Using genetics to explore complement C5 as a druggable protein in periodontitis.

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 1ß (IL-1ß), and tumor necrosis factor (TNF). Summary statistics of plasma levels (C5, IL-17, IL-1ß, 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.

Central corneal thickness and the risk of primary open-angle glaucoma: a Mendelian randomisation mediation analysis.

BACKGROUND: The association of central corneal thickness (CCT) with primary open-angle glaucoma (POAG) remains uncertain. Although several observational studies assessing this relationship have reported an inverse association between CCT and POAG, this could be the result of collider bias. In this study, we leveraged human genetic data to assess through Mendelian randomisation (MR) the effect of CCT on POAG risk and whether this effect is mediated by intraocular pressure (IOP) changes. METHODS: We used 24 single-nucleotide polymorphisms (SNPs) associated with CCT (p value<5×10-8) from a genome-wide association study (GWAS) (N=17 803) provided by the International Glaucoma Genetics Consortium and 53 SNPs associated with IOP (p value<5×10-8) from a GWAS of the UK Biobank (UKBB) (N=97 653). We related these instruments to POAG using a GWAS meta-analysis of 8283 POAG cases and 753 827 controls from UKBB and FinnGen. RESULTS: MR analysis suggested a positive association between CCT and POAG (OR of POAG per 50 µm increase in CCT: 1.38; 95% CI: 1.18 to 1.61; p value<0.01). MR mediation analysis showed that 28.4% of the total effect of CCT on POAG risk was mediated through changes in IOP. The primary results were consistent with estimates of pleiotropy-robust MR methods. CONCLUSION: Contrary to most observational studies, our results showed that a higher CCT is associated with an increased risk of POAG.

Intraocular pressure, primary open-angle glaucoma and the risk of retinal vein occlusion: A Mendelian randomization mediation analysis.

BACKGROUND: The etiological connection between intraocular pressure (IOP) and the risk of retinal vein occlusion (RVO) remains elusive, particularly regarding whether this risk emanates from the direct influence of elevated intraocular pressure (IOP), irrespective of the presence of primary open-angle glaucoma (POAG), or if it arises as a consequence of the sequelae of POAG. Therefore, we conducted a Mendelian Randomization (MR) mediation analysis to elucidate the mediating role of POAG in the association between IOP and RVO. METHODS: We identified 47 single-nucleotide polymorphisms (SNPs) associated with IOP (P-value < 5 × 10-8) leveraging data from a genome-wide association study (GWAS) (N = 97,653) obtained from the UK Biobank and 50 SNPs associated with POAG (P-value < 5 × 10-8) from a GWAS meta-analysis (16,677 cases and 199,580 controls). We related these SNPs with RVO using a GWAS of 775 RVO cases and 376,502 controls from FinnGen. By utilizing univariable and multivariable MR analyses we calculated the total effect of IOP on RVO and estimated the degree to which POAG mediates this association. RESULTS: MR analyses showed that higher IOP is associated with higher RVO risk (odds ratio of RVO per 1 mmHg increase in IOP: 1.53; 95% confidence interval: 1.04 to 2.26; p-value = 0.03). Moreover, our MR mediation analysis suggested that 91.6% of the total effect of IOP on RVO risk was mediated through POAG. The primary results were consistent with estimates of pleiotropy-robust MR methods. CONCLUSION: Our findings suggest that higher IOP increases the risk of RVO and that the majority of this effect is mediated through POAG.

Complement C3 as a potential drug target in periodontitis: Evidence from the cis-Mendelian randomization approach.

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.

Targeted proteomics in a population-based study identifies serum PECAM-1 and TRIM21 as inflammation markers for periodontitis.

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.

Cannabis use and the risk of primary open-angle glaucoma: a Mendelian randomization study.

Several observational studies have investigated the association between cannabis use and intraocular pressure, but its association with primary open-angle glaucoma (POAG) remains unclear. In this study, we leveraged human genetic data to assess through Mendelian randomization (MR) whether cannabis use affects POAG. We used five single-nucleotide polymorphisms (SNPs) associated with lifetime cannabis use (P-value < 5 × 10-8) from a genome-wide association study (GWAS) (N = 184,765) by the International Cannabis Consortium, 23andMe, and UK Biobank and eleven SNPs associated with cannabis use disorder (P-value < 5 × 10-7) from a GWAS meta-analysis of (17,068 cases and 357,219 controls of European descent) from Psychiatric Genomics Consortium Substance Use Disorders working group, Lundbeck Foundation Initiative for Integrative Psychiatric Research, and deCode. We associated the selected five SNPs from the GWAS of lifetime cannabis use and the eleven SNPs from the GWAS of cannabis use disorder, with the largest to date GWAS meta-analysis of POAG (16,677 cases and 199,580 controls). MR analysis suggested no evidence for a causal association of lifetime cannabis use and cannabis use disorder with POAG (odds ratio (OR) of outcome per doubling of the odds of exposure (95% confidence interval): 1.04 (0.88; 1.23) for lifetime cannabis use and 0.97 (0.92; 1.03) for cannabis use disorder). Sensitivity analyses to address pleiotropy and weak instrument bias yielded similar estimates to the primary analysis. In conclusion, our results do not support a causal association between cannabis use and POAG.

Physical activity and the risk of periodontitis: an instrumental variable study.

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.

Downregulation of interleukin 6 signaling might reduce the risk of periodontitis: a drug target Mendelian randomization study.

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.

Optimizing a Diagnostic Model of Periodontitis by Using Targeted Proteomics.

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.

Time-Varying Use of Proton Pump Inhibitors and Cognitive Impairment and Dementia: A Real-World Analysis from Germany.

BACKGROUND: Cumulative evidence of dementia risk in patients taking proton pump inhibitors (PPIs) is still inconclusive, probably due to a variety of study designs. OBJECTIVE: This study aimed to compare how the association between dementia risk and use of PPIs differs by different outcome and exposure definitions. METHODS: We conceptualized a target trial using claims data with 7,696,127 individuals aged 40 years or older without previous dementia or mild cognitive impairment (MCI) from the Association of Statutory Health Insurance Physicians in Bavaria. Dementia was defined as either including or excluding MCI to compare how the results alter by different outcome definitions. We used weighted Cox models to estimate the PPI initiation effect on dementia risk and weighted pooled logistic regression to assess the effect of time-varying use versus non-use during 9 years of study period, including 1 year of wash-out period (2009-2018). The median follow-up time of PPI initiators and non-initiators was 5.4 and 5.8 years, respectively. We also evaluated the association between each PPI agent (omeprazole, pantoprazole, lansoprazole, esomeprazole, and combined use) and dementia risk. RESULTS: A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03-1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80-1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03-1.05) and 1.82 (1.77-1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk. A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03-1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80-1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03-1.05) and 1.82 (1.77-1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk.A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03-1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80-1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03-1.05) and 1.82 (1.77-1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk.A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03-1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80-1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03-1.05) and 1.82 (1.77-1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk.A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03-1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80-1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03-1.05) and 1.82 (1.77-1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk.A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03-1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80-1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03-1.05) and 1.82 (1.77-1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk.A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03-1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80-1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03-1.05) and 1.82 (1.77-1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk.A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03-1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80-1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03-1.05) and 1.82 (1.77-1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk.A total of 105,220 (3.6%) PPI initiators and 74,697 (2.6%) non-initiators were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio (HR) for dementia was 1.04 [95% confidence interval (CI) 1.03-1.05]. The HR for time-varying PPI use versus non-use was 1.85 (1.80-1.90). When MCI was included in the outcome, the number of outcomes increased to 121,922 in PPI initiators and 86,954 in non-initiators, but HRs remained similar, showing 1.04 (1.03-1.05) and 1.82 (1.77-1.86), respectively. Pantoprazole was the most frequently used PPI agent. Although the estimated HRs for the time-varying use effect of each PPI showed different ranges, all agents were associated with an increased dementia risk. CONCLUSION: Our large study supports existing evidence that PPI use is related to an increased risk of dementia.

Inhibition of tumor necrosis factor receptor 1 and the risk of periodontitis.

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.

Effect of interleukin-17 on periodontitis development: An instrumental variable analysis.

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.

Association between total body bone mineral density and periodontitis: A Mendelian randomization study.

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.

Genotype-driven NPC1L1 and PCSK9 inhibition and reduced risk of periodontitis.

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.

Do proton pump inhibitors increase the risk of dementia? A systematic review, meta-analysis and bias analysis.

AIM: Previous studies on the association between proton pump inhibitor (PPI) intake and the increased risk of dementia has shown discrepancies in their conclusions. We aimed to provide updated evidence based on extensive bias assessments and quantitative sensitivity analyses. METHODS: We searched the databases PubMed, EMBASE, SCOPUS, CENTRAL and clinicaltrials.gov for prospective studies that examined an association between PPI use and dementia, up to February 2022. Each study was assessed using the Cochrane risk of bias assessment tools for non-randomized studies of interventions (ROBINS-I) or randomized trials (RoB2). Pooled risk ratios (RRs) and 95% prediction intervals were computed using random-effects models. Sensitivity analyses were adjusted for small-study bias. RESULTS: We included nine observational studies with 204 108 dementia cases in the primary analysis on the association between PPI use vs. non-use and dementia, and the RR was 1.16 (95% CI = 1.00; 1.35). After adjusting for small-study bias by Copas selection model and Rücker's shrinkage procedure, the RR was 1.16 (1.02; 1.32) and 1.15 (1.13; 1.17), respectively. A subgroup analysis of PPI use vs. non-use regarding Alzheimer's disease risk yielded an RR of 1.15 (0.89; 1.50). The secondary analysis on the risk of dementia by use of PPI vs. histamine-2 receptor antagonist showed an RR of 1.03 (0.66; 1.62). CONCLUSION: This meta-analysis provided no clear evidence for an association between PPI intake and the risk of dementia. Due to discrepancies in sensitivity analyses, however, some risk of dementia by PPI use cannot be ruled out. Since an unequivocal conclusion is still pending, further research is warranted.

Proton pump inhibitors and the risk of cardiovascular events and cardiovascular mortality: A systematic review and meta-analysis of observational studies.

BACKGROUND AND AIMS: Observational research has indicated that proton pump inhibitors (PPIs) might increase the long-term risk of cardiovascular events. This study evaluated the evidence from observational studies for an effect of PPI monotherapy on the risk of incident cardiovascular events and cardiovascular mortality. METHODS: The databases MEDLINE, EMBASE, and Scopus were systematically searched up to September 2021. The primary outcome was first cardiovascular event, i.e. first myocardial infarction or first ischaemic stroke. The secondary outcome was cardiovascular mortality. Studies were included following a detailed risk of bias assessment with the ROBINS-I tool. Sensitivity and bias analyses adjusted for potential publication bias, immortal time bias, and unmeasured confounding. RESULTS: We included ten studies with 75,371 first cardiovascular events, as well as seven studies on cardiovascular mortality with 50,329 cardiovascular deaths in total. The pooled hazard ratios (HRs) for PPI use and cardiovascular events were 1.05 with a 95% confidence interval of (0.96; 1.15) before and 0.99 (0.93; 1.04) after adjusting for observational study design bias. The pooled HRs for PPI use and cardiovascular mortality were 1.27 (1.11; 1.44) before and 1.06 (0.96; 1.16) after adjusting for publication bias and observational study design bias. CONCLUSION: It is questionable, whether PPI monotherapy constitutes a cardiovascular risk factor.

No bidirectional relationship between depression and periodontitis: A genetic correlation and Mendelian randomization study.

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 (rg = 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.

Association between bone turnover markers and periodontitis: A population-based cross-sectional study.

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; eß=1.008 ; 95% confidence interval [CI]: 1.001-1.015), mean clinical attachment loss (mean CAL; eß=1.027 ; 95% CI: 1.011-1.044), and proportion of sites with bleeding on probing (%BOP; eß=1.055 ; 95% CI: 1.005-1.109). Similar associations were seen for BAP with %BOP ( eß=1.121 ; 95% CI: 1.042-1.205), proportion of sites with PPD ≥4 mm (%PPD4) ( eß=1.080 ; 95% CI: 1.005-1.161), and sclerostin with %BOP ( eß=1.308 ; 95% CI: 1.005-1.704). WNT5A was inversely associated with mean PPD ( eß=0.956 ; 95% CI: 0.920-0.993) and %PPD4 ( eß=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.

Cannabis use and the risk of periodontitis: A two-sample Mendelian randomization study.

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.