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Aim: We aimed to assess the association of different genotypes with increased aggressive periodontitis susceptibility by studying functional relevant variants in the pathogen-recognition receptor Toll-like receptor 4 (TLR4) and variants in the promoter region of the pro-inflammatory cytokine interleukin-18 (IL-18). Material and Methods: One hundred and eleven patients with aggressive periodontitis and 80 periodontally healthy controls were genotyped for four functional variants in the TLR4 gene (c.896A>G and c.1196C>T) and in the IL-18 promoter (c.-368G>C and c.-838C>A). The genotype and allele frequencies, as well as the frequency of combined genotypes were compared between study groups. Results: There were no statistical differences in genotype and allele frequencies within the four variants between the groups. All study subjects were further classified into carriers and non-carriers of at least one variant of both genes. The logistic regression analysis adjusted for gender and smoking showed no association between carrier status of at least one variant of both genes and periodontal status (OR=1.41, 95% CI: 0.43-4.70). Conclusions: Our results reject the hypothesis that functionally relevant IL-18 and TLR4 gene mutations have a major effect on aggressive periodontitis susceptibility alone or in combination. [ABSTRACT FROM AUTHOR]

AIM: The autosomal-recessive Papillon-Lefèvre syndrome (PLS) is characterized by severe aggressive periodontitis, combined with palmoplantar hyperkeratosis, and is caused by mutations in the Cathepsin C (CTSC) gene. This study aimed to identify CTSC mutations in different PLS phenotypes, including atypical forms and isolated pre-pubertal aggressive periodontitis (PAP). MATERIAL AND METHODS: Thirteen families with different phenotypes were analysed by direct sequencing of the entire coding region and the regulatory regions of CTSC. The function of novel mutations was tested with enzyme activity measurements. RESULTS: In 11 of 13 families, 12 different pathogenic CTSC mutations were found in 10 typical PLS patients, three atypical cases and one PAP patient. Out of four novel mutations, three result in protein truncation and are thus considered to be pathogenic. The homozygous c.854C>T nucleotide exchange (p.P285L) was associated with an almost complete loss of enzyme activity. The observed phenotypic heterogeneity could not be associated with specific genotypes. CONCLUSIONS: The phenotypic variability of the PLS associated with an identical genetic background may reflect the influence of additional genetic or environmental factors on disease characteristics. CTSC mutation analyses should be considered for differential diagnosis in all children suffering from severe aggressive periodontitis. [ABSTRACT FROM AUTHOR]

Aim: Epidemiological and clinical studies indicated a relationship of periodontitis with rheumatoid arthritis (RA). We aimed to identify shared genetic susceptibility loci of RA and periodontitis., Materials and Methods: Forty-seven risk genes of genome-wide significance of RA and SLE were genotyped in a German case-control sample of aggressive periodontitis (AgP), using Immunochip genotyping arrays (Illumina, 600 cases, 1440 controls) and Affymetrix 500 K Genotyping Arrays (280 cases and 983 controls). Significant associations were replicated in 168 Dutch AgP cases and 679 controls and adjusted for the confounders smoking and sex., Results: Variants at IRF5 and PRDM1 showed association with AgP. Upon covariate adjustment for smoking and sex, the most strongly associated variant at IRF5 was the rare variant rs62481981 (ppooled  = 0.0012, odds ratio [OR] = 3.1, 95% confidence interval [95% CI] = 1.6-6.1; 801 cases, 1476 controls).Within PRDM1 it was rs6923419 (ppooled  = 0.004, OR = 0.7, 95% CI = 0.6-0.9; 833 cases, 1440 controls). The associations lost significance after correction for multiple testing in the replication. Both genes are implicated in beta-interferon signalling and are also genome-wide associated with SLE and inflammatory bowel disease., Conclusion: The study gives no definite evidence for a pathogenic genetic link of periodontitis and RA but suggests IRF5 and PRDM1 as shared susceptibility factors., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: Periodontitis (PD) is influenced by genetic as well as lifestyle and socio-economic factors. Epidemiological studies show that men are at greater risk of severe forms of PD, suggesting interplay between sex and genetic factors. We aimed to systematically analyse patients with aggressive periodontitis (AgP) for gene-sex interactions., Materials and Methods: Three hundred and twenty-nine German AgP cases and 983 controls were genotyped with Affymetrix 500K Arrays and were analysed by logistic regression analysis. The most significant gene-sex interaction was replicated in an independent sample of 382 German/Austrian AgP cases and 489 controls., Results: Ten single-nucleotide polymorphisms (SNPs) in strong linkage disequilibrium (r(2)  > 0.85) upstream the gene neuropeptide Y (NPY) suggested gene-sex interaction (p < 5 × 10(-5) ). SNP rs198712 showed the strongest association in interaction with sex (p = 5.4 × 10(-6) ) with odds ratios in males and females of 1.63 and 0.69 respectively. In the replication, interaction of sex with rs198712 was verified with p = 0.022 (pooled p = 4.03 × 10(-6) ) and similar genetic effects. Analysis of chromatin elements from ENCODE data revealed tissue-specific transcription at the associated non-coding region., Conclusion: This study is the first to observe a sexually dimorphic role of alleles at NPY in humans and support previous genome-wide findings of a role of NPY in severe PD., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: Identification of variants within genes SLC23A1 and SLC23A2 coding for vitamin C transporter proteins associated with aggressive (AgP) and chronic periodontitis (CP)., Material and Methods: Employment of three independent case-control samples of AgP (I. 283 cases, 979 controls; II. 417 cases, 1912 controls; III. 164 cases, 357 controls) and one sample of CP (1359 cases, 1296 controls)., Results: Stage 1: Among the tested single-nucleotide polymorphisms (SNPs), the rare allele (RA) of rs6596473 in SLC23A1 showed nominal significant association with AgP (p = 0.026, odds ratio [OR] 1.26, and a highly similar minor allele frequency between different control panels. Stage 2: rs6596473 showed no significant association with AgP in the replication with the German and Dutch case-control samples. After pooling the German AgP populations (674 cases, 2891 controls) to significantly increase the statistical power (SP = 0.81), rs6596473 RA showed significant association with AgP prior to and upon adjustment with the covariates smoking and gender with padj  = 0.005, OR = 1.35. Stage 3: RA of rs6596473 showed no significant association with severe CP., Conclusion: SNP rs6596473 of SLC23A1 is suggested to be associated with AgP. These results add to previous reports that vitamin C plays a role in the pathogenesis of periodontitis., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.)

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.)