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Aims: Various studies have reported that young European women are more likely to develop early-onset periodontitis compared to men. A potential explanation for the observed variations in sex and age of disease onset is the natural genetic variation within the autosomal genomes. We hypothesized that genotype-by-sex (G × S) interactions contribute to the increased prevalence and severity., Materials and Methods: Using the case-only design, we tested for differences in genetic effects between men and women in 896 North-West European early-onset cases, using imputed genotypes from the OmniExpress genotyping array. Population-representative 6823 controls were used to verify that the interacting variables G and S were uncorrelated in the general population., Results: In total, 20 loci indicated G × S associations (P < 0.0005), 3 of which were previously suggested as risk genes for periodontitis (ABLIM2, CDH13, and NELL1). We also found independent G × S interactions of the related gene paralogs MACROD1/FLRT1 (chr11) and MACROD2/FLRT3 (chr20). G × S-associated SNPs at CPEB4, CDH13, MACROD1, and MECOM were genome-wide-associated with heel bone mineral density (CPEB4, MECOM), waist-to-hip ratio (CPEB4, MACROD1), and blood pressure (CPEB4, CDH13)., Conclusions: Our results indicate that natural genetic variation affects the different heritability of periodontitis among sexes and suggest genes that contribute to inter-sex phenotypic variation in early-onset periodontitis., (© 2021 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Periodontitis has low-prevalence, highly severe disease manifestations with an early onset and rapid progression. The diagnosis is based on severe destruction of the alveolar bone in adolescents and young adults. Genetic susceptibility variants and smoking are well-established risk factors, but their interactions in modifying disease susceptibility have not been studied. We aimed to identify genetic risk variants of early-onset periodontitis that unmask their effects on tobacco smoke exposure. To this end, we analyzed 79,780,573 common variants in 741 northwest Europeans diagnosed to have >30% bone loss at >2 teeth before 35 y of age, using imputed genotypes of the OmniExpress BeadChip. Never versus ever smokers were compared in a logistic regression analysis via a case-only approach. To explore the effect of tobacco smoke on the expression of the G×S-associated genes, cultures of primary gingival fibroblasts ( n = 9) were exposed to cigarette smoke extract, and transcripts were quantified by reverse transcription polymerase chain reaction. We identified 16 loci for which our analysis suggested an association with G×S increased disease risk ( P < 5 × 10 -5 ). Nine loci had previously been reported to be associated with spirometric measures of pulmonary function by an earlier G×S genome-wide association study. Genome-wide significant cis expression quantitative trait loci were reported for G×S-associated single-nucleotide polymorphisms at ST8SIA1 and SOST , indicating a causal role of these genes in tobacco-related etiopathology. Notably, SOST is a negative regulator of bone growth, and ST8SIA1 has a role in tissue remodeling. Cigarette smoke extract significantly altered the expression of 2 associated genes: SSH1 ( P = 5 × 10 -07 ), which is required for NF-κB activation and innate immune responses to bacterial invasion, and ST8SIA1 ( P = 0.0048). We conclude that the genetic predisposition to early-onset periodontitis is in part triggered by smoking and that tobacco smoke directly affects the expression of genes involved in bone homeostasis, tissue repair, and immune response.

Objectives: We aimed to assess how the 2018 and 1999 classifications of periodontal diseases reflect (a) patients' characteristics, (b) disease severity/extent/progression and (c) tooth loss (TL) during observation period., Methods: A total of 251 patients were followed over 21.8 ± 6.2 years. For the 1999 classification, using clinical attachment level (CAL), patients were classified as localized/generalized, mild/moderate/severe and aggressive/chronic periodontitis. For the 2018 classification, patients were staged according to their CAL or bone loss (BL) and the number of lost teeth (stages I-IV). Further factors like probing pocket depths (PPD) or furcation involvement modified the stage. The extent was sub-classified as generalized/localized. Patients were graded according to the BL/age index, smoking and/or diabetes., Results: According to the 1999 classification, most patients suffered from generalized severe chronic periodontitis (203/251) or generalized aggressive periodontitis (45/251). Patients with aggressive periodontitis were younger and less often female or smokers. They showed similar TL (0.25 ± 0.22 teeth/patient*year) as generalized severe chronic periodontitis patients (0.23 ± 0.25 teeth/patient*year). According to the 2018 classification, most patients were classified as generalized III-C (140/251), III-B (31/251) or IV-C (64/251). Patients' age, smoking status, CAL, PPD and BL were well reflected. TL differed between IV-C (0.36 ± 0.47), generalized III-C (0.21 ± 0.24) and localized forms (0.10-0.15)., Conclusions: Patients' characteristics, disease severity/extent/progression and TL were well reflected by the 2018 classification., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Evidence for a shared genetic basis of association between coronary artery disease (CAD) and periodontitis (PD) exists. To explore the joint genetic basis, we performed a GWAS meta-analysis. In the discovery stage, we used a German aggressive periodontitis sample (AgP-Ger; 680 cases vs 3,973 controls) and the CARDIoGRAMplusC4D CAD meta-analysis dataset (60,801 cases vs 123,504 controls). Two SNPs at the known CAD risk loci ADAMTS7 (rs11634042) and VAMP8 (rs1561198) passed the pre-assigned selection criteria (P AgP-Ger  < 0.05; P CAD  < 5 × 10 -8 ; concordant effect direction) and were replicated in an independent GWAS meta-analysis dataset of PD (4,415 cases vs 5,935 controls). SNP rs1561198 showed significant association (PD[Replication]: P = 0.008 OR = 1.09, 95% CI = [1.02-1.16]; PD [Discovery + Replication]: P = 0.0002, OR = 1.11, 95% CI = [1.05-1.17]). For the associated haplotype block, allele specific cis-effects on VAMP8 expression were reported. Our data adds to the shared genetic basis of CAD and PD and indicate that the observed association of the two disease conditions cannot be solely explained by shared environmental risk factors. We conclude that the molecular pathway shared by CAD and PD involves VAMP8 function, which has a role in membrane vesicular trafficking, and is manipulated by pathogens to corrupt host immune defense.

Aim: This study assessed the long-term annual costs for treating aggressive periodontitis (AgP) patients., Methods: A cohort of compliant AgP patients was retrospectively evaluated. Costs for active periodontal therapy (APT, including scaling and root planing, open flap debridement, root resections, but not pocket elimination or regenerative surgery) and supportive periodontal therapy (SPT, including also costs for restorative, endodontic, prosthetic and surgical treatments) were estimated from a mixed payer perspective in Germany. The impact of tooth- and patient-level factors on annual costs was assessed using mixed modelling., Results: A total of 52 patients (mean [SD] age: 35.2/6.8 years), with 26.5 (4.0) teeth (38% with bone loss >50%) were treated. Mean follow-up (retention) time was 16.9 (5.4) years. Total treatment costs per patient and per tooth were 6,998 (3,807) and 267 (148) Euro, respectively. Approximately 87% of the costs were generated during SPT, 13% during APT. Annual patient- and tooth-level costs were 536 (209) and 20.1 (65.0) Euro, respectively. Annual tooth-level costs were significantly increased in patients aged 34 years or older, male patients, former or current smokers, teeth with furcation involvement degree II/III, and bone loss 50%-70%., Conclusions: Annual treatment costs for treating AgP patients were similar to those found for chronic periodontitis patients. Certain parameters might predict costs., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: This retrospective longitudinal study assessed the risk of and prognostic factors for tooth loss in patients with generalized aggressive periodontitis (GAgP) after periodontal treatment in a university setting., Methods: Fifty-seven patients (1,505 teeth) were examined before (T0) and after active periodontal therapy (APT, T1) as well as after 17.4 ± 4.8 [range: 9-28] years of supportive periodontal therapy (SPT, T2). Descriptive statistics and a Cox-proportional-hazards shared-frailty model were applied., Results: Overall, 98 and 134 teeth were lost during APT and SPT, respectively, with 0.14 ± 0.18 teeth being lost per patient and year. During SPT, three patients (5%) lost ≥10 teeth, 14 (25%) lost 4-9 teeth, 40 lost 0-3 (70%) teeth, respectively. One-third (n = 19) of all patients lost no teeth. Mean PPD of the teeth surviving SPT was stable from T1 (3.5 ± 1.1 mm) to T2 (3.4 ± 1.1 mm). Nearly, 84% of all survived teeth showed stable or improved bone level at T2. Risk of tooth loss was significantly increased in active smokers (HR[95% CI]: 4.94[1.91/12.75]), the upper dental arch (1.94[1,16/3.25]), with each mm of residual PPD (1.41[1.29/1.53]), teeth with furcation involvement (FI) (HR 4.00-4.44 for different degrees) and mobility (5.39 [2.06/14.1] for degree III)., Conclusion: Within the provided conservative treatment regimen, GAgP patients lost only few teeth., (© 2017 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: 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: 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.)

Objectives: Psychosocial variables have received increased attention in periodontology. Attachment theory adds to known risk factors by linking early interactional experiences with adult tendencies of stress-regulation, health behaviour, symptom reporting, and healthcare utilization. The study investigates associations between attachment patterns and periodontal parameters., Methods: Within the context of a longitudinal study on periodontal diseases, 310 patients with aggressive (AgP) and chronic periodontitis (CP) filled out questionnaires on psychological attachment patterns. The influence of attachment style on health behaviour, treatment attendance and utilization, and periodontal variables was tested., Results: We found associations between psychological attachment anxiety on smoking and higher number of session use, independent of disease severity, which was more pronounced for women. Patients with higher attachment avoidance attended periodontal treatment later when diagnosed with CP and earlier with AgP. For men, we found differential associations for attachment avoidance and anxiety and number of teeth at beginning of treatment., Conclusion: Psychological attachment patterns are a promising target for understanding periodontal disease in addition to known psychosocial risk factors., (© 2013 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.)

Aim: The aim of this study was to determine the survival rates of questionable and hopeless teeth in patients with aggressive periodontitis (AgP) and chronic periodontitis (CP) during 15 years of supportive periodontal therapy (SPT)., Materials and Methods: Thirty-four AgP and 34 CP patients (SPT≥10 years) with bone loss of ≥50% at ≥2 teeth were consecutively recruited. Bone loss was measured on digitized radiographs and teeth were categorized as "questionable" (≥50 to <70% bone loss) or as "hopeless" (≥70%). Progression in pocket probing depths (PPD) during SPT, tooth loss and reasons for extraction were analysed., Results: In AgP patients, 262 teeth were considered as questionable and 63 as hopeless (CP: 149/51). During active periodontal therapy, 25 questionable and 26 hopeless teeth were extracted (CP: 12/16). During 15.3 ± 4.1 years of SPT of AgP 28 questionable and 15 hopeless teeth were removed (CP: 28/12). The mean tooth loss per patient during SPT in total was 0.14 (AgP) and 0.16 (CP) teeth/year. There were no significant differences in tooth loss or longitudinal progression of PPD between AgP and CP patients., Conclusions: In patients with AgP, 88.2% (209 of 237) of questionable and 59.5% (22 of 37) of hopeless teeth survived 15 years during regular SPT in a dental school department., (© 2011 John Wiley & Sons A/S.)