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

Michael Nolde; Zoheir Alayash; Stefan Lars Reckelkamm; Thomas Kocher; Benjamin Ehmke; Birte Holtfreter; Hansjörg Baurecht; Marios K Georgakis; Sebastian-Edgar Baumeister

doi:10.3389/fimmu.2023.1160148

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

Front Immunol. 2023 Jun 5:14:1160148. doi: 10.3389/fimmu.2023.1160148. eCollection 2023.

Authors

Michael Nolde¹, Zoheir Alayash¹, Stefan Lars Reckelkamm¹, Thomas Kocher², Benjamin Ehmke³, Birte Holtfreter², Hansjörg Baurecht⁴, Marios K Georgakis^{5

6}, Sebastian-Edgar Baumeister¹

Affiliations

¹ Institute of Health Services Research in Dentistry, University of Münster, Münster, Germany.
² Department of Restorative Dentistry, Periodontology, Endodontology, and Preventive and Pediatric Dentistry, University Medicine Greifswald, Greifswald, Germany.
³ Clinic for Periodontology and Conservative Dentistry, University of Münster, Münster, Germany.
⁴ Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.
⁵ Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
⁶ Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge, MA, United States.

Abstract

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.

Keywords: cell signaling; cytokine(s); epidemiology; host modulation therapy; periodontal disease(s)/periodontitis.

MeSH terms

Down-Regulation
Genome-Wide Association Study
Humans
Interleukin-6* / genetics
Mendelian Randomization Analysis
Periodontitis* / complications
Periodontitis* / genetics
Receptors, Interleukin-6 / genetics

Substances

Interleukin-6
Receptors, Interleukin-6