Christian Graetz

Validation of reported genetic risk factors for periodontitis in a large-scale replication study.

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.

Genetic evidence for PLASMINOGEN as a shared genetic risk factor of coronary artery disease and periodontitis

Background—Genetic studies demonstrated the presence of risk alleles in the genes ANRIL and CAMTA1/VAMP3 that are shared between coronary artery disease (CAD) and periodontitis. We aimed to identify further shared genetic risk factors to better understand conjoint disease mechanisms. Methods and Results—In-depth genotyping of 46 published CAD risk loci of genome-wide significance in the worldwide largest case–control sample of the severe early-onset phenotype aggressive periodontitis (AgP) with the Illumina Immunochip (600 German AgP cases, 1448 controls) and the Affymetrix 500K array set (283 German AgP cases and 972 controls) highlighted ANRIL as the major risk gene and revealed further associations with AgP for the gene PLASMINOGEN (PLG; rs4252120: P=5.9×10−5; odds ratio, 1.27; 95% confidence interval, 1.3–1.4 [adjusted for smoking and sex]; 818 cases; 5309 controls). Subsequent combined analyses of several genome-wide data sets of CAD and AgP suggested TGFBRAP1 to be associated with AgP (rs2679895: P=0.0016; odds ratio, 1.27 [95% confidence interval, 1.1–1.5]; 703 cases; 2.143 controls) and CAD (P=0.0003; odds ratio, 0.84 [95% confidence interval, 0.8–0.9]; n=4117 cases; 5824 controls). The study further provides evidence that in addition to PLG, the currently known shared susceptibility loci of CAD and periodontitis, ANRIL and CAMTA1/VAMP3, are subjected to transforming growth factor-&bgr; regulation. Conclusions—PLG is the third replicated shared genetic risk factor of atherosclerosis and periodontitis. All known shared risk genes of CAD and periodontitis are members of transforming growth factor-&bgr; signaling.

Peri-Implantitis versus Periodontitis: Functional Differences Indicated by Transcriptome Profiling

BACKGROUND Periodontitis and Periimplantitis are oftentimes discussed as one entity, which is reflected by therapeutical as well as by scientific approaches. It is unclear, to which extent the similarity of the clinical characteristics is attributed to similarities in the underlying disease mechanisms. PURPOSE The main objective of the study is to display if or how different periimplantitis and periodontitis are on the mRNA level, representing a high-resolution map of disease-associated events. MATERIALS AND METHODS Aiming to describe the pathophysiological mechanisms in vivo, primary gingival tissue from 7 periimplantitis patients, 7 periodontitis patients and 8 healthy controls was employed in order to generate genome wide transcriptome profiles. RESULTS On the basis of quantitative transcriptome analysis, we could show that periimplantitis and periodontitis exhibit significantly different mRNA signatures. Additionally we present a disease associated mRNA profile, which displays potential periimplantitis disease mechanisms. A gene ontology analysis revealed various pathways, supporting the hypothesis of periimplantitis being a complex inflammatory disorder with a unique pathophysiology. While in periimplantitis tissue the regulation of transcripts related to innate immune responses and defense responses were dominating, in periodontitis tissues bacterial response systems prevailed. CONCLUSIONS Taken together, our results suggest considering periimplantitis and periodontitis as disease entities with shared as well as with distinct features, which should be reflected on the therapeutical as well as on the scientific level.

Toothbrushing Education via a Smart Software Visualization System

BACKGROUND The aim of this study is to evaluate the efficiency of a recently developed smart digital toothbrush monitoring and training system (DTS) in terms of correct brushing motion and grip axis orientation in an at-home environment. METHODS Twenty-one participants (11 test individuals [DTSG] and 10 control individuals [COG]) received instructions on the modified Bass technique (MBT) after their toothbrushing performance was monitored and they received professional tooth cleaning (T0). After 36 hours (T1), without mechanical oral hygiene measures, plaque and gingival indices were recorded, and the brushing technique was reviewed. After randomization, participants individually performed oral hygiene for 6 weeks (T2) with the provided oral hygiene kits. The DTSG group additionally used DTS. During the following 8 weeks (T3), participants used their original brushing devices without any additional interference. Investigators at each visit were masked regarding group identity. Data were statistically evaluated using Mann-Whitney U, Friedman, Wilcoxon, and paired tests and Pearson correlation. RESULTS At T0, 27.27% of DTSG participants used the MBT correctly (COG, 50%), increasing to 54.55% (COG, 60%) after professional instruction (T1) and further to 90.91% at T2 (COG, 60%) (P <0.001). Plaque scores were reduced in DTSG (P <0.05). At T3, 80% of the DTSG (COG, 40%) totally adopted the MBT (P <0.05). The plaque scores on buccal surfaces of the DTSG showed an additional slight improvement between T2 and T3, in contrast to a decline on oral surfaces (P <0.001). At T2 and T3, the DTSG brushed >120 seconds (COG, 90% and 50%) (P <0.05). CONCLUSION Apparently, the tested DTS effectively improves the brushing technique and leads to a prolonged learning effect, including improved oral hygiene.

Retention costs of periodontally compromised molars in a German population

AIM This study assessed the long-term costs per retention year for periodontally affected molars. METHODS A cohort of 379 compliant subjects was retrospectively evaluated. Periodontal, restorative, endodontic, prosthetic and surgical treatment costs were estimated based on fee items of the private German health insurance. Costs/year were calculated and the impact of tooth- and subject-related factors on this cost-effectiveness ratio assessed using generalized linear-mixed modelling. RESULTS 2306 molars received non-regenerative initial and supportive therapy and were followed until extraction or censoring (in mean (SD): 16.5 [6.8] years). Per year, 0.07 (SD: 0.12) deep scalings, 0.04 (0.11) open flap debridements, 0.01 (0.04) resective therapies and 2.49 (0.12) SPTs had been provided. Few teeth received non-periodontal treatments. Costs/year decreased significantly with each tooth a patient had at baseline (mean difference: -0.01, 95% CI: -0.02/-0.01 Euro/year), and increased with each mm of probing-pocket depth (0.04 [0.03/0.06] Euro/year), in upper (0.07 [0.11/0.31] Euro/year) or mobile molars (up to 0.33 [0.18/0.48] Euro/year), those with bone loss (up to 0.11 [0.04/0.17] Euro/year), endodontic treatment (0.24 [0.15/0.33] Euro/year), peri-apical lesions (0.24 [0.11/0.38]) and prosthetic treatment (0.54 [0.49/0.59] Euro/year). CONCLUSIONS Annual costs for retaining periodontally affected molars were limited, and associated mainly with tooth-level factors.

A genome-wide association study identifies nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis.

Abstract 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.

Influence of psychological attachment patterns on periodontal disease – a pilot study with 310 compliant patients

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.

Periodontal Probing Versus Radiographs for the Diagnosis of Furcation Involvement

BACKGROUND Decisions in periodontal therapy for multirooted teeth are essentially based on accurate diagnosis of the furcation involvement (FI). Furcation probing (FP) is still the basic diagnostic measure, although the assessment may be difficult. The aim of this study is to evaluate the validity of FP and radiographic assessment of FI compared with visual assessment during open flap surgery (OFS). METHODS In this retrospective clinical cohort study, 215 participants with periodontal disease and at least one molar treated with OFS were enrolled, and a total of 834 molars were assigned for FI by FP and in radiographs analyzed by an experienced (EE) and less experienced examiner (LE). For the investigation, 143 panoramic radiographs (OPGs) and 77 intra-oral radiographs (I-Os) were evaluated. RESULTS The Class of FI by FP was confirmed in 56%, whereas 15% were overestimated and 29% underestimated. FI Class 0 and I had been detected with high probability (74% and 54%, respectively). Of all FI Class III, 57% were detected correctly by radiographs and 32% by FP. FP and OFS revealed a weighted κ-coefficient (κw) = 0.588; radiographs and OFS had κw = 0.542 (OPG κw = 0.555 and I-O κw = 0.521). The interrater reliability for radiographs was dependent on the experience of the examiner (EE κw = 0.618; LE κw = 0.426). CONCLUSIONS Experience in analyzing conventional radiographs increases the potential of correct diagnosis of advanced FI. The reliability of FP compared with radiographic assessment depends on the anatomy and location of the tooth. Both diagnostic tools should be used in cases of suspected FI.

Common genetic risk variants of TLR2 are not associated with periodontitis in large European case‐control populations

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.

Number of teeth predict depressive symptoms in a longitudinal study on patients with periodontal disease

OBJECTIVE Periodontal disease is associated with a wide range of psychosocial risk-factors. Disease-related tooth-loss has been associated with an increase in depressive symptoms in cross-sectional studies. However, while depression is a known risk-factor for the outcome of chronic diseases, it remains unclear if tooth loss can also predict depressive symptoms over the course of treatment. Aim of the current pilot study was to test, to what extend the number of teeth predict depressive symptoms several years later. METHODS Tooth status of 310 patients with chronic and aggressive periodontitis was evaluated at the beginning of a specialized, university based outpatient treatment. We assessed depressive symptoms with the Patient Heath Questionnaire (PHQ) on average 13years later. Regression analyses were used to relate initial number of teeth to self-reported depression scores. RESULTS Fewer teeth at the beginning of the treatment were related to higher scores of depressive symptoms, even when controlling for several covariates. CONCLUSIONS Tooth loss is a potential risk-factor for the development of depression in periodontal disease. Further longitudinal studies that control for initial depressive symptoms are needed to identify disease mechanisms.