title: TLR4 Asp299Gly polymorphism may be protective against chronic periodontitis.
abstract: OBJECTIVE
  Periodontitis results from interplay between genetic and environmental factors. Single nucleotide polymorphisms (SNPs) in the coding region of the toll-like receptor 4 gene (TLR4) may be associated with periodontitis, although previous studies have been inconclusive. Moreover, the interaction between environmental factors, such as cigarette smoking (a major risk factor for periodontitis), and Porphyromonas gingivalis (a major periodontal pathogen) with the TLR4 coding region Asp299Gly SNP (rs4986790; a SNP associated with lipopolysaccharide-mediated inflammatory responses in periodontitis), have been largely ignored in previous reports. Therefore, the objective of this study was to examine the association between TLR4 Asp299Gly (rs4986790) with alveolar bone height loss (ABHL) and periodontitis, accounting for interactions between this SNP with smoking and P. gingivalis prevalence. The CD14/-260 SNP (rs2569190) served as a control, as a recent meta-analysis suggested no relationship between this SNP and periodontitis.
  
  
  METHODS
  This multicenter study included 617 participants who had rheumatoid arthritis or osteoarthritis. This report presents a secondary outcome from the primary case-control study examining the relationship of periodontitis with established rheumatoid arthritis. The Centers for Disease Control/American Academy of Periodontology case definitions of periodontitis were used for this analysis. Participants received a full-mouth clinical periodontal examination and panoramic radiograph. Percentage ABHL was measured on posterior teeth. The TLR4 Asp299Gly and CD14/-260 SNPs were selected a priori and genotypes were determined using the ImmunoChip array (Illumina(®) ). Minor allele frequencies and associations with periodontitis and ABHL did not differ according to rheumatoid arthritis vs. osteoarthritis status; therefore, data from these two groups were pooled. The presence of P. gingivalis was detected in subgingival plaque by PCR. Multivariate ordinal logistic regression examined associations between the SNPs and periodontitis or ABHL. SNP interactions with smoking and P. gingivalis were analyzed.
  
  
  RESULTS
  A significant, negative interaction was observed between the TLR4 SNP and the presence of P. gingivalis (p = 0.045) with respect to periodontitis. The TLR4 minor variant was also associated with less ABHL: 16.8% of individuals with low ABHL, 9.0% with moderate ABHL and 11.2% with high ABHL had the minor allele [p = 0.029; odds ratio = 0.58 (95% confidence interval: 0.36-0.95)]. The interaction between the TLR4 SNP and smoking was not significant with respect to periodontitis or ABHL. The CD14 SNP was not associated with periodontitis or ABHL.
  
  
  CONCLUSIONS
  The TLR4 Asp299Gly SNP significantly interacted with P. gingivalis in conferring a decreased risk of periodontitis and may be protective against ABHL, a feature of periodontitis. Agents blocking TLR4 signaling, a strategy currently under investigation for the treatment of other inflammatory conditions, may warrant investigation in the context of periodontitis related to the presence of P. gingivalis.
authors.affiliation: University of Nebraska Medical Center College of Dentistry, Lincoln, NE, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Sellers
authors.affiliation: Department of Surgical Specialties, University of Nebraska Medical Center College of Dentistry, Lincoln, NE, USA.|Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Payne
authors.affiliation: Department of Biostatistics, University of Nebraska Medical Center College of Public Health, Omaha, NE, USA.
authors.forename: F
authors.initials: F
authors.lastname: Yu
authors.affiliation: Omaha Veterans Affairs Medical Center and Department of Internal Medicine, University of Nebraska Medical Center College of Medicine, Omaha, NE, USA.|Department of Epidemiology, University of Nebraska Medical Center College of Public Health, Omaha, NE, USA.
authors.forename: T D
authors.initials: TD
authors.lastname: LeVan
authors.affiliation: Department of Oral Biology, University of Florida College of Dentistry, Gainesville, FL, USA.
authors.forename: C
authors.initials: C
authors.lastname: Walker
authors.affiliation: Omaha Veterans Affairs Medical Center and Department of Internal Medicine, University of Nebraska Medical Center College of Medicine, Omaha, NE, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Mikuls
mesh_terms: D016022:Case-Control Studies; D055113:Chronic Periodontitis / Q000235:genetics*; D006801:Humans; D010518:Periodontitis; D020641:Polymorphism, Single Nucleotide; D016966:Porphyromonas gingivalis; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4
keywords: Porphyromonas gingivalis; alveolar bone loss; cluster of differentiation (CD) antigens; periodontitis; single nucleotide polymorphism; toll-like receptors