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.

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) 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) from a GWAS meta-analysis (16,677 cases and 199,580 controls).

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.

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.

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) 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) 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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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

Background: Observational and 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.

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.

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.

Emulating a target trial of proton pump inhibitors and dementia risk using claims data.

Background And Purpose: Understanding the adverse effects of proton pump inhibitors (PPIs) is important due to their widespread use, but the available evidence for an increased dementia risk amongst patients taking PPIs is inconclusive. The present study aimed to estimate the causal effect of PPIs on the risk of dementia by target trial emulation and time-varying exposure modeling.

Methods: Using claims data of 2,698,176 insured people of a large German statutory health insurer, a target trial was conceptualized in which individuals aged 40 years and older were classified as PPI initiators or non-initiators between 2008 and 2018, and were followed until diagnosis of dementia, death, loss to follow-up or end of study.

A Mendelian randomization study on the effect of 25-hydroxyvitamin D levels on periodontitis.

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.

Who gets prescriptions for proton pump inhibitors and why? A drug-utilization study with claims data in Bavaria, Germany, 2010-2018.

Purpose: The German annual drug prescription-report has indicated overuse of proton pump inhibitors (PPIs) for many years; however, little was known about the characteristics of people using PPIs. This study aimed to provide comprehensive utilization data and describe frequencies of potential on- and off-label PPI-indications in Bavaria, Germany.

Methods: Claims data of statutorily insured people from 2010 to 2018 were used.

Understanding the consequences of educational inequalities on periodontitis: A Mendelian randomization study.

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.