Biomarkers of Periodontitis and Its Differential DNA Methylation and Gene Expression in Immune Cells: A Systematic Review

Abstract

The characteristic epigenetic profile of periodontitis found in peripheral leukocytes denotes its impact on systemic immunity. In fact, this profile not only stands for periodontitis as a low-grade inflammatory disease with systemic effects but also as an important source of potentially valuable clinical biomarkers of its systemic effects and susceptibility to other inflammatory conditions. Thus, we aimed to identify relevant genes tested as epigenetic systemic biomarkers in patients with periodontitis, based on the DNA methylation patterns and RNA expression profiles in peripheral immune cells. A detailed protocol was designed following the Preferred Reporting Items for Systematic Review and Meta-analysis -PRISMA guideline. Only cross-sectional and case-control studies that reported potential systemic biomarkers of periodontitis in peripheral immune cell types were included. DNA methylation was analyzed in leukocytes, and gene expression was in polymorphonuclear and mononuclear cells. Hypermethylation was found in TLR regulators genes: MAP3K7, MYD88, IL6R, RIPK2, FADD, IRAK1BP1, and PPARA in early stages of periodontitis, while advanced stages presented hypomethylation of these genes. TGFB1I1, VNN1, HLADRB4, and CXCL8 genes were differentially expressed in lymphocytes and monocytes of subjects with poorly controlled diabetes mellitus, dyslipidemia, and periodontitis in comparison with controls. The DAB2 gene was differentially overexpressed in periodontitis and dyslipidemia. Peripheral blood neutrophils in periodontitis showed differential expression in 163 genes. Periodontitis showed an increase in ceruloplasmin gene expression in polymorphonuclears in comparison with controls. Several genes highlight the role of the epigenetics of peripheral inflammatory cells in periodontitis that could be explored in blood as a source of biomarkers for routine testing.

The role of the CX3CL1/CX3CR1 axis as potential inflammatory biomarkers in subjects with periodontitis and rheumatoid arthritis: A systematic review

“…In recent years, biomarkers of inflammation have been used as molecular tools for diagnosing periodontitis 2 . The most frequently studied inflammatory mediators are cytokines such as TNF‐α, IFN‐γ, IL‐10, IL‐17A, IL‐6, IL‐23, IL‐21, and chemokines such as IL‐8, CXCL10, CXCL13, CX3CL1, and its receptor CX3CR1, the latter two being potentially promising markers.…”

“…Periodontitis is a chronic and multifactorial inflammatory disease caused by constant exposure to a polymicrobial dysbiotic film with a high prevalence of Gram-negative bacteria such as Prevotella intermedia, Fusobacterium nucleatum, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola, and in the presence of a dysregulated immune response in a genetically susceptible host. 1 Periodontitis is considered the sixth most common osteolytic disease affecting humans, 2 has a prevalence of 62.3%, and in its most severe form, can affect up to 23.6% of the world population. 3 The most current classification proposed by the global workshop is based on the complexity/severity and progression of the disease represented by Stages I-IV and Grades A-C. 4 Affected individuals clinically present bleeding on probing (BOP), suppuration, dental mobility, changes in the levels of insertion (clinical attachment loss [CAL]), and bone loss, ultimately leading to extraction or loss of teeth, which has a significant impact on the individual's oral health-related quality of life.…”

Differential Expressions of ADAM28 and ADAMTSL3 in Gingival Tissue of Patients with Periodontitis

“…As the 6 th most prevalent ubiquitous and irreversible chronic inflammatory disease in humans, periodontitis nowadays affects nearly 14% of the world population according to the World Health Organization (WHO) (Alsalleeh et al 2022, Cardenas et al 2022. Periodontitis was reported to be strongly associated with age, gender, oral hygiene, smoking status, ethnicity, lower socioeconomic status, and systemic diseases (Tabassum et al 2022), including obesity, diabetes, nonalcoholic liver disease, and cancers (Mei et al 2023, Zhang et al 2023.…”

“…Periodontitis was reported to be strongly associated with age, gender, oral hygiene, smoking status, ethnicity, lower socioeconomic status, and systemic diseases (Tabassum et al 2022), including obesity, diabetes, nonalcoholic liver disease, and cancers (Mei et al 2023, Zhang et al 2023. Periodontitis with a high prevalence in older adults was pathologically caused by dysbiotic changes of the subgingival microbiota attached to the tooth, and finally leading to bone destruction, tooth movement and tooth loss if left untreated (Cardenas et al 2022, Liaw et al 2022. Thereafter, patients with periodontitis usually showed affects their quality of life by the decreased self-confidence and poor esthetics (Elgendy et al 2023).…”

“…DNA methylation is a widely studied epigenetic mechanism due to its role in disease processes (Liaw et al 2022), which is relevant to the pathogenesis of immunoinflammatory diseases, such as periodontitis (Azevedo et al 2020, Schulz et al 2016. DNA methylation modifications could exhibit a more stable nature of gene regulation without changing gene sequence (Wang et al 2021), provoke alterations in cellular functioning, and favor the risk of appearance and/or progression of periodontitis (Cardenas et al 2022). For example, TLR2 upregulation in association with single CpG-sites' methylation from the TLR2 gene promoter was found in peripheric mononuclear blood cells from apical periodontitis subjects (Bordagaray et al 2022).…”