title: Identification of pathogen and host-response markers correlated with periodontal disease.
abstract: BACKGROUND
  Periodontitis is the major cause of tooth loss in adults and is linked to systemic illnesses, such as cardiovascular disease and stroke. The development of rapid point-of-care (POC) chairside diagnostics has the potential for the early detection of periodontal infection and progression to identify incipient disease and reduce health care costs. However, validation of effective diagnostics requires the identification and verification of biomarkers correlated with disease progression. This clinical study sought to determine the ability of putative host- and microbially derived biomarkers to identify periodontal disease status from whole saliva and plaque biofilm.
  
  
  METHODS
  One hundred human subjects were equally recruited into a healthy/gingivitis group or a periodontitis population. Whole saliva was collected from all subjects and analyzed using antibody arrays to measure the levels of multiple proinflammatory cytokines and bone resorptive/turnover markers.
  
  
  RESULTS
  Salivary biomarker data were correlated to comprehensive clinical, radiographic, and microbial plaque biofilm levels measured by quantitative polymerase chain reaction (qPCR) for the generation of models for periodontal disease identification. Significantly elevated levels of matrix metalloproteinase (MMP)-8 and -9 were found in subjects with advanced periodontitis with Random Forest importance scores of 7.1 and 5.1, respectively. The generation of receiver operating characteristic curves demonstrated that permutations of salivary biomarkers and pathogen biofilm values augmented the prediction of disease category. Multiple combinations of salivary biomarkers (especially MMP-8 and -9 and osteoprotegerin) combined with red-complex anaerobic periodontal pathogens (such as Porphyromonas gingivalis or Treponema denticola) provided highly accurate predictions of periodontal disease category. Elevated salivary MMP-8 and T. denticola biofilm levels displayed robust combinatorial characteristics in predicting periodontal disease severity (area under the curve = 0.88; odds ratio = 24.6; 95% confidence interval: 5.2 to 116.5).
  
  
  CONCLUSIONS
  Using qPCR and sensitive immunoassays, we identified host- and bacterially derived biomarkers correlated with periodontal disease. This approach offers significant potential for the discovery of biomarker signatures useful in the development of rapid POC chairside diagnostics for oral and systemic diseases. Studies are ongoing to apply this approach to the longitudinal predictions of disease activity.
authors.affiliation: Department of Periodontics and Oral Medicine, Michigan Center for Oral Health Research, University of Michigan School of Dentistry, Ann Arbor, MI 48106, USA.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Ramseier
authors.forename: Janet S
authors.initials: JS
authors.lastname: Kinney
authors.forename: Amy E
authors.initials: AE
authors.lastname: Herr
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: James V
authors.initials: JV
authors.lastname: Sugai
authors.forename: Charlie A
authors.initials: CA
authors.lastname: Shelburne
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Rayburn
authors.forename: Huu M
authors.initials: HM
authors.lastname: Tran
authors.forename: Anup K
authors.initials: AK
authors.lastname: Singh
authors.forename: William V
authors.initials: WV
authors.lastname: Giannobile
mesh_terms: D000328:Adult; D000368:Aged; D016301:Alveolar Bone Loss / Q000145:classification / Q000382:microbiology; D001419:Bacteria / Q000145:classification*; D018441:Biofilms; D015415:Biomarkers / Q000032:analysis; D055113:Chronic Periodontitis / Q000382:microbiology; D003773:Dental Plaque / Q000382:microbiology; D018450:Disease Progression; D005260:Female; D005891:Gingivitis / Q000382:microbiology; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D007378:Interleukins / Q000032:analysis; D039841:Leukocyte L1 Antigen Complex / Q000032:analysis; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D008875:Middle Aged; D053244:Osteoprotegerin / Q000032:analysis; D017622:Periodontal Attachment Loss / Q000145:classification / Q000382:microbiology; D010510:Periodontal Diseases / Q000145:classification / Q000382:microbiology*; D010519:Periodontium / Q000382:microbiology; D016966:Porphyromonas gingivalis / Q000302:isolation & purification; D012463:Saliva / Q000382:microbiology; D048373:Treponema denticola / Q000302:isolation & purification; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007378:Interleukins; D039841:Leukocyte L1 Antigen Complex; D053244:Osteoprotegerin; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9