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

Alayash, Zoheir; Baumeister, Sebastian‐Edgar; Holtfreter, Birte; Kocher, Thomas; Baurecht, Hansjörg; Ehmke, Benjamin; Reckelkamm, Stefan Lars; Nolde, Michael

doi:10.3389/fimmu.2023.1094175

Cited by 2 publications

(1 citation statement)

References 49 publications

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“…Drug target MR (or cis-MR) is a study design that leverages large genetic data to estimate the effect of drug therapy in the absence of evidence from randomized clinical trials (RCTs). While estimates from other observational study designs are often biased by unmeasured confounding, MR uses genetic instrumental variables to imitate the randomization of RCTs to yield unconfounded effect estimates and has recently been introduced to the field of periodontology ( 6 , 21 ). For an unbiased effect estimation, three instrumental variable assumptions must be true: The relevance assumption demands a strong association between genetic instruments and the exposure.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2023

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AimInterleukin 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 methodsAs 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.ResultsGenetically 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).ConclusionIn 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.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2023

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Genetically Supported Drug Targets and Dental Traits: A Mendelian Randomization Study

Liu,

Wang,

Duan

et al. 2024

J Dent Res

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Current interventions for oral/dental diseases heavily rely on operative/surgical procedures, while the discovery of novel drug targets may enable access to noninvasive pharmacotherapy. Therefore, this study aims to leverage large-scale data and Mendelian randomization (MR) techniques, utilizing genetic variants as instruments, to identify potential therapeutic targets for oral and dental diseases supported by genetic evidence. By intersecting 4,302 druggable genes with expression quantitative trait loci from 31,684 blood samples, we identified 2,580 druggable targets as exposures. Single nucleotide polymorphisms associated with dental disease/symptom traits were collected from FinnGen R9, the Gene–Lifestyle Interactions in Dental Endpoints consortium, and the UK Biobank to serve as outcomes for both discovery and replication purposes. Through MR analysis, we identified 43 druggable targets for various dental disease/symptom traits. To evaluate the viability of these targets, we replicated the analysis using circulating protein quantitative trait loci as exposures. Additionally, we conducted sensitivity, colocalization, Gene Ontology/Kyoto Encyclopedia of Genes and Genomes annotation, protein–protein interaction analyses, and validated dental trait–associated druggable gene expression in animal models. Among these targets, IL12RB1 (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.01–1.01) and TNF (OR, 0.98; 95% CI, 0.97–0.99) exhibited therapeutic promise for oral ulcers, whereas CXCL10 (OR, 0.84; 95% CI, 0.76–0.91) was for periodontitis. Through a rigorous quality control and validation pipeline, our study yields compelling evidence for these druggable targets, which may enhance the clinical prognosis by developing novel drugs or repurposing existing ones.

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

Cited by 2 publications

References 49 publications

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

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

Genetically Supported Drug Targets and Dental Traits: A Mendelian Randomization Study

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