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Aim: An excessively activated or dysregulated complement system has been proven to be a vital contributor to the pathogenesis of periodontitis. It has been previously hypothesized that inhibiting the activity of complement component C5 by targeting the C5a receptor is a powerful candidate for treating periodontitis. Here, we apply the drug target instrumental variable (IV) approach to investigate the therapeutic effect of genetically proxied inhibition of C5 on periodontitis., Method: In our primary analysis, we used 26 independent 'cis' single nucleotide polymorphisms as IVs from the vicinity of the encoding locus of C5 that are associated with plasma C5 levels. In a secondary analysis, we assess the validity of our primary findings, exploring the involvement of alternative downstream biomarkers, interleukin 17 (IL-17), interleukin 1β (IL-1β), and tumor necrosis factor (TNF). Summary statistics of plasma levels (C5, IL-17, IL-1β, and TNF) were obtained from a genome-wide association study (GWAS) of 35,559 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., Results: In our primary approach, inhibiting C5 reduced the risk of periodontitis (Odds ratio 0.89 per 1 standard deviation reduction in C5; 95% confidence Interval 0.80-0.98, p value=0.022). Our secondary analysis suggests an involvement of IL-17 within the potential causal pathway, but was inconclusive for other biomarkers., Conclusions: The findings from our study suggest that C5 inhibition may reduce the risk of periodontitis, prioritizing C5 inhibitors as a potential adjunctive therapeutic intervention in this disease., 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 © 2024 Alayash, Baumeister, Holtfreter, Kocher, Baurecht, Ehmke, Reckelkamm and Nolde.)

Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Epidemiological studies have consistently shown that Sjögren's disease (SjD) increases the risk of dental caries. Despite similar evidence indicating an elevated risk of periodontitis, SjD remains a disputed risk factor for this disease. The risk of bias in observational research is a major impediment to confirming this link. Within an instrumental variable framework, genetic variants associated with a risk factor can be used to proxy its effect on an outcome while avoiding common sources of observational study bias. In this study, we leveraged an instrumental variable approach to investigate whether SjD affects the risk of caries and periodontitis. A total of 57 genetic variants strongly associated with SjD were identified from a genome-wide association study of 2,247 European descent cases and 332,115 controls. We tested for associations of these genetic instruments with caries (measured as the number of decayed, missing, and filled surfaces in 26,792 individuals) and periodontitis (17,353 clinical periodontitis cases and 28,210 European controls). Several sensitivity analyses were used to further validate the primary inverse variance weighted (IVW) estimate. IVW analysis revealed an adverse effect of SjD on caries (β = 0.039, P = 6.3e-16) and periodontitis (odds ratio = 1.033, P = 2.3e-05). Sensitivity analyses, conducted to assess the robustness to potential violations of instrumental variable assumptions, further support these findings. Our results showed that SjD has a detrimental effect on caries and also suggest that SjD promotes periodontitis., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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.)

Objectives: Periodontitis (PD) can cause systematic inflammation and is associated with various metabolic processes in the body. However, robust serum markers for these relationships are still lacking. This study aims to identify novel circulating inflammation-related proteins associated with PD using targeted proteomics., Materials and Methods: We used population-based, cross-sectional data from 619 participants of the Polish Longitudinal University Study (Bialystok PLUS). Mean pocket probing depth (mPPD) and proportion of bleeding on probing (pBOP) served as exposure variables. Fifty-two inflammation-related proteins were measured using the Olink Target 96 Cardiovascular III and the Olink Target 96 Immune Response panels. Associations between periodontal measures and proteins were tested using covariate-adjusted linear regression models., Results: At a false discovery rate of < 0.05, we identified associations of mPPD and pBOP with platelet-endothelial cell adhesion molecule-1 (PECAM-1) and tripartite motif-containing protein 21 (TRIM21)., Conclusion: This study revealed novel associations between PD and serum levels of PECAM-1 and TRIM21. Our results suggest that these proteins might be affected by molecular processes that take place in the inflamed periodontium., Clinical Relevance: Novel associations of PECAM-1 and TRIM21 with PD indicate promising serum markers for understanding the disease's pathophysiological processes and call for further biomedical investigations., (© 2023. The Author(s).)

Objectives: Observational studies suggested an inverse association between physical activity and periodontitis. However, observational studies might be subject to unobserved confounding and reverse causation bias. We conducted an instrumental variable study to strengthen the evidence on the relationship between physical activity and periodontitis., Materials and Methods: We used genetic variants associated with self-reported and accelerometer-assessed physical activity in 377,234 and 91,084 UK Biobank participants, respectively, as instruments. For these instruments, genetic associations with periodontitis were obtained from 17,353 cases and 28,210 controls in the GeneLifestyle Interactions in Dental Endpoints consortium., Results: We found no evidence for effects of self-reported moderate-to-vigorous physical activity, self-reported vigorous physical activity, accelerometry "average accelerations," and "fraction of accelerations > 425 milli-gravities" on periodontitis. For example, the odds ratio for self-reported moderate-to-vigorous physical activity was 1.07 (95% credible interval: 0.87; 1.34) in Causal Analysis using Summary Effect Estimates. We conducted sensitivity analyses to rule out weak instrument bias and correlated horizontal pleiotropy., Conclusions: The study does not support an effect of physical activity on the risk of periodontitis., Clinical Relevance: This study provides little evidence that recommending physical activity would help prevent periodontitis., (© 2023. The Author(s).)

Periodontitis (PD), a widespread chronic infectious disease, compromises oral health and is associated with various systemic conditions and hematological alterations. Yet, to date, it is not clear whether serum protein profiling improves the assessment of PD. We collected general health data, performed dental examinations, and generated serum protein profiles using novel Proximity Extension Assay technology for 654 participants of the Bialystok PLUS study. To evaluate the incremental benefit of proteomics, we constructed two logistic regression models assessing the risk of having PD according to the CDC/AAP definition; the first one contained established PD predictors, and in addition, the second one was enhanced by extensive protein information. We then compared both models in terms of overall fit, discrimination, and calibration. For internal model validation, we performed bootstrap resampling ( n = 2000). We identified 14 proteins, which improved the global fit and discrimination of a model of established PD risk factors, while maintaining reasonable calibration (area under the curve 0.82 vs 0.86; P < 0.001). Our results suggest that proteomic technologies offer an interesting advancement in the goal of finding easy-to-use and scalable diagnostic applications for PD that do not require direct examination of the periodontium.

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.)

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.)

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.)

Aim: Higher educational attainment is associated with a lower risk of periodontitis, but the extent to which this association is causal and mediated by intermediate factors is unclear., Materials and Methods: Using summary data from genetic association studies from up to 1.1 million participants of European descent, univariable and multivariable Mendelian randomization analyses were performed to infer the total effect of educational attainment on periodontitis and to estimate the degree to which income, smoking, alcohol consumption, and body mass index mediate the association., Results: The odds ratio of periodontitis per 1 standard deviation increment in genetically predicted education was 0.78 (95% CI: 0.68-0.89). The proportions mediated of the total effect of genetically predicted education on periodontitis were 64%, 35%, 15%, and 46% for income, smoking, alcohol consumption, and body mass index, respectively., Conclusions: Using a genetic instrumental variable approach, this study triangulated evidence from existing observational epidemiological studies and suggested that higher educational attainment lowers periodontitis risk. Measures to reduce the burden of educational disparities in periodontitis risk may tackle downstream risk factors, particularly income, smoking, and obesity., (© 2021 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)