were included. Patients presented with no significant medical history. All patients underwent periodontal therapy, which consisted of full-mouth mechanical debridement at baseline and the 3-, 6-, and 12-month appointments. Additionally, all patients were prescribed a 1-week regimen of systemic antibiotics at the initial appointment. Clinical parameters were analyzed, including probing depth, clinical attachment level (CAL), bleeding on probing, and percentage of visible plaque.Overall, periodontal therapy was found to be effective in improving the clinical outcomes of both primary and permanent dentitions. Although baseline CALs were similar between the groups, the reduction in mean CAL at 3, 6, and 12 months and reduction in percentage plaque at 3 months were significantly greater in primary dentition compared with permanent dentition.Non-surgical therapy with systemic antibiotics is effective for LAgP in both primary and permanent dentitions. A greater reduction in CAL in LAgP of primary dentition may suggest that younger children may carry a greater propensity for positive treatment outcomes and healing potential compared with children/young adults with permanent dentition.
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Project description:Aggressive periodontitis (AgP), Stage III or IV and Grade C according to the new periodontitis classification, is characterized by the rapid destruction of periodontal tissues in the systemically healthy population and often causes premature tooth loss. The presence of familial aggregation suggests the involvement of genetic factors in the pathogenesis. However, the genes associated with the onset and progression of the disease and details of its pathogenesis have not yet been fully identified. In recent years, the genome-wide approach (GWAS), a comprehensive genome analysis method using bioinformatics, has been used to search for disease-related genes, and the results have been applied in genomic medicine for various diseases, such as cancer. In this review, we discuss GWAS in the context of AgP. First, we introduce the relationship between single-nucleotide polymorphisms (SNPs) and susceptibility to diseases and how GWAS is useful for searching disease-related SNPs. Furthermore, we summarize the recent findings of disease-related genes using GWAS on AgP inside and outside Japan and a possible mechanism of the pathogenesis of AgP based on available literature and our research findings. These findings will lead to advancements in the prevention, prognosis, and treatment of AgP.
| S-EPMC10582758 | biostudies-literature
Project description:This study aimed to evaluate the potential risk for localized aggressive periodontitis (LAgP) in African American children by detection of the potential periodontal pathogen Aggregatibacter actinomycetemcomitans (Aa) using polymerase chain reaction (PCR) and microbiome analysis.Twenty-one pre-adolescents (age range equals 10.7 to 13.1 years old) were recruited, for this IRB-approved study. Oral examination included limited periodontal examination determining bleeding index (BOP) and periodontal probing (PD). An oral mucosa sample was used for analysis.Nine of 21 children were Aa+ by PCR. The Aa+ group had a significantly higher proportion of teeth with BOP and PD greater than four mm than the Aa- group (P=0.014 and 0.006 for percent BOP and percent PD equal to or greater than four mm, respectively; Mann Whitney Test). No significant differences in microbe abundance or composition were found from comparison of Aa+ versus Aa- samples.Detection of Aa from preadolescent African American children was associated with signs of periodontal inflammation. Although none of these children were diagnosed with LAgP, PCR targeting Aa could be a risk factor. Further study is indicated; however, the usefulness of PCR in dental practice setting to assess risk may be cost-effective for early diagnosis and prevention of LAgP.
| S-EPMC5682943 | biostudies-literature
Project description:AimThe objective of this case-control study was to compare the inflammatory response of peripheral blood from localized aggressive periodontitis (LAP) patients when stimulated with healthy or diseased plaque samples.Materials and methodsWhole blood and subgingival plaque samples were collected from 13 LAP subjects, 14 siblings of LAP subjects and six periodontally healthy individuals. Whole blood was stimulated for 24 h with plaque samples generated from healthy or diseased sites. The levels of 14 cyto/chemokines were detected using multiplex technology.ResultsLocalized aggressive periodontitis-derived cultures displayed higher levels of G-CSF, INFγ, IL10, IL12p40, IL1β, IL-6, IL-8, MCP-1, MIP-1α, and TNFα, than control cultures regardless of stimulus used. Whole blood from healthy siblings displayed higher levels of IL-6 compared to control subjects, but lower levels than those observed in cultures from LAP participants.ConclusionsThis study suggests that although bacteria is an important factor in eliciting the hyper-inflammatory response observed in LAP patients, the predisposition of host's response to bacterial presence may play a more significant role than the components of the stimulatory plaque.
| S-EPMC4975966 | biostudies-literature