Abstract
BackgroundWe have previously demonstrated a Toll-like receptor (TLR)-mediated hyper-responsive phenotype in our cohort of localized aggressive periodontitis (LAP) individuals. However, mechanisms related to this phenotype are still not clear in the literature. The objective of this cross-sectional study is to examine the role of epigenetic regulation, specifically DNA methylation status of genes in the TLR pathway in this cohort. Peripheral blood was collected from 20 LAP patients and 20 healthy unrelated controls. Whole blood was stimulated with 1 μl (100 ng/μl) of purified Escherichia coli lipopolysaccharide (LPS) for 24 h and cyto/chemokines in the supernatants analyzed by Luminex multiplex assays. Genomic DNA extracted from buffy coats prepared from a second tube of whole blood was used for DNA methylation analysis by pyrosequencing of seven TLR signaling genes (FADD, MAP3K7, MYD88, IL6R, PPARA, IRAK1BP1, RIPK2).ResultsSignificant differences in the methylation status were observed at specific CpG positions in LAP patients compared to healthy controls and interestingly also between severe and moderate LAP. Specifically, subjects with moderate LAP presented hypermethylation of both the upregulating (MAP3K7, MYD88, IL6R, and RIPK2) and downregulating (FADD, IRAK, and PPARA) genes, while severe LAP presented hypomethylation of these genes. Further analysis on CpG sites with significant differences in methylation status correlates with an increased pro-inflammatory cytokine profile for LAP patients.ConclusionsOur findings suggest that epigenetic modifications of genes in the TLR pathway may orchestrate the thresholds for balancing induction and prevention of tissue destruction during the course of disease, and thus differ significantly at different stages of the disease, where moderate LAP shows hypermethylation and severe LAP shows hypomethylation of several genes.Trial registrationhttps://clinicaltrials.gov, NCT01330719
Highlights
We have previously demonstrated a Toll-like receptor (TLR)-mediated hyper-responsive phenotype in our cohort of localized aggressive periodontitis (LAP) individuals
The objective of this study is to examine the role of Deoxyribonucleic acid (DNA) methylation status in the promoter regions of genes involved in TLR signaling pathways in LAP patients, potentially providing a link between methylation pattern and disease as well as the degree of inflammatory hyper-responsiveness
The DNA methylation status varied among the analyzed dinucleotide CpG sites, with several significant differences in methylation pattern in the promoter region for each of the seven genes involved in TLR signaling when comparing healthy controls, moderate LAP, and severe LAP patients
Summary
We have previously demonstrated a Toll-like receptor (TLR)-mediated hyper-responsive phenotype in our cohort of localized aggressive periodontitis (LAP) individuals. Mechanisms related to this phenotype are still not clear in the literature The objective of this cross-sectional study is to examine the role of epigenetic regulation, DNA methylation status of genes in the TLR pathway in this cohort. The etiology of inflammatory periodontal diseases involves a multitude of factors, both intrinsic and extrinsic, that together determine clinical presentation. This disease is first initiated from a previous infection of the gingival. Previous research from our group has shown that LAP individuals, and to a lesser extent their unaffected siblings, exhibit an elevated immune response when compared to healthy controls, further suggesting that genetics may play a role in this hyper-responsiveness [3]. It has been shown that a portion of these inflammatory genes may be regulated by epigenetic modifications [10]
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