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Aim: To propose a framework for consistently applying the 2018 periodontal status classification scheme to epidemiological surveys (Application of the 2018 periodontal status Classification to Epidemiological Survey data, ACES)., Proposed Framework: We specified data requirements and workflows for either completed or planned epidemiological surveys, utilizing commonly collected measures of periodontal status (clinical attachment levels [CAL], probing depths, bleeding on probing), as well as additional necessary variables for the implementation of the 2018 periodontal status classification (tooth loss due to periodontitis and complexity factors). Following detailed instructions and flowcharts, survey participants are classified as having periodontal health, gingivitis or periodontitis. Rates of edentulism must also be reported. In cases of periodontitis, instructions on how to compute the stage and extent are provided. Assessment of grade can be derived from CAL measurements (or from radiographic alveolar bone loss data) in relation to root length and the participant's age., Conclusions: ACES is a framework to be used in epidemiological studies of periodontal status that (i) have been completed, and in which stage and grade according to the 2018 classification are inferred retroactively, or (ii) are being planned. Consistent use of the proposed comprehensive approach will facilitate the comparability of periodontitis prevalence estimates across studies., (© 2024 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Aim: To investigate the medium-term associations of serum protein subfractions derived from proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy with periodontitis and tooth loss., Materials and Methods: A total of 3031 participants of the cohort Study of Health in Pomerania (SHIP-TREND) were included. In addition to conventional serum testing, serum lipoprotein contents and subfractions were analysed by 1 H-NMR spectroscopy. Confounder-adjusted associations of lipoprotein variables with periodontitis and the number of missing teeth variables were analysed using mixed-effects models with random intercepts for time across individuals, accounting for multiple testing., Results: While only spurious associations between lipoprotein levels from conventional blood tests were found-that is, triglycerides were associated with mean clinical attachment level (CAL) and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio with the number of missing teeth - several associations emerged from serum lipoprotein subfractions derived from 1 H-NMR analysis. Specifically, elevated LDL triglycerides were associated with higher levels of mean probing depth (PD), mean CALs, and increased odds of having <20 teeth. HDL-4 cholesterol levels were inversely associated with mean PD. Systemic inflammation (C-reactive protein) might mediate the effects of LDL and HDL triglyceride contents on periodontitis severity., Conclusions: Several associations between serum lipoprotein subfractions and periodontitis were observed. As the underlying biochemical mechanisms remain unclear, further research is needed., (© 2023 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Aim: To estimate association between the use of interdental cleaning aids (IDAs) and type on 7-year follow-up levels of interdental plaque, interdental gingival inflammation, interdental periodontitis severity, the number of interdental sound surfaces and the number of missing teeth in a population-based cohort study., Materials and Methods: We used 7-year follow-up data of 2224 participants from the Study of Health in Pomerania (SHIP-TREND). We applied generalized linear and ordinal logistic models, adjusting for confounding and selection bias using inverse probability treatment weighting and multiple imputation., Results: Flossers were 32% less likely to have higher interdental plaque (iPlaque) levels than non-users of IDAs (odds ratio [OR] = 0.68; 95% confidence interval [CI]: 0.50-0.94); flossing resulted in 5% lower means of iPlaque. Effects on interdental bleeding on probing (iBOP), mean interdental probing depths and mean interdental clinical attachment levels were direction-consistent but statistically non-significant. Interdental brushing was associated with lower follow-up levels for interdental plaque (OR = 0.73; 95% CI: 0.57-0.93) and iBOP (OR = 0.69; 95% CI: 0.53-0.89). IDAs were more effective in reducing iPlaque in participants with periodontitis, whereas iBOP reduction was more pronounced in participants with no or mild periodontitis. The analyses did not suggest that the use of IDAs affected caries. Finally, applying change score analyses, flossing reduced tooth loss incidence (incidence rate ratio [IRR] = 0.71) compared with non-users of IDAs., Conclusions: Recommending flossing and interdental brushing in dental practices represents an approach to the prevention of gingivitis and consequently periodontitis., (© 2023 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Aim: Evidence from a Phase IIa trial showed that a complement C3-targeted drug reduced gingival inflammation in patients with gingivitis. Using drug-target Mendelian randomization (MR), we investigated whether genetically proxied C3 inhibition alters the risk of periodontitis., Materials and Methods: We used multiple 'cis' instruments from the vicinity of the encoding loci of C3. Instrument selection was restricted to the drug target encoding loci (chromosome 19; 6,677,715-6,730,573 (GRCh37/hg19)). We selected three uncorrelated single-nucleotide polymorphisms (rs141552034, rs145406915, rs11569479) that were associated with serum C3 levels (p value <1 × 10 -4 ) from a genome-wide association study (GWAS) of 5368 European descent individuals. We extracted association statistics from a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Wald ratios were combined using inverse-variance weighted meta-analysis to estimate the odds ratio (OR) of the genetically proxied inhibition of C3 in relation to periodontitis., Results: MR analysis revealed that the inhibition of C3 reduces the odds of periodontitis (OR 0.91 per 1 standard deviation reduction in C3; 95% confidence interval 0.87-0.96, p value = .0003)., Conclusions: Findings from our MR analysis suggest a potential protective effect of C3 blockade against periodontitis., (© 2023 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Objective: To conduct a systematic review of the published scientific evidence to evaluate the efficacy of nonsurgical periodontal therapy (NSPT) in treating periodontitis in patients with concurrent systemic conditions (diabetes, CVD, erectile dysfunction, chronic kidney disease, rheumatoid arthritis, polycystic ovarian syndrome, obesity, pregnancy). We hypothesised that NSPT results in better periodontal outcomes when compared to untreated controls after follow-up., Materials and Methods: A systematic search (PUBMED/EMBASE) was conducted from 1995 to 2023 to identify randomised controlled trials (RCTs) with a minimum follow-up of 3 months. The primary outcome was the difference in mean probing depth (PD), and the secondary outcomes were mean clinical attachment loss (CAL), percentage of sites with PD ≤ 3 mm (%PD ≤ 3 mm) and percentage of sites with bleeding on probing (%BOP) between the treated and untreated control group in patients with comorbidities., Results: The electronic search resulted in 2,403 hits. After removing duplicates, 1,565 titles and abstracts were screened according to the eligibility criteria, resulting in 126 articles for full-text screening. Following this, 44 studies were analysed. Restricting to studies with low bias or some concerns, NSPT group demonstrated a 0.55 mm lower mean PD (95%CI: -0.69; -0.41) after 3 months compared to the control group., Conclusion: Compared to the untreated controls, NSPT notably reduced mean PD, mean CAL, and %BOP while increasing %PD ≤ 3 mm in patients with concurrent systemic conditions. These findings suggest that NSPT is also an effective procedure in managing periodontitis in patients with concurrent systemic conditions., Trial Registration: This systematic review was registered under the protocol registration number CRD42021241517/PROSPERO., (© 2023. The Author(s).)

Background: Recent studies have highlighted the role of low-grade systemic inflammation in linking periodontitis to cardiovascular disease (CVD) outcomes, but many aspects remain unclear. This study examines the independent and reciprocal associations of periodontitis and low-grade systemic inflammation with all-cause and CVD mortality in a large-scale cohort., Methods: A total of 3047 participants from the prospective, population-based Study of Health in Pomerania (SHIP-START) were followed for a period of 13.0 ± 2.4 years. For the association between various inflammation/periodontitis measures and mortality, hazard ratios (HRs) were obtained from covariate-adjusted Cox proportional hazards models. Interactions were analysed in joint models: on the multiplicative scale, HRs were reported and on the additive scale, relative excess risks due to interaction (RERI) were calculated. Subject and variable-specific interval records were used to account for time-varying exposures and covariates., Results: During the observation period, 380 (12.5%) individuals died from CVD (n = 125) or other causes (n = 255). All markers of periodontitis and inflammation showed apparent associations with all-cause mortality (HRs per SD-increase: mean PPD: 1.068 (95% confidence interval (CI): 0.988-1.155), mean CAL: 1.205 (95% CI: 1.097-1.323), missing teeth: 1.180 (95% CI: 1.065-1.307), periodontitis score: 1.394 (95% CI: 1.202-1.616), leukocytes: 1.264 (95% CI: 1.163-1.374), fibrinogen: 1.120 (95% CI: 1.030-1.218), CRP: 1.231 (95% CI: 1.109-1.366), inflammation score: 1.358 (95% CI: 1.210-1.523)). For CVD mortality, all PPD related variables showed significant associations. Interaction modelling revealed some variation with respect to mortality type and exposure combinations. On the additive scale, RERIs for periodontitis score and inflammation score implied 18.9% and 27.8% excess mortality risk for all-cause and CVD mortality, respectively. On the multiplicative scale, the HRs for interaction were marginal., Conclusions: Both periodontitis and inflammation were significantly associated with all-cause mortality and CVD mortality. On the additive scale, a substantial excess risk was observed due to the interaction of periodontitis and inflammation, suggesting that the greatest treatment benefit may be achieved in patients with both periodontitis and high systemic inflammation. As periodontal therapy has been reported to also reduce systemic inflammation, the possibility of a reduction in CVD mortality risk by anti-inflammatory treatments, including periodontal interventions, seems worthy of further investigation., (© 2023. The Author(s).)

Aim: Assessment of treatment response after systemic amoxicillin/metronidazole adjunctive to subgingival instrumentation (SI) according to stages and grades of the 2018 classification of periodontal diseases., Materials and Methods: We carried out exploratory re-analysis of the placebo-controlled, multi-centre ABPARO trial (52; 45/60 years of age; 205 males, 114 active smokers). Patients were randomized to SI with systemic amoxicillin 500 mg/metronidazole 400 mg (three times a day for 7 days, n = 205; ANTI) or placebo (n = 200; PLAC) and maintenance therapy every 3 months. Patients were reclassified according to the 2018 classification (stage/extent/grade). Treatment effect was the percentage of sites per patient with new attachment loss ≥1.3 mm (PSAL ≥ 1.3 mm) at 27.5 months post-baseline/randomization., Results: All patients were assigned according to the stage (n = 49 localized stage III, n = 206 generalized stage III, n = 150 stage IV). Because of missing radiographs, only 222 patients were assigned to grades (n = 73 B, n = 149 C). Treatment (PLAC/ANTI) resulted in PSAL ≥ 1.3 mm (median; lower/upper quartile) in localized stage III (PLAC: 5.7; 3.3/8.4% vs. ANTI: 4.9; 3.0/8.3%; p = .749), generalized stage III (8.0; 4.5/14.3% vs. 4.7; 2.4/9.0%; p < .001), stage IV (8.5; 5.1/14.4% vs. 5.7; 3.3/10.6%; p = .008), grade B (4.4; 2.4/6.7% vs. 3.6; 1.9/4.7%; p = .151) and grade C (9.4; 5.3/14.3% vs. 4.8; 2.5/9.4%; p < .001)., Conclusions: In generalized periodontitis stage III/grade C, a clinically relevant lower percentage of disease progression after adjunctive systemic amoxicillin/metronidazole was observed compared to placebo (PLAC: 9.7; 5.8/14.3% vs. ANTI: 4.7; 2.4/9.0%; p < .001)., (© 2023 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Aim: To explore whether adjunctive antibiotics can relevantly influence long-term microbiota changes in stage III-IV periodontitis patients., Materials and Methods: This is a secondary analysis of a randomized clinical trial on periodontal therapy with adjunctive 500 mg amoxicillin and 400 mg metronidazole or placebo thrice daily for 7 days. Subgingival plaque samples were taken before and 2, 8, 14 and 26 months after mechanical therapy. The V4-hypervariable region of the 16S rRNA gene was sequenced with Illumina MiSeq 250 base pair paired-end reads. Changes at the ribosomal sequence variant (RSV) level, diversity and subgingival-microbial dysbiosis index (SMDI) were explored with a negative binomial regression model and non-parametric tests., Results: Overall, 50.2% of all raw reads summed up to 72 RSVs (3.0%) that were generated from 163 stage III-IV periodontitis patients. Of those, 16 RSVs, including Porphyromonas gingivalis, Tannerella forsythia and Aggregatibacter actinomycetemcomitans, changed significantly over 26 months because of adjunctive systemic antibiotics. SMDI decreased significantly more in the antibiotic group at all timepoints, whereas the 2-month differences in alpha and beta diversity between groups were not significant at 8 and 14 months, respectively., Conclusions: Mechanical periodontal therapy with adjunctive antibiotics induced a relevant and long-term sustainable change towards an oral microbiome more associated with oral health., (© 2023 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Aim: Interleukin 6 (IL-6) is considered to play a role in the dysbiotic host response in the development of periodontitis. While the inhibition of the IL-6 receptor using monoclonal antibodies is a well-established therapy for some diseases, so far, its potential benefit in patients with periodontitis has not been examined. We tested the association of genetically proxied downregulation of IL-6 signaling with periodontitis to explore whether downregulation of IL-6 signaling could represent a viable treatment target for periodontitis., Materials and Methods: As proxies for IL-6 signaling downregulation, we selected 52 genetic variants in close vicinity of the gene encoding IL-6 receptor that were associated with lower circulating C-reactive protein (CRP) levels in a genome-wide association study (GWAS) of 575 531 participants of European ancestry from the UK Biobank and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Associations with periodontitis were tested with inverse-variance weighted Mendelian randomization in a study of 17 353 cases and 28 210 controls of European descent in the Gene-Lifestyle Interactions in Dental Endpoints (GLIDE) consortium. In addition, the effect of CRP reduction independent of the IL-6 pathway was assessed., Results: Genetically proxied downregulation of IL-6 signaling was associated with lower odds of periodontitis (odds ratio (OR) = 0.81 per 1-unit decrement in log-CRP levels; 95% confidence interval (CI): [0.66;0.99]; P = 0.0497). Genetically proxied reduction of CRP independent of the IL-6 pathway had a similar effect (OR = 0.81; 95% CI: [0.68; 0.98]; P = 0.0296)., Conclusion: In conclusion, genetically proxied downregulation of IL-6 signaling was associated with lower odds of periodontitis and CRP might be a causal target for the effect of IL-6 on the risk of periodontitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nolde, Alayash, Reckelkamm, Kocher, Ehmke, Holtfreter, Baurecht, Georgakis and Baumeister.)

Background: The purpose of the study was to examine the association between total body bone mineral density (BMD) and periodontitis using Mendelian randomization (MR) analysis., Methods and Materials: We used 81 single nucleotide polymorphisms (SNPs) associated with BMD at a p-value of < 5 × 10 -8 from a genome-wide association study (GWAS) of 66,628 individuals of European descent. The GWAS for periodontitis was derived from a meta-analysis of seven cohort studies that included 17,353 cases and 28,210 controls of European ancestry., Results: MR showed no association between BMD and periodontitis (odds ratio per standard deviation increment in genetically predicted BMD = 1.00; 95% confidence interval: 0.92-1.08). Leave-one-out analyses and pleiotropy-robust methods did not indicate any bias., Conclusions: The MR study provided no evidence that BMD might be causally linked to periodontitis. Hence it may be concluded as the key finding that BMD depletion does not increase the risk of periodontitis., (© 2022 The Authors. Journal of Periodontology published by Wiley Periodicals LLC on behalf of American Academy of Periodontology.)

Background: Circulating levels of interleukin-17 (IL-17) are associated with the presence and severity of periodontitis. However, whether IL-17 is causal for disease development is unknown. We investigated the effect of genetically proxied IL-17 on periodontitis using instrumental variable analysis., Methods: We identified 12 genetic variants from genome-wide association study (GWAS) of 7760 European descent individuals, used these variants as instrumental variables for IL-17, and linked them to a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Generalized weighted least squares analysis accounted for linkage disequilibrium of variants., Results: We found an inverse association of genetically proxied IL-17 and periodontitis (odds ratio, 0.84; 95% confidence interval: 0.75-0.94; p = 0.003), which was corroborated after sensitivity analysis for horizontal pleiotropy., Conclusion: The findings suggest that IL-17 protects against initial periodontitis., (© 2023 The Authors. Journal of Periodontology published by Wiley Periodicals LLC on behalf of American Academy of Periodontology.)

Aim: The aim of this study was to evaluate whether extraction thresholds in persons with severe periodontitis have changed between 2000 and 2010 and whether potential shifts have contributed to the reported decrease in tooth extractions in German adults over the last decades., Materials and Methods: Data from two German population-based cohort studies in Northeast Germany (Studies of Health in Pomerania; SHIP-START [baseline 1997-2001; 11-year follow-up] and SHIP-TREND [baseline 2008-2012; 7-year follow-up]) were used. In SHIP-START (SHIP-TREND), 522 (478) participants with severe periodontitis according to the CDC/AAP case definition were included. Patterns of maximum probing depth (PD) and maximum clinical attachment level (CAL) for retained and extracted teeth were compared between SHIP-START and SHIP-TREND participants., Results: No major differences in patterns of baseline maximum CAL of retained or extracted teeth were detected between SHIP-START and SHIP-TREND. Extraction thresholds were identified at the baseline at maximum CAL ≥6 and ≥9 mm. Tooth-level incidence rates for extraction for baseline maximum CAL of 6 mm were comparable between SHIP-START and SHIP-TREND (17.1 vs. 15.9 events per 1000 person-years)., Conclusions: After a decade, teeth in persons with severe periodontitis were still undergoing extraction with minor or moderate attachment loss. A change in extraction pattern did not contribute to the higher tooth retention rate., (© 2022 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Purpose: Cortisol has obesogenic, hyperglycemic and immunomodulating effects. Preclinical and observational research suggested that it is associated with periodontitis but the evidence for potential causality in humans is sparse. We triangulated results from prospective observational and Mendelian randomization (MR) analyses to further explore this., Methods: Using pooled data from 3,388 participants of two population cohort studies embedded in the Study of Health in Pomerania (SHIP) project, we associated serum cortisol levels with periodontal outcomes measured after a median follow-up time of 6.9 years, adjusting for confounding and selection bias using propensity score weighting and multiple imputation. We further examined the effect of genetically proxied plasma morning cortisol levels on periodontitis using two-sample MR of 17,353 cases and 28,210 controls., Results: In SHIP, we found that cortisol levels were positively associated with follow-up levels of mean clinical attachment level (CAL), deep interdental CAL and bleeding on probing but were unrelated to mean probing pocket depth and deep periodontal pockets. In MR analysis, cortisol was not associated with periodontitis., Conclusion: The observational study revealed a prospective association of spot cortisol with makers of periodontitis. Contrary to observational studies, genetically instrumented, long-term cortisol was unrelated to periodontitis. Our results find no univocal evidence that cortisol plays a role in periodontitis pathology, casting doubt on cortisol-related pathways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Baumeister, Reckelkamm, Grabe, Nauck, Klinger-König, Völzke, Kocher, Friedrich and Holtfreter.)

Aim: To investigate the effect of genetically proxied inhibition of tumor necrosis factor receptor 1 (TNFR1) on the risk of periodontitis., Materials and Methods: Genetic instruments were selected from the vicinity of TNFR superfamily member 1A (TNFRSF1A) gene (chromosome 12; base pairs 6,437,923-6,451,280 as per GRCh37 assembly) based on their association with C-reactive protein (N= 575,531). Summary statistics of these variants were obtained from a genome-wide association study (GWAS) of 17,353 periodontitis cases and 28,210 controls to estimate the effect of TNFR1 inhibition on periodontitis using a fixed-effects inverse method., Results: Considering rs1800693 as an instrument, we found no effect of TNFR1 inhibition on periodontitis risk (Odds ratio (OR) scaled per standard deviation increment in CRP: 1.57, 95% confidence interval (CI): 0.38;6.46). Similar results were derived from a secondary analysis that used three variants (rs767455, rs4149570, and rs4149577) to index TNFR1 inhibition., Conclusions: We found no evidence of a potential efficacy of TNFR1 inhibition on periodontitis risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Alayash, Baumeister, Holtfreter, Kocher, Baurecht, Ehmke, Reckelkamm and Nolde.)

Aim: Epidemiological and pre-clinical studies suggest a chemoprotective role of lipid-lowering agents in periodontitis. We tested the association of genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), Niemann-Pick C1-Like 1 (NPC1L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9) with periodontitis., Materials and Methods: Genetic variants in HMGCR, NCP1L1 and PCSK9 associated with low-density lipoprotein (LDL) cholesterol in a genome-wide association study (GWAS) meta-analysis (N = 188,578) were used to proxy therapeutic inhibition of HMGCR, NPC1L1 and PCSK9. For these genetic variants, associations with periodontitis were obtained from GWAS of 17,353 cases and 28,210 controls in the GeneLifestyle Interactions in Dental Endpoints consortium. Generalized weighted least squares analysis accounted for linkage disequilibrium of genotypes to derive pooled estimates., Results: While genetically proxied HMGCR inhibition equivalent to 1 mmol/L reduction in LDL was not associated with odds of periodontitis (odds ratio [OR] = 0.92 [95% confidence interval [CI]: 0.73; 1.16]; p = .4905; false discovery rate [FDR] = 0.4905), genetically proxied NPC1L1 (OR = 0.53 [95% CI: 0.35; 0.81]; p = .0038; FDR = 0.0077) and PCSK9 (OR = 0.84 [95% CI: 0.74; 0.95]; p = .0051; FDR = 0.0077) inhibition lowered the odds of periodontitis., Conclusions: Genetically proxied inhibition of NCP1L1 and PCSK9 was associated with lower odds of periodontitis., (© 2022 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Genetic risk factors play important roles in the etiology of oral, dental, and craniofacial diseases. Identifying the relevant risk loci and understanding their molecular biology could highlight new prevention and management avenues. Our current understanding of oral health genomics suggests that dental caries and periodontitis are polygenic diseases, and very large sample sizes and informative phenotypic measures are required to discover signals and adequately map associations across the human genome. In this article, we introduce the second wave of the Gene-Lifestyle Interactions and Dental Endpoints consortium (GLIDE2) and discuss relevant data analytics challenges, opportunities, and applications. In this phase, the consortium comprises a diverse, multiethnic sample of over 700,000 participants from 21 studies contributing clinical data on dental caries experience and periodontitis. We outline the methodological challenges of combining data from heterogeneous populations, as well as the data reduction problem in resolving detailed clinical examination records into tractable phenotypes, and describe a strategy that addresses this. Specifically, we propose a 3-tiered phenotyping approach aimed at leveraging both the large sample size in the consortium and the detailed clinical information available in some studies, wherein binary, severity-encompassing, and "precision," data-driven clinical traits are employed. As an illustration of the use of data-driven traits across multiple cohorts, we present an application of dental caries experience data harmonization in 8 participating studies ( N = 55,143) using previously developed permanent dentition tooth surface-level dental caries pattern traits. We demonstrate that these clinical patterns are transferable across multiple cohorts, have similar relative contributions within each study, and thus are prime targets for genetic interrogation in the expanded and diverse multiethnic sample of GLIDE2. We anticipate that results from GLIDE2 will decisively advance the knowledge base of mechanisms at play in oral, dental, and craniofacial health and disease and further catalyze international collaboration and data and resource sharing in genomics research.

Background: Twenty five-hydroxy vitamin D (25OHD) levels have been proposed to protect against periodontitis based on in vitro and observational studies but evidence from long-term randomized controlled trials (RCTs) is lacking. This study tested whether genetically proxied 25OHD is associated with periodontitis using Mendelian randomization (MR)., Methods: Genetic variants strongly associated with 25OHD in a genome-wide association study (GWAS) of 417,580 participants of European ancestry were used as instrumental variables, and linked to GWAS summary data of 17,353 periodontitis cases and 28,210 controls. In addition to the main analysis using an inverse variance weighted (IVW) model, we applied additional robust methods to control for pleiotropy. We also undertook sensitivity analyses excluding single nucleotide polymorphisms (SNPs) used as instruments with potential pleiotropic effects and used a second 25OHD GWAS for replication. We identified 288 SNPs to be genome-wide significant for 25OHD, explaining 7.0% of the variance of 25OHD levels and providing ≥90% power to detect an odds ratio (OR) of ≤ 0.97., Results: MR analysis suggested that a 1 standard deviation increase in natural log-transformed 25OHD was not associated with periodontitis risk (IVW OR = 1.04; 95% confidence interval (CI): 0.97-1.12; P-value = 0.297). The robust models, replication, and sensitivity analyses were coherent with the primary analysis., Conclusions: Collectively, our findings suggest that 25OHD levels are unlikely to have a substantial effect on the risk of periodontitis, but large long-term RCTs are needed to derive definitive evidence on the causal role of 25OHD in periodontitis., (© 2022 The Authors. Journal of Periodontology published by Wiley Periodicals LLC on behalf of American Academy of Periodontology.)

Background: Observational and in-vivo research suggested a bidirectional relationship between depression and periodontitis. We estimated the genetic correlation and examined directionality of causation., Methods: The study used summary statistics from published genome wide association studies, with sample sizes ranging from 45,563 to 797,563 individuals of European ancestry. We performed linkage disequilibrium score regression (LDSC) to estimate global correlation and used Heritability Estimation from Summary Statistics (ρ-HESS) to further examine local genetic correlation. Latent Heritable Confounder Mendelian randomization (LHC-MR), Causal Analysis using Summary Effect estimates (CAUSE), and conventional MR approaches assessed bidirectional causation., Results: LDSC observed only weak genetic correlation (r g = 0.06, P-Value = 0.619) between depression and periodontitis. Analysis of local genetic correlation using ρ-HESS did not reveal loci of significant local genetic covariance. LHC-MR, CAUSE and conventional MR models provided no support for bidirectional causation between depression and periodontitis, with odds ratios ranging from 1.00 to 1.06 in either direction., Conclusions: Results do not support shared heritability or a causal connection between depression and periodontitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nolde, Holtfreter, Kocher, Alayash, Reckelkamm, Ehmke, Baurecht and Baumeister.)

Aim: This study aimed to leverage human genetic data to investigate whether cannabis use causally affects periodontitis., Materials and Methods: Data were obtained from summary statistics of genome-wide association studies of lifetime cannabis use (N = 184,765), cannabis use disorder (17,068 cases; 357,219 controls), and periodontitis (17,353 cases; 28,210 controls). We performed two-sample Mendelian randomization (MR) analysis using 6 genetic variants as instrumental variables for lifetime cannabis use and 11 variants as instruments for cannabis use disorder to estimate associations with periodontitis., Results: There was no evidence for an association between genetic liability for lifetime cannabis use or cannabis use disorder with periodontitis. The estimates from the primary analyses were supported in multivariable MR analysis, which considered potential pleiotropic pathways and in weak instrument analyses., Conclusions: This study provides little evidence to support a detrimental effect of genetic liability for cannabis use on periodontal health., (© 2022 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Aim: To examine the associations between bone turnover markers and periodontitis in two cross-sectional population-based studies., Materials and Methods: We used data from two independent adult samples (N = 4993), collected within the Study of Health in Pomerania project, to analyse cross-sectional associations of N-procollagen type 1 amino-terminal propeptide (P1NP), C-terminal cross-linking telopeptide, osteocalcin, bone-specific alkaline phosphatase (BAP), fibroblast growth factor 23, wingless-type mouse mammary tumour virus integration site family member 5a (WNT5A), and sclerostin values with periodontitis. Confounder-adjusted gamma and fractional response regression models were applied., Results: Positive associations were found for P1NP with mean pocket probing depth (PPD; e β = 1.008 ; 95% confidence interval [CI]: 1.001-1.015), mean clinical attachment loss (mean CAL; e β = 1.027 ; 95% CI: 1.011-1.044), and proportion of sites with bleeding on probing (%BOP; e β = 1.055 ; 95% CI: 1.005-1.109). Similar associations were seen for BAP with %BOP ( e β = 1.121 ; 95% CI: 1.042-1.205), proportion of sites with PPD ≥4 mm (%PPD4) ( e β = 1.080 ; 95% CI: 1.005-1.161), and sclerostin with %BOP ( e β = 1.308 ; 95% CI: 1.005-1.704). WNT5A was inversely associated with mean PPD ( e β = 0.956 ; 95% CI: 0.920-0.993) and %PPD4 ( e β = 0.794 ; 95% CI: 0.642-0.982)., Conclusions: This study revealed scattered associations of P1NP, BAP, WNT5A, and sclerostin with periodontitis, but the results are contradictory in the overall context. Associations reported in previous studies could not be confirmed., (© 2022 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Periodontitis is a multifactorial disease. The aim of this explorative study was to investigate the role of Interleukin-(IL)-1, IL-4, GATA-3 and Cyclooxygenase-(COX)-2 polymorphisms after non-surgical periodontal therapy with adjunctive systemic antibiotics (amoxicillin/metronidazole) and subsequent maintenance in a Caucasian population. Analyses were performed using blood samples from periodontitis patients of a multi-center trial (ClinicalTrials.gov NCT00707369=ABPARO-study). Polymorphisms were analyzed using quantitative real-time PCR. Clinical attachment levels (CAL), percentage of sites showing further attachment loss (PSAL) ≥1.3 mm, bleeding on probing (BOP) and plaque score were assessed. Exploratory statistical analysis was performed. A total of 209 samples were genotyped. Patients carrying heterozygous genotypes and single-nucleotide-polymorphisms (SNP) on the GATA-3-IVS4 +1468 gene locus showed less CAL loss than patients carrying wild type. Heterozygous genotypes and SNPs on the IL-1A-889, IL-1B +3954, IL-4-34, IL-4-590, GATA-3-IVS4 +1468 and COX-2-1195 gene loci did not influence CAL. In multivariate analysis, CAL was lower in patients carrying GATA-3 heterozygous genotypes and SNPs than those carrying wild-types. For the first time, effects of different genotypes were analyzed in periodontitis progression after periodontal therapy and during supportive treatment using systemic antibiotics demonstrating a slight association of GATA-3 gene locus with CAL. This result suggests that GATA-3 genotypes are a contributory but non-essential risk factor for periodontal disease progression.

Aim: To investigate the associations of tobacco smoking and alcohol consumption with periodontitis using Mendelian randomization (MR) analysis., Materials and Methods: We used 17 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for the number of cigarettes per day from a genome-wide association study (GWAS) of 337,334 individuals, 109 SNPs for a lifetime smoking index from GWAS of 462,690 participants, and 33 SNPs for the number of drinks per week from GWAS of 941,280 individuals. The periodontitis GWAS included 12,289 cases and 22,326 controls. Wald ratios were obtained by dividing the SNP-periodontitis effects by SNP-exposure effects and pooled using an inverse-variance weighted model., Results: Genetic liabilities for higher number of cigarettes per day (odds ratio [OR] per one standard deviation (1SD) increment = 1.56; 95% CI: 1.18-2.07, p-value = .0018, Q-value = .0054), lifetime smoking index (OR per 1SD = 1.26; 95% CI: 1.04-1.53, p-value = .0161, Q-value = .0242), and drinks per week (OR per 1SD = 1.41; 95% CI: 1.04-1.90, p-value = .0265, Q-value = .0265) were associated with increased odds of periodontitis. Estimates were consistent across robust and multivariable MR analyses., Conclusions: The findings of this MR analysis suggest an association between tobacco smoking and alcohol consumption with periodontitis., (© 2021 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Objectives: Observational research suggests that periodontitis affects pulmonary function; however, observational studies are subject to confounding and reverse causation, making causal inference and the direction of these associations difficult. We used Mendelian randomization (MR) to assess the potential causal association between genetic liability to periodontitis and pulmonary function., Materials and Methods: We used six single-nucleotide polymorphisms (SNPs) associated with periodontitis (P < 5 × 10 -6 ) from a genome-wide association study (GWAS) of 17,353 European descent periodontitis cases and 28,210 controls from the GeneLifestyle Interactions in Dental Endpoints consortium and the UK Biobank, and related these to SNPs from a lung function GWAS including 79,055 study participants of the SpiroMeta Consortium., Results: MR analysis suggested no effect of periodontitis on the ratio of forced expiratory volume in one second to lower forced vital capacity (standard deviation increment in outcome per doubling of the odds of the exposure (95% confidence interval) =  - 0.004 (- 0.028; 0.020)). Replication analysis using genetic instruments from two different GWAS and sensitivity analyses to address potential pleiotropy led to no substantial changes in estimates., Conclusions: Collectively, these findings do not support a relationship between genetic liability for periodontitis and pulmonary function., Clinical Relevance: Periodontitis does not seem to be a risk factor for worsening of pulmonary function., (© 2021. The Author(s).)

Background: Periodontitis is among the most common chronic diseases worldwide, and it is one of the main reasons for tooth loss. Comprehensive profiling of the metabolite content of the saliva can enable the identification of novel pathways associated with periodontitis and highlight non-invasive markers to facilitate time and cost-effective screening efforts for the presence of periodontitis and the prediction of tooth loss., Methods: We first investigated cross-sectional associations of 13 oral health variables with saliva levels of 562 metabolites, measured by untargeted mass spectrometry among a sub-sample (n = 938) of the Study of Health in Pomerania (SHIP-2) using linear regression models adjusting for common confounders. We took forward any candidate metabolite associated with at least two oral variables, to test for an association with a 5-year tooth loss over and above baseline oral health status using negative binomial regression models., Results: We identified 84 saliva metabolites that were associated with at least one oral variable cross-sectionally, for a subset of which we observed robust replication in an independent study. Out of 34 metabolites associated with more than two oral variables, baseline saliva levels of nine metabolites were positively associated with a 5-year tooth loss. Across all analyses, the metabolites 2-pyrrolidineacetic acid and butyrylputrescine were the most consistent candidate metabolites, likely reflecting oral dysbiosis. Other candidate metabolites likely reflected tissue destruction and cell proliferation., Conclusions: Untargeted metabolic profiling of saliva replicated metabolic signatures of periodontal status and revealed novel metabolites associated with periodontitis and future tooth loss., (© 2021. The Author(s).)

Although a potential link between periodontitis and cardiorespiratory fitness might provide a reasonable explanation for effects of tooth-related alterations seen on cardiometabolic diseases, evidence is currently limited. Thus, we investigated the association between clinically assessed periodontitis and cardiopulmonary exercise testing (CPET). Data from 2 independent cross-sectional population-based studies (5-y follow-up of the Study of Health in Pomerania [SHIP-1; N  = 1,639] and SHIP-Trend-0 [ N  = 2,439]) were analyzed. Participants received a half-mouth periodontal examination, and teeth were counted. CPET was based on symptom limited-exercise tests on a bicycle ergometer. Associations of periodontitis parameters with CPET parameters were analyzed by confounder-adjusted multivariable linear regression. In the total sample, mean pocket probing depth (PPD), mean clinical attachment levels, and number of teeth were consistently associated with peak oxygen uptake (peakVO 2 ) and exercise duration in both studies, even after restriction to cardiorespiratory healthy participants. Statistically significant associations with oxygen uptake at anaerobic threshold (VO 2 @AT), slope of the efficiency of ventilation in removing carbon dioxide, and peak oxygen pulse (VÉ/VCO 2 slope) occurred. Further, interactions with age were identified, such that mainly older individuals with higher levels of periodontal disease severity were associated with lower peakVO 2 . Restricted to never smokers, associations with mean clinical attachment levels and the number of teeth mostly diminished, while associations of mean PPD with peakVO 2 , VO 2 @AT, VÉ/VCO 2 slope, and exercise duration in SHIP-1 and SHIP-Trend-0 were confirmed. In SHIP-1, mean peakVO 2 was 1,895 mL/min in participants with a mean PPD of 1.6 mm and 1,809 mL/min in participants with a mean PPD of 3.7 mm. To conclude, only mean PPD reflecting current disease severity was consistently linked to cardiorespiratory fitness in 2 cross-sectional samples of the general population. If confirmed in well-designed large-scale longitudinal studies, the association between periodontitis and cardiorespiratory fitness might provide a biologically plausible mechanism linking periodontitis with cardiometabolic diseases.

Objectives: To predict patients' tooth loss during supportive periodontal therapy across four German university centers., Methods: Tooth loss in 897 patients in four centers (Kiel (KI) n = 391; Greifswald (GW) n = 282; Heidelberg (HD) n = 175; Frankfurt/Main (F) n = 49) during supportive periodontal therapy (SPT) was assessed. Our outcome was annualized tooth loss per patient. Multivariable linear regression models were built on data of 75 % of patients from one center and used for predictions on the remaining 25 % of this center and 100 % of data from the other three centers. The prediction error was assessed as root-mean-squared-error (RMSE), i.e., the deviation of predicted from actually lost teeth per patient and year., Results: Annualized tooth loss/patient differed significantly between centers (between median 0.00 (interquartile interval: 0.00, 0.17) in GW and 0.09 (0.00, 0.19) in F, p = 0.001). Age, smoking status and number of teeth before SPT were significantly associated with tooth loss (p < 0.03). Prediction within centers showed RMSE of 0.14-0.30, and cross-center RMSE was 0.15-0.31. Predictions were more accurate in F and KI than in HD and GW, while the center on which the model was trained had a less consistent impact. No model showed useful predictive values., Conclusion: While covariates were significantly associated with tooth loss in linear regression models, a clinically useful prediction was not possible with any of the models and generalizability was not given. Predictions were more accurate for certain centers., Clinical Relevance: Association should not be confused with predictive value: Despite significant associations of covariates with tooth loss, none of our models was useful for prediction. Usually, model accuracy was even lower when tested across centers, indicating low generalizability., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aim: The aim of this study was to evaluate the effect of non-surgical periodontal therapy on circulating levels of the systemic inflammation-associated biomarkers orosomucoid (ORM), high-sensitivity C-reactive protein (hsCRP), chemerin, and retinol-binding protein 4 (RBP4) in overweight or normal-weight patients with periodontitis at 27.5 months after therapy., Materials and Methods: This exploratory subanalysis includes patients from the ABPARO-trial (ClinicalTrials.gov NCT00707369). The per-protocol collective provided untreated periodontitis patients with high (≥28 kg/m 2 ) or moderate (21-24 kg/m 2 ) BMI. Out of the per-protocol collective, 80 patients were randomly selected and stratified for BMI group, sex, and treatment group (antibiotics/placebo), resulting in 40 overweight and normal-weight patients. Patients received non-surgical periodontal therapy and maintenance at 3-month intervals. Plasma samples from baseline and 27.5 months following initial treatment were used to measure the concentrations of ORM, hsCRP, chemerin, and RBP4., Results: At the 27.5-month examination, ORM and hsCRP decreased noticeably in the overweight group (ORM: p = .001, hsCRP: p = .004) and normal-weight patients (ORM: p = .007, hsCRP: p < .001). Chemerin decreased in the overweight group (p = .048), and RBP4 concentrations remained stable., Conclusion: Non-surgical periodontal therapy reduced systemically elevated inflammation-associated biomarkers in periodontitis patients. These improvements were more pronounced in overweight patients than in normal-weight patients., (© 2020 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

The aim of this follow-up study was, to compare the effects of mechanical periodontal therapy with or without adjunctive amoxicillin and metronidazole on the subgingival microbiome of smokers with periodontitis using 16S rDNA amplicon next generation sequencing. Fifty-four periodontitis patients that smoke received either non-surgical periodontal therapy with adjunctive amoxicillin and metronidazole (n = 27) or with placebos (n = 27). Subgingival plaque samples were taken before and two months after therapy. Bacterial genomic DNA was isolated and the V4 hypervariable region of the bacterial 16S rRNA genes was amplified. Up to 96 libraries were normalized and pooled for Illumina MiSeq paired-end sequencing with almost fully overlapping 250 base pairs reads. Exact ribosomal sequence variants (RSVs) were inferred with DADA2. Microbial diversity and changes on the genus and RSV level were analyzed with non-parametric tests and a negative binomial regression model, respectively. Before therapy, the demographic, clinical, and microbial parameters were not significantly different between the placebo and antibiotic groups. Two months after the therapy, clinical parameters improved and there was a significantly increased dissimilarity of microbiomes between the two groups. In the antibiotic group, there was a significant reduction of genera classified as Porphyromonas, Tannerella , and Treponema , and 22 other genera also decreased significantly, while Selenomonas, Capnocytophaga, Actinomycetes , and five other genera significantly increased. In the placebo group, however, there was not a significant decrease in periodontal pathogens after therapy and only five other genera decreased, while Veillonella and nine other genera increased. We conclude that in periodontitis patients who smoke, microbial shifts occurred two months after periodontal therapy with either antibiotics or placebo, but genera including periodontal pathogens decreased significantly only with adjunctive antibiotics., (Copyright © 2020 Hagenfeld, Matern, Prior, Harks, Eickholz, Lorenz, Kim, Kocher, Meyle, Kaner, Schlagenhauf, Harmsen and Ehmke.)

Objective: The selection of proper outcome measures is a critical step in clinical research. Most randomized clinical trials (RCTs) assessing the effects of initial anti-infective periodontal therapies use surrogate outcomes as primary outcome variables, such as mean changes in probing depth (PD) or in clinical attachment. However, these parameters do not reflect disease remission/control at patient level, which has led to subjective interpretations of the data from RCTs and Systematic Reviews. Based on a comprehensive analysis of 724 patients from USA, Germany and Brazil treated for periodontitis, this paper suggests that the clinical endpoint of "≤4 sites with PD≥5mm" is effective in determining disease remission/control after active periodontal treatment and therefore, may represent a pertinent endpoint for applying the treat-to-target concept in RCTs. Furthermore, regression models showed that the presence of >10% and >20% sites with bleeding on probing in the mouth post-treatment increases the risk of a patient leaving the endpoint from 1-2 years (OR=3.5 and 8.7, respectively). Researchers are encouraged to present results on this outcome when reporting their trials, as this will allow for an objective comparison across studies and facilitate systematic reviews, and consequently, the extrapolation of data from research to clinical practice., Competing Interests: The authors did not declare any conflicts of interest., (Copyright© by the International Academy of Periodontology.)

Objectives: In this retrospective study, we compared tooth loss between patients receiving periodontal therapy (PT) in four German university centres, stratified according to periodontal treatment phase., Materials and Methods: Overall, 896 patients (Kiel (KI) n = 391; Greifswald (GW) n = 282; Heidelberg (HD) n = 174; Frankfurt a.M. (F) n = 49) were examined initially (T0), after active periodontal therapy (APT, T1) and after supportive periodontal therapy (SPT, T2). Descriptive analyses and multivariable negative binomial regression models were performed., Results: Follow-up periods differed significantly between the centres, ranging between 6.7 ± 3.0 (GW) and 18.2 ± 5.5 (KI) years (p < 0.001). At T0, age, gender, smoking and diabetes showed notable regional distinctions (p < 0.001). However, the number of teeth per patient was similar (between 24.0 ± 4.6 (F) and 24.5 ± 4.1 (HD); p = 0.27). During PT, the number of extracted teeth differed significantly between centres, with greater differences during SPT (0.9 ± 1.8 (GW) to 2.3 ± 2.8 (KI), p < 0.001) compared to APT (0.4 ± 0.9 (F) to 1.0 ± 2.1 (KI), p = 0.02). Annual tooth loss during SPT remained low in all centres (between 0.10 ± 0.14 (F) to 0.15 ± 0.30 (HD), p < 0.001)., Conclusion: Within the limitation of the study, PT leads to a low risk of tooth loss in all university centres irrespective of patients' baseline characteristics., Clinical Relevance: Within the limitations of this retrospective investigation, long-term tooth retention seems to be feasible for most patients, as long as a systematic and structured treatment approach is applied., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Women are generally periodontally healthier than men but they exhibit higher systemic levels of inflammatory markers. Our aim is to evaluate whether this paradox may be explained by different ramifications of adiposity or body shape., Methods: In 3,268 subjects from the Study of Health in Pomerania, we determined anthropometric and periodontal parameters, C-reactive protein (CRP), and fibrinogen as markers of inflammation. Behavioural and environmental risk factors and hand grip strength were assessed as factors interfering with the outcomes in question. We evaluated sex-specific associations of adiposity characteristics and periodontal variables such as probing depth (PD) with CRP and fibrinogen., Results: After adjusting for age, waist-to-hip ratio (WHR), glycated hemoglobin, smoking, education, and grip strength, the opposite sex role of periodontitis and obesity on CRP levels were confirmed. WHR and body mass index (BMI) were associated with CRP in both men and women (P < 0.001). CRP was associated with PD in men (P = 0.001) but not in women (P = 0.11). When adjusted for BMI this association was attenuated in men by 15% (P = 0.002) but in women by 70% (P = 0.58). PD was related to plaque and bleeding on probing (P < 0.001) in both sexes and also to WHR in women (P = 0.026) and men (P = 0.002). BMI attenuated this association in women but not in men. HbA1c contributed significantly to PD in women (P = 0.013) but not in men (P = 0.76)., Conclusions: Systemic CRP concentrations are affected by periodontitis and obesity in men. In women adiposity is more significant than in men overriding the impact of periodontal measures., (© 2019 American Academy of Periodontology.)

The aim of the present study was to construct a biological age score reflecting one's physiologic capability and aging condition with respect to tooth loss over 10 y. From the follow-up to the population-based Study of Health in Pomerania (i.e., SHIP-2), 2,049 participants were studied for their baseline biomarker measures 10 y before (i.e., in SHIP-0). Metabolic and periodontal data were regressed onto chronological age to construct a score designated as "biological age." For either sex separately, the impact of this individualized score was used to predict tooth loss in the follow-up cohort in comparison with each participant's chronological age. Outcome data after 10 y with respect to tooth loss, periodontitis, obesity, and inflammation were shown to be better for biologically younger subjects than as expected by their chronological age, whereas for the older subjects, data were worse. Especially for tooth loss, a striking increase was observed in subjects whose biological age at baseline appeared to be higher than their chronological age. Biological age produced significantly better tooth loss predictions than chronological age ( P < 0.001). Areas under receiver operating characteristic curves for tooth loss of ≥3 teeth in men during follow-up were 0.811 and 0.745 for biological and chronological age, respectively. For women, these figures were 0.788 and 0.724. For total tooth loss, areas under the curve were 0.890 and 0.749 in men and 0.872 and 0.752 in women. Biological age combines various measures into a single score and allows identifying individuals at increased risk of tooth loss.

Prediction models learn patterns from available data (training) and are then validated on new data (testing). Prediction modeling is increasingly common in dental research. We aimed to evaluate how different model development and validation steps affect the predictive performance of tooth loss prediction models of patients with periodontitis. Two independent cohorts (627 patients, 11,651 teeth) were followed over a mean ± SD 18.2 ± 5.6 y (Kiel cohort) and 6.6 ± 2.9 y (Greifswald cohort). Tooth loss and 10 patient- and tooth-level predictors were recorded. The impact of different model development and validation steps was evaluated: 1) model complexity (logistic regression, recursive partitioning, random forest, extreme gradient boosting), 2) sample size (full data set or 10%, 25%, or 75% of cases dropped at random), 3) prediction periods (maximum 10, 15, or 20 y or uncensored), and 4) validation schemes (internal or external by centers/time). Tooth loss was generally a rare event (880 teeth were lost). All models showed limited sensitivity but high specificity. Patients' age and tooth loss at baseline as well as probing pocket depths showed high variable importance. More complex models (random forest, extreme gradient boosting) had no consistent advantages over simpler ones (logistic regression, recursive partitioning). Internal validation (in sample) overestimated the predictive power (area under the curve up to 0.90), while external validation (out of sample) found lower areas under the curve (range 0.62 to 0.82). Reducing the sample size decreased the predictive power, particularly for more complex models. Censoring the prediction period had only limited impact. When the model was trained in one period and tested in another, model outcomes were similar to the base case, indicating temporal validation as a valid option. No model showed higher accuracy than the no-information rate. In conclusion, none of the developed models would be useful in a clinical setting, despite high accuracy. During modeling, rigorous development and external validation should be applied and reported accordingly.

Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health.

Periodontitis is one of the most prevalent oral diseases worldwide and is caused by multifactorial interactions between host and oral bacteria. Altered cellular metabolism of host and microbes releases a number of intermediary end products known as metabolites. There is an increasing interest in identifying metabolites from oral fluids such as saliva to widen the understanding of the complex pathogenesis of periodontitis. It is believed that some metabolites might serve as indicators toward early detection and screening of periodontitis and perhaps even for monitoring its prognosis in the future. Because contemporary periodontal screening methods are deficient, there is an urgent need for novel approaches in periodontal screening procedures. To this end, we associated oral parameters (clinical attachment level, periodontal probing depth, supragingival plaque, supragingival calculus, number of missing teeth, and removable denture) with a large set of salivary metabolites ( n = 284) obtained by mass spectrometry among a subsample ( n = 909) of nondiabetic participants from the Study of Health in Pomerania (SHIP-Trend-0). Linear regression analyses were performed in age-stratified groups and adjusted for potential confounders. A multifaceted image of associated metabolites ( n = 107) was revealed with considerable differences according to age groups. In the young (20 to 39 y) and middle-aged (40 to 59 y) groups, metabolites were predominantly associated with periodontal variables, whereas among the older subjects (≥60 y), tooth loss was strongly associated with metabolite levels. Metabolites associated with periodontal variables were clearly linked to tissue destruction, host defense mechanisms, and bacterial metabolism. Across all age groups, the bacterial metabolite phenylacetate was significantly associated with periodontal variables. Our results revealed alterations of the salivary metabolome in association with age and oral health status. Among our comprehensive panel of metabolites, periodontitis was significantly associated with the bacterial metabolite phenylacetate, a promising substance for further biomarker research.

Aim: The aim was to identify benefit thresholds for clinical variables. We hypothesize, if variables fall below or exceed these threshold levels, systemic amoxicillin/metronidazole may contribute to reducing progression of periodontitis., Material & Methods: This is an explorative per-protocol collective analysis (n = 345) conducted on the placebo-controlled, multi-centre ABPARO trial (ClinicalTrials.gov NCT00707369). Patients received debridement with systemic amoxicillin 500 mg/metronidazole 400 mg (3×/day, 7 days, n = 170) or placebo (n = 175) and maintenance therapy every three months. To identify thresholds, each of the following baseline characteristics was classified into two groups (≥threshold value/ 5 mm (5.2%) at baseline compared to the placebo (9.0%, 11.6%, and 12.5%, respectively; p < 0.005)., Conclusions: The clinical benefits of systemic amoxicillin/metronidazole may depend on periodontitis severity and patients' age., (© 2019 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Rationale & Objective: Previous studies have yielded inconclusive findings regarding the relationship between periodontitis and kidney function. We sought to investigate whether periodontitis is associated with subsequent decreases in kidney function (reductions in estimated glomerular filtration rate [eGFR] and increased urinary albumin-creatinine ratio [UACR]) in the general population., Study Design: Population-based cohort study., Setting & Participants: We used baseline and 11-year follow-up data from 2,297 and 1,512 adult participants, respectively, in the Study of Health in Pomerania (SHIP). Age range was limited to 20 to 59 years to avoid the potential influence of tooth loss., Exposures: Periodontal status defined by periodontal pocket probing depth (PPD) and clinical attachment level. Mean levels and the percentage of sites ≥ 3mm was determined for either all sites (PPD) or interproximal sites (clinical attachment level). All PPDs≥4mm were summed to calculate the total PPD., Outcomes: GFR estimated from serum creatinine and serum cystatin C (eGFR cr-cys ). Moderately increased albuminuria defined as UACR>30mg/g., Analytical Approach: Adjusted linear and logistic mixed regression models., Results: At baseline and follow-up, average eGFR cr-cys was 118.3 and 105.0mL/min/1.73m 2 , respectively. Using mixed models, no consistently significant associations between periodontitis variables and eGFR cr-cys were detected. Long-term changes in UACR were inconsistently associated with periodontitis measures. After imputation of missing data, associations were either attenuated or no longer detectable., Limitations: Because periodontal assessments were performed using a partial recording protocol, periodontal disease severity estimates might have been underestimated, resulting in attenuated effect estimates., Conclusions: We found no consistent evidence for an association between periodontitis and decreased kidney function. In contrast to previous studies, these results do not support the hypothesis that periodontitis is an important risk factor for chronic kidney disease., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Evidence is limited regarding whether periodontal treatment improves hemoglobin A1c (HbA1c) among people with prediabetes and periodontal disease, and it is unknown whether improvement of metabolic status persists >3 mo. In an exploratory post hoc analysis of the multicenter randomized controlled trial "Antibiotika und Parodontitis" (Antibiotics and Periodontitis)-a prospective, stratified, double-blind study-we assessed whether nonsurgical periodontal treatment with or without an adjunctive systemic antibiotic treatment affects HbA1c and high-sensitivity C-reactive protein (hsCRP) levels among periodontitis patients with normal HbA1c (≤5.7%, n = 218), prediabetes (5.7% < HbA1c < 6.5%, n = 101), or unknown diabetes (HbA1c ≥ 6.5%, n = 8) over a period of 27.5 mo. Nonsurgical periodontal treatment reduced mean pocket probing depth by >1 mm in both groups. In the normal HbA1c group, HbA1c values remained unchanged at 5.0% (95% CI, 4.9% to 6.1%) during the observation period. Among periodontitis patients with prediabetes, HbA1c decreased from 5.9% (95% CI, 5.9% to 6.0%) to 5.4% (95% CI, 5.3% to 5.5%) at 15.5 mo and increased to 5.6% (95% CI, 5.4% to 5.7%) after 27.5 mo. At 27.5 mo, 46% of periodontitis patients with prediabetes had normal HbA1c levels, whereas 47.9% remained unchanged and 6.3% progressed to diabetes. Median hsCRP values were reduced in the normal HbA1c and prediabetes groups from 1.2 and 1.4 mg/L to 0.7 and 0.7 mg/L, respectively. Nonsurgical periodontal treatment may improve blood glucose values among periodontitis patients with prediabetes (ClinicalTrials.gov NCT00707369).

Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. It is classified into the widespread moderate form chronic periodontitis (CP) and the rare early-onset and severe phenotype aggressive periodontitis (AgP). These different disease manifestations are thought to share risk alleles and predisposing environmental factors. To obtain novel insights into the shared genetic etiology and the underlying molecular mechanisms of both forms, we performed a two step-wise meta-analysis approach using genome-wide association studies of both phenotypes. Genotypes from imputed genome-wide association studies (GWAS) of AgP and CP comprising 5,095 cases and 9,908 controls of North-West European genetic background were included. Two loci were associated with periodontitis at a genome-wide significance level. They located within the pseudogene MTND1P5 on chromosome 8 (rs16870060-G, P = 3.69 × 10 -9 , OR = 1.36, 95% CI = [1.23-1.51]) and intronic of the long intergenic non-coding RNA LOC107984137 on chromosome 16, downstream of the gene SHISA9 (rs729876-T, P = 9.77 × 10 -9 , OR = 1.24, 95% CI = [1.15-1.34]). This study identified novel risk loci of periodontitis, adding to the genetic basis of AgP and CP.

Aim: To assess the suitability of self-reported oral health status to predict 5- and 10-year tooth loss without involvement of any clinical measures., Materials and Methods: Within the population Study of Health in Pomerania (SHIP), 2,776 subjects with 5-year follow-up data and 2,016 subjects with 10-year follow-up examination data were studied. Self-rated oral health was assessed at baseline and related to 5- and 10-year tooth loss. Odds ratios and probability of loss were estimated., Results: Five- and 10-year tooth loss was significantly associated with baseline self-rated oral health. The predictive value of oral health ratings for tooth loss was comparable to that of the CDC/AAP case definition or caries and periodontitis diagnostics. In regression analyses including age, sex, smoking, education, income, and further items collected from questionnaires, odds ratios for dichotomous tooth loss associated with rating of oral health as poor were 3.04 (95% CI: 2.43-3.82) and 2.80 (2.11-3.71) after 5 and 10 years, respectively. Prediction with cut-off probability at 0.25 resulted in sensitivity 85.8% and specificity 44.2% for 5 years, and that with cut-off probability at 0.40 resulted in sensitivity 83.5% and specificity 46.5% for 10 years., Conclusion: Self-reported oral health provides reliable predictions of tooth loss comparable to those assessed by clinical diagnostics., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A new periodontitis classification scheme has been adopted, in which forms of the disease previously recognized as "chronic" or "aggressive" are now grouped under a single category ("periodontitis") and are further characterized based on a multi-dimensional staging and grading system. Staging is largely dependent upon the severity of disease at presentation as well as on the complexity of disease management, while grading provides supplemental information about biological features of the disease including a history-based analysis of the rate of periodontitis progression; assessment of the risk for further progression; analysis of possible poor outcomes of treatment; and assessment of the risk that the disease or its treatment may negatively affect the general health of the patient. Necrotizing periodontal diseases, whose characteristic clinical phenotype includes typical features (papilla necrosis, bleeding, and pain) and are associated with host immune response impairments, remain a distinct periodontitis category. Endodontic-periodontal lesions, defined by a pathological communication between the pulpal and periodontal tissues at a given tooth, occur in either an acute or a chronic form, and are classified according to signs and symptoms that have direct impact on their prognosis and treatment. Periodontal abscesses are defined as acute lesions characterized by localized accumulation of pus within the gingival wall of the periodontal pocket/sulcus, rapid tissue destruction and are associated with risk for systemic dissemination., (© 2018 American Academy of Periodontology and European Federation of Periodontology.)

Objective: We used epidemiologic data of clinical periodontal status from two population-based samples in two countries, United States and Germany, to examine 1) the impact of age on the relative contribution of recession and pocketing on the distribution of clinical attachment loss, and 2) whether it is feasible to define age-dependent thresholds for severe periodontitis., Methods: The analytical sample was based on persons aged ≥30 and included 10,713 individuals in the United States, participants in NHANES 2009 to 2014, and 3,071 individuals in Pomerania, Germany, participants in the SHIP-Trend 2008 to 2012. NHANES used a full-mouth examination protocol to collect data on recession (R), pocket depth (PD) and clinical attachment loss (CAL) for six sites/tooth on a maximum of 28 teeth; SHIP-Trend used a half-mouth examination at four sites/tooth. In both samples, percentile distributions of mean CAL/person were generated for each 5-year age interval. Age-dependent thresholds defining the upper quintile of mean CAL were calculated for both samples. The topographic intraoral distribution of CAL and the relative contribution of R and PD on CAL was assessed., Results: Mean CAL increased linearly with age in both samples and was higher in SHIP-Trend than NHANES across the age spectrum. In contrast, mean PD was constant across age groups in both populations. R contributed increasingly to CAL with age, especially after 45 to 49 years. Upper quintile mean CAL thresholds in NHANES were < 3 mm for ages up to 39 years, and under 3.58 mm in all other age groups. Corresponding values in SHIP-Trend were also < 3 mm in ages up to 39 years but increased linearly with age up to 7.21 mm for ages ≥75 years., Conclusions: Despite substantial differences in the overall severity of attachment loss between the two samples, common patterns of CAL and of the relative contribution of R and PD to CAL with increasing age were identified. Although periodontitis severity may vary in different populations, empirical evidence-driven definitions of CAL thresholds signifying disproportionate severity of periodontitis by age are feasible., (© 2018 American Academy of Periodontology and European Federation of Periodontology.)

Aim: As periodontitis may contribute to the pathogenesis of diabetes, the effects of periodontitis on diabetes incidence and HbA1c change was quantified in a prospective cohort., Methods: Data from an 11-year follow-up of the Study of Health in Pomerania were analyzed to evaluate the effects of periodontitis on incident diabetes and long-term HbA1c changes in 2047 subjects aged 20-81years. Diabetes was based on self-reported physician diagnoses, antidiabetic medication use, or HbA1c≥6.5% or non-fasting blood glucose levels ≥11.1mmol/L. To assess periodontal status, periodontal pockets were probed, and their depth and clinical attachment levels measured. For both measures, means and percentages of sites≥3mm were calculated. In addition, all probing depths≥4mm were summed (cumulative probing depth). Modified Poisson and multivariable linear models were applied, adjusted for age, gender, highest level of general education, marital status, waist circumference, physical activity, smoking status and follow-up time., Results: Over a mean follow-up period of 11.1years, 207 subjects developed diabetes. Baseline mean clinical attachment levels (CAL) and probing depths (PPD) were not significantly associated with either diabetes incidence [mean CALs, fourth quartile, incidence rate ratio=0.819, 95% confidence interval (CI): 0.489-1.370; P=0.446] or long-term changes in HbA1c (mean CAL, fourth quartile, β=-0.086, 95% CI: -0.187, -0.016; P=0.098). Sensitivity analyses using alternative exposure definitions confirmed these results., Conclusion: Contrary to the currently available literature, no convincing evidence was found of any potential association between periodontitis and diabetes incidence or HbA1c change., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Periodontitis is one of the most common inflammatory human diseases with a strong genetic component. Due to the limited sample size of available periodontitis cohorts and the underlying trait heterogeneity, genome-wide association studies (GWASs) of chronic periodontitis (CP) have largely been unsuccessful in identifying common susceptibility factors. A combination of quantitative trait loci (QTL) mapping in mice with association studies in humans has the potential to discover novel risk loci. To this end, we assessed alveolar bone loss in response to experimental periodontal infection in 25 lines (286 mice) from the Collaborative Cross (CC) mouse population using micro-computed tomography (µCT) analysis. The orthologous human chromosomal regions of the significant QTL were analyzed for association using imputed genotype data (OmniExpress BeadChip arrays) derived from case-control samples of aggressive periodontitis (AgP; 896 cases, 7,104 controls) and chronic periodontitis (CP; 2,746 cases, 1,864 controls) of northwest European and European American descent, respectively. In the mouse genome, QTL mapping revealed 2 significant loci (-log P = 5.3; false discovery rate = 0.06) on chromosomes 1 ( Perio3) and 14 ( Perio4). The mapping resolution ranged from ~1.5 to 3 Mb. Perio3 overlaps with a previously reported QTL associated with residual bone volume in F2 cross and includes the murine gene Ccdc121. Its human orthologue showed previously a nominal significant association with CP in humans. Use of variation data from the genomes of the CC founder strains further refined the QTL and suggested 7 candidate genes ( CAPN8, DUSP23, PCDH17, SNORA17, PCDH9, LECT1, and LECT2). We found no evidence of association of these candidates with the human orthologues. In conclusion, the CC populations enabled mapping of confined QTL that confer susceptibility to alveolar bone loss in mice and larger human phenotype-genotype samples and additional expression data from gingival tissues are likely required to identify true positive signals.

Background: Non-alcoholic fatty liver disease (NAFLD) affects 20%-30% of adults with risk factors like obesity and insulin resistance putatively acting through chronic low-grade inflammation. Because periodontitis elicits low-grade inflammation, we hypothesized that it could contribute to NAFLD occurrence., Objective: To investigate epidemiologic associations between periodontitis and the incidence of NAFLD among 2,623 participants of the Study of Health in Pomerania., Methods: Periodontitis at baseline was defined as the percentage of sites (0%, <30%, ≥30%) with (i) clinical attachment level (CAL) ≥3 mm; (ii) probing pocket depth (PD) ≥4 mm. Incident NAFLD was defined as a significant increase in liver echogenicity on ultrasound relative to the kidneys, with the diaphragm indistinct or the echogenic walls of the portal veins invisible., Results: After a median 7.7 years of follow-up, 605 incident NAFLD cases occurred at a rate of 32.5 cases per 1,000 person-years. Relative to participants without CAL ≥3 mm, NAFLD incidence was elevated slightly in participants with <30% of sites affected and moderately in participants with ≥30% of sites affected (multivariable-adjusted incidence rate ratio = 1.28, 95% CI, 0.84, 1.95 and 1.60, 95% CI, 1.05-2.43), respectively. A similar dose-response relationship was not observed for PD., Conclusion: History of periodontitis may be a risk factor for NAFLD., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

An association between periodontitis and nonalcoholic fatty liver disease (NAFLD) has been reported by experimental animal and epidemiologic studies. This study investigated whether circulating levels of serum C-reactive protein (CRP) and a weighted genetic CRP score representing markers of inflammatory burden modify the association between periodontitis and NAFLD. Data came from 2,481 participants of the Study of Health in Pomerania who attended baseline examination that occurred between 1997 and 2001. Periodontitis was defined as the percentage of sites (0%, <30%, ≥30%) with probing pocket depth (PD) ≥4 mm, and NAFLD status was determined using liver ultrasound assessment. Serum CRP levels were assayed at a central laboratory, and single-nucleotide polymorphisms previously identified through genome-wide association studies as robustly associated with serum CRP were combined into a weighted genetic CRP score (wGS CRP ). Logistic regression models estimated the association between periodontitis and NAFLD within strata of serum CRP and separately within strata of the wGS CRP . The prevalence of NAFLD was 26.4% (95% confidence interval [CI], 24.6, 28.1) while 17.8% (95% CI, 16.0-19.6) had ≥30% of sites with PD ≥4 mm. Whereas the wGS CRP was not a modifier ( P interaction = 0.8) on the multiplicative scale, serum CRP modified the relationship between periodontitis and NAFLD ( P interaction = 0.01). The covariate-adjusted prevalence odds ratio of NAFLD comparing participants with ≥30% of sites with PD ≥4 mm to those with no site affected was 2.39 (95% CI, 1.32-4.31) among participants with serum CRP <1 mg/L. The corresponding estimate was 0.97 (95% CI, 0.57-1.66) for participants with serum CRP levels of 1 to 3 mg/L and 1.12 (95% CI, 0.65-1.93) for participants with serum CRP >3 mg/L. Periodontitis was positively associated with higher prevalence odds of NAFLD, and this relationship was modified by serum CRP levels.

Aim: Whereas the relationship between myeloperoxidase and periodontitis has been widely examined that between salivary peroxidase and periodontitis has received little attention. We examined how periodontitis depends on both salivary peroxidase activity and concentration., Materials and Methods: A full mouth, clinical assessment of probing depth was performed in a sample of 46 participants aged 25-54 years. To minimise bias, these data were corrected by data from the general population (Study of Health in Pomerania). Using five repeated measurements of activity and concentration over 1 day, we assessed daily biological variability and increased the reliability of salivary peroxidase measurements., Results: Salivary peroxidase activity was associated with probing depth (interquartile range effect = -0.48; robust estimates of 95% confidence interval: -0.90 to -0.31; p = .0052), and its effect was not confounded by salivary peroxidase concentration. In turn, the effect of salivary peroxidase concentration was confounded by salivary peroxidase activity, and it was smaller than that of activity., Conclusions: We found an inverse association between salivary peroxidase activity and probing depth. Thus, our results imply that salivary peroxidase activity could be a protective factor against periodontitis. However, large, well-designed studies are needed to explore the causal mechanisms of this association., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Lifespan is a complex trait, and longitudinal data for humans are naturally scarce. We report the results of Cox regression and Pearson correlation analyses using data of the Study of Health in Pomerania (SHIP), with mortality data of 1518 participants (113 of which died), over a time span of more than 10 years. We found that in the Cox regression model based on the Bayesian information criterion, apart from chronological age of the participant, six baseline variables were considerably associated with higher mortality rates: smoking, mean attachment loss (i.e. loss of tooth supporting tissue), fibrinogen concentration, albumin/creatinine ratio, treated gastritis, and medication during the last 7 days. Except for smoking, the causative contribution of these variables to mortality was deemed inconclusive. In turn, four variables were found to be associated with decreased mortality rates: treatment of benign prostatic hypertrophy, treatment of dyslipidemia, IGF-1 and being female. Here, being female was an undisputed causative variable, the causal role of IFG-1 was deemed inconclusive, and the treatment effects were deemed protective to the degree that treated subjects feature better survival than respective controls. Using Cox modeling based on the Akaike information criterion, diabetes, mean corpuscular hemoglobin concentration, red blood cell count and serum calcium were also associated with mortality. The latter two, together with albumin and fibrinogen, aligned with an"integrated albunemia" model of aging proposed recently.

Aggregatibacter actinomycetemcomitans is a Gram-negative commensal bacterium of the oral cavity which has been associated with the pathogenesis of periodontitis with severe alveolar bone destruction. The role of host factors such as reactive oxygen and nitrogen intermediates in periodontal A. actinomycetemcomitans infection and progression to periodontitis is still ill-defined. Therefore, this study aimed to analyze the role of NADPH oxidase and inducible nitric oxide synthase (iNOS) in a murine model of A. actinomycetemcomitans-induced periodontitis. NADPH oxidase-deficient (gp91 phox knockout [KO]), iNOS-deficient (iNOS KO), and C57BL/6 wild-type mice were orally infected with A. actinomycetemcomitans and analyzed for bacterial colonization at various time points. Alveolar bone mineral density and alveolar bone volume were quantified by three-dimensional micro-computed tomography, and the degree of tissue inflammation was calculated by histological analyses. At 5 weeks after infection, A. actinomycetemcomitans persisted at significantly higher levels in the murine oral cavities of infected gp91 phox KO mice than in those of iNOS KO and C57BL/6 mice. Concomitantly, alveolar bone mineral density was significantly lower in all three infected groups than in uninfected controls, but with the highest loss of bone density in infected gp91 phox KO mice. Only infected gp91 phox KO mice revealed significant loss of alveolar bone volume and enhanced inflammatory cell infiltration, as well as an increased number of osteoclasts. Our results indicate that NADPH oxidase is important to control A. actinomycetemcomitans infection in the murine oral cavity and to prevent subsequent alveolar bone destruction and osteoclastogenesis., (Copyright © 2017 American Society for Microbiology.)