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Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. The disease is characterized by destruction of the alveolar bone due to an aberrant host inflammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported several suggestive susceptibility loci. Here, we conducted a GWAS using a German and Dutch case-control sample of aggressive periodontitis (AgP, 896 cases, 7,104 controls), a rare but highly severe and early-onset form of periodontitis, validated the associations in a German sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positive findings were replicated in a Turkish sample of AgP (223 cases, 564 controls). A locus at SIGLEC5 (sialic acid binding Ig-like lectin 5) and a chromosomal region downstream of the DEFA1A3 locus (defensin alpha 1-3) showed association with both disease phenotypes and were associated with periodontitis at a genome-wide significance level in the pooled samples, with P = 1.09E-08 (rs4284742,-G; OR = 1.34, 95% CI = 1.21-1.48) and P = 5.48E-10 (rs2738058,-T; OR = 1.28, 95% CI = 1.18-1.38), respectively. SIGLEC5 is expressed in various myeloid immune cells and classified as an inhibitory receptor with the potential to mediate tyrosine phosphatases SHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils and mucosal surfaces and a role in phagocyte-mediated host defense. This study identifies the first shared genetic risk loci of AgP and CP with genome-wide significance and highlights the role of innate and adaptive immunity in the etiology of periodontitis., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aim: Many studies investigated the role of genetic variants in periodontitis, but few were established as risk factors. We aimed to validate the associations of recent candidate genes in aggressive periodontitis (AgP)., Material and Methods: We analysed 23 genes in 600 German AgP patients and 1441 controls on the Illumina custom genotyping array Immunochip. We tested a suggestive association in a Dutch and German/Austrian AgP case-control sample, and a German chronic periodontitis (CP) case-control sample using Sequenom iPlex assays. We additionally tested the common known risk variant rs1333048 of the gene ANRIL for its association in a Turkish and Italian population., Results: None of the analysed genes gave statistical evidence for association. Upon covariate adjustment for smoking and gender, in the pooled German-Austrian AgP sample, IL10 SNP rs6667202 was associated with p = 0.016, OR = 0.77 (95% CI = 0.6-0.95), and in the Dutch AgP sample, adjacent IL10 SNP rs61815643 was associated with p = 0.0009, OR = 2.31 (95% CI = 1.4-3.8). At rs61815643, binding of the transcription factor PPARG was predicted. ANRIL rs1333048 was associated in the Turkish sample (pallelic = 0.026, OR = 1.67 [95% CI = 1.11-2.60])., Conclusions: Previous candidate genes carry no susceptibility factors for AgP. Association of IL-10 rs61815643 with AgP is suggested. ANRIL is associated with periodontitis across different populations., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The association between periodontitis and systemic diseases, including cardiovascular diseases and diabetes mellitus (DM), has been recognized repeatedly. Paraoxonase-1 (PON-1) is involved in the prevention of atherosclerosis, and decreased enzyme activity in patients with DM has been shown. The aim of this study is to investigate a possible correlation between decreased PON-1 activity and the association between impaired glucose metabolism or DM and periodontitis., Methods: PON-1 phenotype distribution and enzyme activities were characterized by measuring the hydrolysis of phenylacetate and paraoxon in serum samples of 87 patients with type 2 DM and 46 patients with pre-DM showing impaired fasting plasma glucose and/or impaired oral glucose tolerance. The control group comprised 64 individuals with normal fasting plasma glucose and normal glucose tolerance. Altogether, 154 study participants were available for complete clinical periodontal examination., Results: No difference in periodontitis prevalence existed between the study groups. However, patients with DM had an increased risk of suffering from generalized periodontitis (adjusted odds ratio = 4.05; 95% confidence interval = 1.24 to 13.18; P = 0.02), and their PON-1 activity was reduced compared to controls. In contrast, patients with pre-DM showed neither an increased periodontitis risk nor an impaired paraoxonase status. PON-1 was not associated directly with periodontitis. Nevertheless, concerning patients with DM, poor oral hygiene, male sex, and PON-1 phenotype were found to be significant predictors for periodontitis extent., Conclusions: Type 2 DM, but not a prediabetic state, increases the risk of generalized periodontitis. PON-1 status in patients with type 2 DM may contribute to this association.

Aim: Involvement of TLR2 in the pathophysiology of periodontitis has widely been discussed, but hitherto, no validated genetic associations were reported. Previous association studies lacked sufficient statistical power and adequate haplotype information to draw unambiguous conclusions. The aim of this study was to comprehensively investigate TLR2 linkage disequilibrium (LD) regions for their potential associations with periodontitis in two large analysis populations of aggressive (AgP) and chronic periodontitis (CP) of North West European descent., Materials and Methods: The study population comprised 598 AgP patients, 914 CP patients and 1804 healthy controls. Analysis of TLR2 LD regions was performed with haplotype tagging SNPs (tagSNPs) using SNPlex and TaqMan genotyping assays. Genotypic, dominant, multiplicative, and recessive genetic models were tested. The genotypes were adjusted for the covariates smoking, diabetes, and gender. Resequencing was performed by Sanger technology., Results: Upon covariate adjustment and correction for multiple testing, no tagSNPs showed significant associations with AgP or CP. Targeted resequencing of exon 3 in 47 AgP cases identified carriership of two common and three rare variants., Conclusion: Common LD regions of TLR2 do not show genetic associations with periodontitis in the North West European population. Resequencing of exon 3 could not identify disease-associated rare variants in TLR2., (© 2012 John Wiley & Sons A/S.)

COX-2 plays an important role in periodontitis by mediating inflammatory reactions in periodontal tissues, and the COX-2 polymorphisms rs20417 and rs689466 have been reported to be associated with periodontitis in populations of Taiwanese and Chinese ethnicity. To test whether these variants were associated with periodontitis in populations of European ethnicity, we genotyped the single-nucleotide polymorphisms (SNPs) rs689466 and rs6681231, the latter a haplotype tagging SNP (htSNP) for rs20417 (r2>0.95), in our large-analysis population of individuals with aggressive (n = 532) and chronic periodontitis (n = 1052), and 2873 healthy control individuals. The rare G allele of htSNP rs6681231 was associated with aggressive periodontitis prior to and after adjustment for the covariates smoking, diabetes, and gender, with an odds ratio of 1.57 (95% confidence interval 1.18-2.08; p = 0.002). The validation of the association of rs20417 by the htSNP rs6681231 provides evidence for a general genetic risk of COX-2 variants in the pathogenesis of periodontitis.

Periodontal diseases are complex inflammatory diseases and affect up to 20% of the worldwide population. An unbalanced reaction of the immune system toward microbial pathogens is considered as the key factor in the development of periodontitis. Defensins have a strong antimicrobial function and are important contributors of the immune system toward maintaining health. Here, we present the first systematic association study of DEFB1. Using a haplotype-tagging single nucleotide polymorphism (SNP) approach, including described promoter SNPs of DEFB1, we investigated the associations of the selected variants in a large population (N=1337 cases and 2887 ethnically matched controls). The 3' untranslated region SNP, rs1047031, showed the most significant association signal for homozygous carriers of the rare A allele (P=0.002) with an increased genetic risk of 1.3 (95% confidence interval: 1.11-1.57). The association was consistent with the specific periodontitis forms: chronic periodontitis (odds ratio=2.2 (95% confidence interval: 1.16-4.35), P=0.02), and aggressive periodontitis (odds ratio=1.3 (95% confidence interval 1.04-1.68), P=0.02). Sequencing of regulatory and exonic regions of DEFB1 identified no other associated variant, pointing toward rs1047031 as likely being the causative variant. Prediction of microRNA targets identified a potential microRNA-binding site at the position of rs1047031.

The aim of the study was to assess whether genotypes in the Toll-like receptor 4 gene and in the promoter of the interleukin-18 gene are associated with the susceptibility to chronic periodontitis. 108 chronic periodontitis patients and 76 controls were genotyped for c.896A>G/1196C>T (TLR4 gene) and for c.-368G>C/ c.-838C>A (IL-18 promoter). There were no significant differences in genotype and allele distributions between the study groups. Periodontitis severity in patients with TLR4 c.896AG/1196CT genotype was significantly higher than wildtype carriers. The percentage of teeth with clinical attachment loss > or = 5 mm was 77.3% and 58.8%, respectively (p < or = 0.006, t-test). All subjects were further classified into carriers and non-carriers of at least one variant of each gene. A logistic regression analysis adjusted for gender, smoking, and age showed no association between gene variant carrier status and periodontitis (OR = 1.98, 95% CI 0.61-6.39). The results did not show that IL-18 and TLR4 variants have an effect on the susceptibility to chronic periodontitis. Considering the low number of periodontitis patients carrying TLR4 variants (11%), a comparison of the periodontitis severity depending on the genotype has to be interpreted cautiously.