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Objectives The aim of this study was to investigate the inflammatory response in aggressive periodontitis (AgP) patients after periodontal therapy and associate these changes to subjects’ interleukin-6 (IL-6) genetic variants. Materials and methods Twelve non-smoking UK Caucasian patients with AgP were selected based on their IL6 haplotypes (six haplotype positive and six haplotype negative based on polymorphisms rs 2069827 and rs 2069825) and underwent full mouth non-surgical periodontal therapy, followed by open flap surgery. Gingival crevicular fluid (GCF) and peripheral blood samples were taken at baseline and at six different time points after treatment. Gingival biopsy samples were harvested during surgery and underwent immunohistochemical analysis for identification of IL-6. Results An overall improvement in clinical periodontal parameters was observed following periodontal therapy. Haplotype status was associated with clinical presentation, Aggregatibacter actinomycetemcomitans counts in subgingival plaque samples, white cell count, neutrophils, red cell count and haemoglobin. GCF IL-6 concentrations increased dramatically 1 day after surgery and IL-6 haplotype-positive subjects exhibited a higher magnitude in this increase. Conclusions IL6 haplotypes may have an effect on clinical presentation and magnitude and kinetics of local and systemic inflammatory responses following non-surgical and surgical periodontal therapy in aggressive periodontitis. Clinical relevance Detecting IL-6 haplotype-positive periodontitis patients might become helpful in identifying subjects prone to excessive inflammatory response and increased periodontal breakdown.

Host genetic predispositions to dysregulated immune response can influence the development of the aggressive form of periodontitis (AgP) through susceptibility to oral dysbiosis and subsequent host-microbe interaction. This case-control study aimed to perform a multilocus analysis of functional variants in selected interleukin (IL) genes in patients with the generalized form of AgP in a homogenous population. Twelve polymorphisms in IL-1 gene cluster, IL-6 and its receptor, IL-10, IL-17A, and IL-18 were determined in 91 AgP patients and 210 controls. Analysis of seven selected periodontal bacteria in subgingival sulci/pockets was performed with a commercial DNA-microarray kit in a subgroup of 76 individuals. The pilot in vitro study included stimulation of peripheral blood monocytes (PBMC) from 20 individuals with periodontal bacteria and measurement of IL-10 levels using the Luminex method. Only the unctional polymorphism IL-10 −1087 A/G (rs1800896) and specific IL-10 haplotypes were associated with the development of the disease (p < 0.05, Pcorr > 0.05). Four bacterial species occurred more frequently in AgP than in controls (p < 0.01, Pcorr < 0.05). Elevated IL-10 levels were found in AgP patients, carriers of IL-10 −1087GG genotype, and PBMCs stimulated by periodontal bacteria (p < 0.05, Pcorr > 0.05). We therefore conclude that a combination of genetic predisposition to the altered expression of IL-10 and the presence of specific periodontal bacteria may contribute to Th1/Th2 balance disruption and AgP development.

Interleukin (IL) 1-ra is a potent endogenous competitive inhibitor of IL-α and β and has an anti-inflammatory role. Study objectives were: 1) to assess the associations of IL-1RN genetic single nucleotide polymorphism (SNP) (rs419598) with generalized chronic periodontitis (GCP), generalized aggressive periodontitis (GAgP), and absence of periodontitis and 2) to assess its association with the load of five periodontopathogenic bacteria and periodontal clinical variables. A cross-sectional analytic study was conducted in 123 patients with GCP, 60 patients with GAgP, and 20 controls. Reverse hybridization PCR was used for genotyping analysis to detect SNPs in IL-1A (rs1800587), IL-1B (rs1143634), and IL-1RN (rs419598) genes and for determination of the load of five periodontopathogenic bacteria. The severity and extension of periodontitis were assessed. Multinomial logistic regression and mediated regression analyses were performed. Considering results for GCP and GAgP patients together, the presence of polymorphism in IL-1A and/or IL-1B gene was associated with a higher likelihood of periodontitis, (OR = 8.11; 95%CI [1.85-35.48]), but this likelihood was reduced when IL-1RN polymorphism was also present, (OR = 5.91; 95%CI [1.08-32.27]). IL-1RN polymorphism was significantly associated with lower counts of red complex bacteria, specifically Porphyromona gingivalis, Tannerella forsythia, and Prevotella intermedia, which were associated with improved clinical outcomes. The polymorphic expression of IL-1RN (rs419598) gene may be associated with a reduced susceptibility to GAgP and GCP in populations of European descent. This effect may be mediated by a decreased load of Porphyromona gingivalis, Tannerella forsythia, and Prevotella intermedia.

Aggressive periodontitis (AgP) occurs at an early age and causes rapid periodontal tissue destruction. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) encodes a protein with two caspase recruitment domains and eleven leucine-rich repeats. This protein is expressed mainly in peripheral blood leukocytes and is involved in immune response. NOD2 variants have been associated with increased susceptibility to Crohn’s disease, and recently, NOD2 was reported as a causative gene in AgP. The present study aimed to identify potential NOD2 variants in an AgP cohort (a total of 101 patiens: 37 patients with positive family histories and 64 sporadic patients). In the familial group, six patients from two families had a reported heterozygous missense variant (c.C931T, p.R311W). Four patients in the sporadic group had a heterozygous missense variant (c.C1411T, p.R471C), with no reported association to the disease. Overall, two NOD2 variants, were identified in 10% of our AgP cohort. These variants were different from the major variants reported in Crohn’s disease. More cases need to be investigated to elucidate the role of NOD2 variants in AgP pathology.

To suggest candidate genes involved in periodontitis, we combined gene expression data of periodontal biopsies from Collaborative Cross (CC) mouse lines, with previous reported quantitative trait loci (QTL) in mouse and with human genome-wide association studies (GWAS) associated with periodontitis. Periodontal samples from two susceptible, two resistant and two lines that showed bone formation after periodontal infection were collected during infection and naïve status. Differential expressed genes (DEGs) were analyzed in a case-control and case-only design. After infection, eleven protein-coding genes were significantly stronger expressed in resistant CC lines compared to susceptible ones. Of these, the most upregulated genes were MMP20 (P = 0.001), RSPO4 (P = 0.032), CALB1 (P = 1.06×10 −4 ), and AMTN (P = 0.05). In addition, human orthologous of candidate genes were tested for their association in a case-controls samples of aggressive (AgP) and chronic (CP) periodontitis (5,095 cases, 9,908 controls). In this analysis, variants at two loci, TTLL11/PTGS1 (rs9695213, P = 5.77×10 −5 ) and RNASE2 (rs2771342, P = 2.84×10 −5 ) suggested association with both AgP and CP. In the association analysis with AgP only, the most significant associations were located at the HLA loci HLA- DQH1 (rs9271850, P = 2.52×10 −14 ) and HLA- DPA1 (rs17214512, P = 5.14×10 −5 ). This study demonstrates the utility of the CC RIL populations as a suitable model to investigate the mechanism of periodontal disease.

Epidemiological studies have indicated a relationship between coronary heart disease (CHD) and periodontitis. Recently, CDKN2BAS was reported as a shared genetic risk factor of CHD and aggressive periodontitis (AgP), but the causative variant has remained unknown. To identify and validate risk variants in different European populations, we first explored 150 kb of the genetic region of CDKN2BAS including the adjacent genes CDKN2A and CDKN2B, covering 51 tagging single nucleotide polymorphisms (tagSNPs) in AgP and chronic periodontitis (CP) in individuals of Dutch origin (n=313). In a second step, we tested the significant SNP associations in an independent AgP and CP population of German origin (n=1264). For the tagSNPs rs1360590, rs3217992, and rs518394, we could validate the associations with AgP before and after adjustment for the covariates smoking, gender and diabetes, with SNP rs3217992 being the most significant (OR 1.48, 95% CI 1.19 to 1.85; p=0.0004). We further showed in vivo gene expression of CDKN2BAS, CDKN2A, CDKN2B, and CDK4 in healthy and inflamed gingival epithelium (GE) and connective tissue (CT), and detected a significantly higher expression of CDKN2BAS in healthy CT compared to GE (p=0.004). After 24 h of stimulation with Porphyromonas gingivalis in Streptococcus gordonii pre-treated gingival fibroblast (HGF) and cultured gingival epithelial cells (GECs), we observed a 25-fold and fourfold increase of CDKN2BAS gene expression in HGFs (p=0.003) and GECs (p=0.004), respectively. Considering the global importance of CDKN2BAS in the disease risk of CHD, this observation supports the theory of inflammatory components in the disease physiology of CHD.

Periodontitis is a loss of supporting connective tissue and alveolar bone around teeth, and if it occurs in an aggressive form it can lead to tooth loss before the age of 20 years. Although the cause of periodontitis in general remains elusive, a particular clone (JP2) of the gram-negative rod Aggregatibacter (Actinobacillus) actinomycetemcomitans is considered a possible aetiological agent of the aggressive form in adolescents living in or originating from north and west Africa, where the disease is highly prevalent. We did a population-based longitudinal study of adolescents to assess the role of the JP2 clone in the initiation of aggressive periodontitis. A total of 700 adolescents from public schools in Rabat, Morocco, were enrolled in the study. We used PCR to detect A actinomycetemcomitans in plaque samples (taken from molar and incisor sites) and to differentiate between the JP2 clone and other non-JP2 genotypes of the bacterium. 18 individuals were found to already have periodontitis and were excluded. The 682 periodontally healthy adolescents (mean age 12·5 years; SD 1·0) were classified according to their A actinomycetemcomitans carrier status at baseline. After 2 years, 428 (62·8%) individuals returned for re-examination, which included recording of periodontal attachment loss measured from the cemento-enamel junction to the bottom of the periodontal pockets of all teeth present. Individuals who carried the JP2 clone of A actinomycetemcomitans alone (relative risk 18·0; 95% CI 7·8–41·2, p<0·0001) or together with non-JP2 clones of A actinomycetemcomitans (12·4; 5·2–29·9, p<0·0001) had a significantly increased risk of periodontal attachment loss. A much less pronounced disease risk was found in those carrying non-JP2 clones only (3·0; 1·3–7·1, p=0·012). The JP2 clone of A actinomycetemcomitans is likely to be an important aetiological agent in initiation of periodontal attachment loss in children and adolescents. Co-occurrence of non-JP2 clones of A actinomycetemcomitans reduces the risk of development of periodontitis, suggesting competition for the ecological niche between the JP2 and non-JP2 clones of this species.

ObjectivesThe aim of this study is to investigate the potential role of ANRIL polymorphisms in susceptibility to periodontitis.MethodsThe authors searched Pubmed, Web of Science, and Scopus up to April 2021 to identify all published studies without any language restriction on the association between ANRIL and periodontitis. A meta-analysis of all ANRIL variants replicated by three or more studies was performed by testing multiple genetic models of association. Pooled odds ratios and 95% confidence intervals (CI) were used to estimate associations. Tests for sensitivity and publication bias were performed.ResultsTwenty-two variants in the ANRIL gene were examined for their potential association with the risk of periodontitis. However, only 4 (rs1333048, rs1333042, rs2891168, rs496892) are replicated at least three or more studies. The ANRIL rs1333048 was the most replicated polymorphisms with five articles, seven different populations comprising of 1331 cases, and 2624 controls. The pooled overall analysis showed that rs1333048, rs1333042, rs2891168, and rs496892 polymorphisms were associated with susceptibility to periodontitis in the whole population in allele contrast and dominant models. Moreover, similar to the overall analysis, rs1333048 polymorphism showed a significant association with grade C periodontitis (known as aggressive periodontitis in 1999 classification) in allele contrast (OR = 1.16) and dominant models (1.19). Interestingly, subgroup analysis also showed rs1333048 polymorphism might influence predisposition to a slowly progressive form of periodontitis (known as chronic periodontitis in 1999 classification).ConclusionOur findings suggest that the ANRIL rs1333048, rs1333042, rs2891168, and rs496892 polymorphisms might influence predisposition to periodontitis, particularly in Caucasians.Clinical significanceANRIL gene may represent a potential risk marker for periodontitis.

Aggressive periodontitis is an inflammation of the periodontal tissue that usually affects adolescents and young adults aged <30 years, caused by attachment loss and fast bone degradation. The correlation between the epigenetic status and the initiation and progression of numerous acquired diseases was documented. Consequently, targeting epigenetic factors within periodontal tissues stands as an appealing prospect for both the diagnosis and treatment of periodontitis. In addition to the role of pathogenic bacteria and their products, alterations in gene expression due to extrinsic and intrinsic factors can cause disturbances in the host's immune response. Epigenetic changes, whether DNA methylation or microRNA (miRNA) dysregulation, can cause changes in gene expression in aggressive periodontitis and lead to more severe and rapid loss of the periodontal tissues. This study aimed to elucidate the relationships between oral hygiene, pathogenic bacteria, and genetics in periodontitis development to promote targeted prevention and treatment for enhanced oral health in individuals at risk of aggressive periodontitis. The method employed in this study entailed a comprehensive review and analysis of scholarly literature on the relationship between epigenetic mechanisms and the development of aggressive periodontitis. In conclusion, epigenetic regulation plays an important role in the pathogenesis of periodontitis through DNA methylation mechanisms that begin with Toll-like receptors (TLRs), cytokine signaling pathways, promoter genes, and progress to pro-inflammatory cells. When periodontal tissue inflammation occurs, miRNA inhibits protein translation from messenger ribonucleic acid (mRNA), which contributes to its aggressiveness.

Background Periodontitis is a major oral health problem and it is considered as one of the reasons for tooth loss in developing and developed nations. The objective of the current review was to investigate the association between IL10 polymorphisms − 1082 A > G (rs1800896), -819C > T (rs1800871), − 592 A > C (rs1800872) and the risk of either chronic periodontitis or aggressive periodontitis. Methods This is a meta- analysis study, following the preferred reporting items for systematic reviews and meta- analyses (PRISMA). Relevant studies were searched in the health related electronic databases. Methodological quality of the included studies were assessed using the Newcastle-Ottawa Scale. For individual studies, odds ratio (OR) and its 95%confidence interval (CI) were calculated to assess the strength of association between IL10 polymorphisms (− 1082 A > G, -819C > T, − 592 A > C) and the risk of periodontitis. For pooling of the estimates across studies included, the summary OR and its 95% CIs were calculated with random-effects model. The pooled estimates were done under four genetic models such as the allelic contrast model, the recessive model, the dominant model and the additive model. Trial sequential analysis (TSA) was done for estimation of the required information size for this meta-analysis study. Results Sixteen studies were identified for this review. The included studies were assessed to be of moderate to good methodological quality. A significant association between polymorphism of IL10 –1082 A > G polymorphism and the risk of chronic periodontitis in the non-Asian populations was observed only in the recessive model (OR,1.42; 95% CI:1.11, 1.8, I 2 : 43%). The significant associations between − 592 A > C polymorphism and the risk of aggressive periodontitis in the non-Asian populations were observed in particular genetic models such as allele contrast (OR, 4.34; 95%CI:1.87,10.07, I 2 : 65%) and recessive models (OR, 2.1; 95% CI:1.16, 3.82, I 2 : 0%). The TSA plot revealed that the required information size for evidence of effect was sufficient to draw a conclusion. Conclusions This meta-analysis suggested that the IL10 –1082 A > G polymorphism was associated with chronic periodontitis CP risk in non-Asians. Thus, in order to further establish the associations between IL1 0 (− 819 C > T, − 592 A > C) in Asian populations, future studies should include larger sample sizes with multi-ethnic groups.