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Objective: Periodontitis is a complex and multifactorial disease and it is challenging to decipher its underlying causes and mechanisms. This study attempted to explore potential circulating proteins in connection to periodontitis through proteome-wide Mendelian randomisation (MR). Methods: We analysed 1722 circulating proteins to identify prospective drug targets for tackling periodontitis, using the genomic dataset from the FinnGen study. Two-sample MR was conducted to evaluate the bidirectional relationship between circulating proteins and periodontitis risk. A dataset from the UK Biobank was used to validate the findings. Single-cell analysis was performed to assess the cellular expression of the identified proteins within gingival tissues. Results: MR analyses found that genetically predicted circulating levels of von Willebrand factor A domain-containing 1 (von Willebrand factor A domain containing 1 [VWA1], odds ratios: 0.94, 95% CI 0.92-0.97, P = 1.28 × 10−5) were inversely associated with periodontitis. In contrast, the level of growth differentiation factor 15 (growth differentiation factor 15 [GDF15], odds ratios: 1.05, 95% CI 1.02-1.07, P = 2.12 × 10−5) might be associated with an increased risk of periodontitis. Single-cell analysis indicated that VWA1 was primarily expressed in endothelial cells of healthy gingival tissues, while the main source of GDF15 was not derived from periodontal cells. Conclusions: The present study suggests that certain plasma proteins like VWA1 and GDF15 may be potentially indicative of the risk and susceptibility to periodontitis. These proteins could possibly be the potential therapeutic targets for treating periodontitis, and further investigation is highly warranted.

Abstract Periodontitis is the sixth most prevalent chronic disease globally and places significant burdens on societies and economies worldwide. Behavioral modification, risk factor control, coupled with cause-related therapy have been the “gold standard” treatment for managing periodontitis. Given that host inflammatory and immunological responses play critical roles in the pathogenesis of periodontitis and impact treatment responses, several adjunctive strategies aimed at modulating host responses and improving the results of periodontal therapy and maintenance have been proposed. Of the many pharmacological host modulators, we focused on non-steroidal anti-inflammatory drugs (NSAIDs), due to their long history and extensive use in relieving inflammation and pain and reducing platelet aggregation. NSAIDs have been routinely indicated for treating rheumatic fever and osteoarthritis and utilized for the prevention of cardiovascular events. Although several efforts have been made to incorporate NSAIDs into the treatment of periodontitis, their effects on periodontal health remain poorly characterized, and concerns over the risk–benefit ratio were also raised. Moreover, there is emerging evidence highlighting the potential of NSAIDs, especially aspirin, for use in periodontal regeneration. This review summarizes and discusses the use of NSAIDs in various aspects of periodontal therapy and regeneration, demonstrating that the benefits of NSAIDs as adjuncts to conventional periodontal therapy remain controversial. More recent evidence suggests a promising role for NSAIDs in periodontal tissue engineering and regeneration.