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BRIEF RESEARCH REPORT article

Front. Immunol.
Sec. Inflammation
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1407431

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

Provisionally accepted
Zoheir Alayash Zoheir Alayash 1*Sebastian-Edgar Baumeister Sebastian-Edgar Baumeister 1Birte Holtfreter Birte Holtfreter 2Thomas Kocher Thomas Kocher 2Hansjörg Baurecht Hansjörg Baurecht 3Benjamin Ehmke Benjamin Ehmke 4Stefan Lars Reckelkamm Stefan Lars Reckelkamm 1Michael Nolde Michael Nolde 1
  • 1 Institute of Health Services Research in Dentistry, University of Münster, Münster, North Rhine-Westphalia, Germany
  • 2 Department of Restorative Dentistry, Periodontology, Endodontology, and Preventive and Pediatric Dentistry, University of Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany
  • 3 Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Bavaria, Germany
  • 4 Clinic for Periodontology and Conservative Dentistry, University of Münster, Münster, North Rhine-Westphalia, Germany

The final, formatted version of the article will be published soon.

    Aim: 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 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.

    Keywords: Complement C5, Immunomodulation, Periodontitis, Drug Discovery, instrumental variable analysis Study funding: The authors did not receive funding for this study

    Received: 26 Mar 2024; Accepted: 20 Sep 2024.

    Copyright: © 2024 Alayash, Baumeister, Holtfreter, Kocher, Baurecht, Ehmke, Reckelkamm and Nolde. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Zoheir Alayash, Institute of Health Services Research in Dentistry, University of Münster, Münster, 48149, North Rhine-Westphalia, Germany

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.