Mass Spectrometry-Based Proteomics for Discovering Salivary Biomarkers in Periodontitis: A Systematic Review

Abstract

<p>Abstract: Periodontitis is one of the primary causes of tooth loss, and is also related to various<br>systemic diseases. Early detection of this condition is crucial when it comes to preventing further<br>oral damage and the associated health complications. This study offers a systematic review of the<br>literature published up to April 2023, and aims to clearly explain the role of proteomics in identifying<br>salivary biomarkers for periodontitis. Comprehensive searches were conducted on PubMed and<br>Web of Science to shortlist pertinent studies. The inclusion criterion was those that reported on<br>mass spectrometry-driven proteomic analyses of saliva samples from periodontitis cohorts, while<br>those on gingivitis or other oral diseases were excluded. An assessment for risk of bias was carried<br>out using the Newcastle–Ottawa Scale and Quality Assessment of Diagnostic Accuracy Studies<br>or the NIH quality assessment tool, and a meta-analysis was performed for replicable candidate<br>biomarkers, i.e., consistently reported candidate biomarkers (in specific saliva samples, and periodontitis subgroups, reported in ≥2 independent cohorts/reports) were identified. A Gene Ontology<br>enrichment analysis was conducted using the Database for Annotation, Visualization, and Integrated Discovery bioinformatics resources, which consistently expressed candidate biomarkers, to<br>explore the predominant pathway wherein salivary biomarkers consistently manifested. Of the<br>15 studies included, 13 were case–control studies targeting diagnostic biomarkers for periodontitis<br>participants (periodontally healthy/diseased, n = 342/432), while two focused on biomarkers responsive to periodontal treatment (n = 26 participants). The case–control studies were considered<br>to have a low risk of bias, while the periodontitis treatment studies were deemed fair. Summary<br>estimate and confidence/credible interval, etc. determination for the identified putative salivary<br>biomarkers could not be ascertained due to the low number of studies in each case. The results<br>from the included case–control studies identified nine consistently expressed candidate biomarkers<br>(from nine studies with 230/297 periodontally healthy/diseased participants): (i) those that were<br>upregulated: alpha-amylase, serum albumin, complement C3, neutrophil defensin, profilin-1, and<br>S100-P; and (ii) those that were downregulated: carbonic anhydrase 6, immunoglobulin J chain, and<br>lactoferrin. All putative biomarkers exhibited consistent regulation patterns. The implications of<br>the current putative marker proteins identified were reviewed, with a focus on their potential roles<br>in periodontitis diagnosis and pathogenesis, and as putative therapeutic targets. Although in its<br>early stages, mass spectrometry-based salivary periodontal disease biomarker proteomics detection<br>appeared promising. More mass spectrometry-based proteomics studies, with or without the aid of<br>already available clinical biochemical approaches, are warranted to aid the discovery, identification,<br>and validation of periodontal health/disease indicator molecule(s). Protocol registration number:<br>CRD42023447722; supported by RD-02-202410 and GRF17119917.<br><br></p>