Prioritization of Candidate Genes for Periodontitis Using Multiple Computational Tools

Zhan, Yuanbo; Zhang, Ruimin; Lv, Hongchao; Song, Xuejing; Xu, Xiaoman; Chai, Lin; Lv, Wenhua; Shang, Zhenwei; Jiang, Yongshuai; Zhang, Ruijie

doi:10.1902/jop.2014.130523

Cited by 40 publications

(40 citation statements)

References 64 publications

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“…13 MMP7 upregulation that we found, support the knowledge of previous functional studies. [16][17][18][19] As a result of our data we found tumor necrosis factor receptor superfamily member 17 (TNFRSF17), Fc receptor-like 5 (FCRL5), marginal zone B and B1 cell-specific protein (MZB1) ve desmocollin-1 (DSC1) genes presented significant expression differences. In our study group, TNFRSF17, FCRL5 and MZB1 genes were upregulated, where as DSC1 gene was downregulated.…”

Section: Discussionmentioning

confidence: 65%

Gene‐Expression Profiles in Generalized Aggressive Periodontitis: A Gene Network‐Based Microarray Analysis

Güzeldemir-Akçakanat

Sunnetci‐Akkoyunlu

Orucguney

et al. 2016

Journal of Periodontology

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Functions of the identified genes that were involved in gene networks were cellular development, cell growth and proliferation, cellular movement, cell-cell signaling and interaction, humoral immune response, protein synthesis, cell death and survival, cell population and organization, organismal injury and abnormalities, molecular transport, and small-molecule biochemistry. The data suggest new networks that have important functions as humoral immune response and organismal injury/abnormalities. Future analyses may facilitate proteomic profiling analyses to identify gene-expression patterns related to clinical outcome.

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Section: Discussionmentioning

confidence: 65%

Gene‐Expression Profiles in Generalized Aggressive Periodontitis: A Gene Network‐Based Microarray Analysis

Güzeldemir-Akçakanat

Sunnetci‐Akkoyunlu

Orucguney

et al. 2016

Journal of Periodontology

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“…Additionally, in vitro investigations demonstrated that periodontitis-associated bacterial DNA upregulates several genes of the innate immune response and induces the production of proinflammatory cytokines through TLR9 in macrophages and epithelial cells (20)(21)(22). In fact, a recent study has identified the TLR9 gene as one of the most promising candidate genes involved in the pathogenesis of periodontitis by using an integrative gene prioritization method (23). Collectively, emerging evidence suggests that TLR9-triggered immune responses may constitute a novel inflammatory pathway in periodontitis (24).…”

mentioning

confidence: 99%

Toll-Like Receptor 9-Mediated Inflammation Triggers Alveolar Bone Loss in Experimental Murine Periodontitis

et al. 2015

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Chronic periodontitis is a local inflammatory disease induced by a dysbiotic microbiota and leading to destruction of the toothsupporting structures. Microbial nucleic acids are abundantly present in the periodontium, derived through release after phagocytic uptake of microbes and/or from biofilm-associated extracellular DNA. Binding of microbial DNA to its cognate receptors, such as Toll-like receptor 9 (TLR9), can trigger inflammation. In this study, we utilized TLR9 knockout (TLR9 ؊/؊ ) mice and wild-type (WT) controls in a murine model of Porphyromonas gingivalis-induced periodontitis and report the first in vivo evidence that TLR9 signaling mediates the induction of periodontal bone loss. P. gingivalis-infected WT mice exhibited significantly increased bone loss compared to that in sham-infected WT mice or P. gingivalis-infected TLR9 ؊/؊ mice, which were resistant to bone loss. Consistent with this, the expression levels of interleukin 6 (IL-6), tumor necrosis factor (TNF), and receptoractivator of nuclear factor kappa B ligand (RANKL) were significantly elevated in the gingival tissues of the infected WT mice but not in infected TLR9؊/؊ mice compared to their levels in controls. Ex vivo studies using splenocytes and bone marrow-derived macrophages revealed significantly diminished cytokine production in TLR9؊/؊ cells relative to the cytokine production in WT cells in response to P. gingivalis, thereby implicating TLR9 in inflammatory responses to this organism. Intriguingly, compared to the cytokine production in WT cells, TLR9؊/؊ cells exhibited significantly decreased proinflammatory cytokine production upon challenge with lipopolysaccharide (LPS) (TLR4 agonist) or Pam3Cys (TLR2 agonist), suggesting possible cross talk between TLR9, TLR4, and TLR2. Collectively, our results provide the first proof-of-concept evidence implicating TLR9-triggered inflammation in periodontal disease pathogenesis, thereby identifying a new potential therapeutic target to control periodontal inflammation.

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“…Three genes that were prioritized in the Zhan et al (2014) ). Noteworthy, VAV1 had been prioritized by the parent single-marker GWAS for its association with moderate CP, and its gene-centric association in the present analysis had a p value of 4.4 × 10 -5 .…”

Section: Gene-centric Association Analysis Resultsmentioning

confidence: 99%

“…We used LocusZoom 1.1 (Pruim et al, 2010) to visualize the genes and loci of interest. We additionally examined genes that were previously implicated in CP (Laine et al, 2012) or were prioritized via bioinformatics tools (Zhan et al, 2014). A comprehensive list of all genes' association results was also generated and has been made available at the http://genomewide.net online repository with links provided in the results section.…”

Section: Gene-centric Association Testingmentioning

confidence: 99%

Chronic Periodontitis Genome-wide Association Studies

et al. 2014

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Recent genome-wide association studies (GWAS) of chronic periodontitis (CP) offer rich data sources for the investigation of candidate genes, functional elements, and pathways. We used GWAS data of CP ( n = 4,504) and periodontal pathogen colonization ( n = 1,020) from a cohort of adult Americans of European descent participating in the Atherosclerosis Risk in Communities study and employed a MAGENTA approach ( i.e., meta-analysis gene set enrichment of variant associations) to obtain gene-centric and gene set association results corrected for gene size, number of single-nucleotide polymorphisms, and local linkage disequilibrium characteristics based on the human genome build 18 (National Center for Biotechnology Information build 36). We used the Gene Ontology, Ingenuity, KEGG, Panther, Reactome, and Biocarta databases for gene set enrichment analyses. Six genes showed evidence of statistically significant association: 4 with severe CP ( NIN, p = 1.6 × 10−7; ABHD12B, p = 3.6 × 10−7; WHAMM, p = 1.7 × 10−6; AP3B2, p = 2.2 × 10−6) and 2 with high periodontal pathogen colonization (red complex– KCNK1, p = 3.4 × 10−7; Porphyromonas gingivalis–DAB2IP, p = 1.0 × 10−6). Top-ranked genes for moderate CP were HGD ( p = 1.4 × 10−5), ZNF675 ( p = 1.5 × 10−5), TNFRSF10C ( p = 2.0 × 10−5), and EMR1 ( p = 2.0 × 10−5). Loci containing NIN, EMR1, KCNK1, and DAB2IP had showed suggestive evidence of association in the earlier single-nucleotide polymorphism–based analyses, whereas WHAMM and AP2B2 emerged as novel candidates. The top gene sets included severe CP (“endoplasmic reticulum membrane,” “cytochrome P450,” “microsome,” and “oxidation reduction”) and moderate CP (“regulation of gene expression,” “zinc ion binding,” “BMP signaling pathway,” and “ruffle”). Gene-centric analyses offer a promising avenue for efficient interrogation of large-scale GWAS data. These results highlight genes in previously identified loci and new candidate genes and pathways possibly associated with CP, which will need to be validated via replication and mechanistic studies.

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Prioritization of Candidate Genes for Periodontitis Using Multiple Computational Tools

Abstract: A combination of computational tools will be useful in mining candidate genes for periodontitis. These theoretical results provide new clues for experimental biologists to plan targeted experiments.

Cited by 40 publications

References 64 publications

Gene‐Expression Profiles in Generalized Aggressive Periodontitis: A Gene Network‐Based Microarray Analysis

Gene‐Expression Profiles in Generalized Aggressive Periodontitis: A Gene Network‐Based Microarray Analysis

Toll-Like Receptor 9-Mediated Inflammation Triggers Alveolar Bone Loss in Experimental Murine Periodontitis

Chronic Periodontitis Genome-wide Association Studies

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