Genetic markers of tumour necrosis factor α in aggressive and chronic periodontitis

J Clin Periodontol 2008; 35: 493–500 doi: 10.1111/j.1600-051X.2008.01226.x Susanne Schulz1, Helmut K. G.
Machulla2, Wolfgang Altermann2,Jana Klapproth1, Uta Zimmermann1, Christiane Gla¨ser3, AlexanderKluttig4, Jamal Stein5, Hans-Gu¨nterSchaller1 and Stefan Reichert1 1University School of Dental Medicine,Department of Operative Dentistry andPeriodontology, Martin-Luther Universityof Halle-Wittenberg, Halle, Germany;2Interbranch HLA Laboratory/Department Schulz S, Machulla HKG, Altermann W, Klapproth J, Zimmermann U, Gla¨ser C, GHATT, Martin-Luther University of Halle- Kluttig A, Stein J, Schaller H-G, Reichert S. Genetic markers of tumour necrosis factor Wittenberg, Halle, Germany; 3Institute of a in aggressive and chronic periodontitis. J Clin Periodontol 2008; 35: 493–500. doi: Martin-Luther University of Halle-Wittenberg,Halle, Germany; 4Institute of Medical Epidemiology, Biostatistics, and Informatics, Aim: Tumour necrosis factor a (TNFa) plays an important role in the pathogenesis of Martin-Luther University of Halle-Wittenberg, periodontitis. TNFa production is influenced by gene polymorphisms. The aim of this study was to evaluate links between genetic variants and chronic/aggressive periodontitis in a multivariate model.
Subjects: One hundred and twenty-three periodontitis patients (chronic: n 5 54,aggressive: n 5 69) and 52 healthy controls without periodontitis were included in thestudy.
Material and Methods: Single nucleotide polymorphisms (SNPs) c. À 308G4A,c. À 238G4A and haplotypes were analysed by a polymerase chain reaction withsequence-specific primers (PCR-SSP). The clinical investigation included smokingstatus, plaque and bleeding indexes, pocket depth and attachment loss.
Results: Prevotella intermedia occurred more frequently in individuals positive forthe À 308GG/ À 238GG haplotype combination (Odds Ratio 5 2, 95% Confidenceinterval: 1.1–3.7, p 5 0.037, 1 À b 5 61%). In binary logistic regression analyses, thisTNFa haplotype could not be shown to be associated with periodontitis consideringsmoking, age, gender and approximal plaque index or subgingival bacterial Key words: aggressive periodontitis; chronic colonization as confounding factors.
periodontitis; haplotype; tumour necrosis Conclusions: Although the genetic background of TNFa could be shown to be associated with subgingival colonization with P. Intermedia, there is no evidence thatit is an independent risk factor for periodontitis in multivariate models.
Accepted for publication 13 February 2008 blasts, the induction of cytokine produc- of matrix metalloproteinases (Borish & affected by certain characteristics of the individual immune system (Honda et al.
factor involved in the aetiology of perio- Parts of the study were funded by a grant (D’Aiuto et al. 2005, 2007, Feng et al.
response via the activation of cells, such Journal compilation r 2008 Blackwell Munksgaard of periodontal bacteria, in a multivariate advanced periodontitis (Galbraith et al.
(Ikezawa et al. 2005, Engebretson et al.
gival hyperplasia or received antibiotics periodontitis. Therefore, the initial aim of this study was to investigate the impact of c. À 238G4A, including their haplotypes, evaluate the influence of genetic variants ders for periodontitis, such as age, gender, Table 1. Clinical characteristics of the groups of patients and healthy controls Individual occurrence of periodontal bacteria in subgingival pockets np40.05 in comparison with the control group (normal distribution of all metric values ! statistical evaluation with parametric tests).
nnp40.05 in comparison with the control group (Chi2-test or Fisher’s exact test if no5).
Journal compilation r 2008 Blackwell Munksgaard Genetic variants of TNFa in periodontitis they were taking medication or smoked.
mal plaque index (API) (Lange et al.
rs361525 (c. À 238G4A), respectively.
taken at six sites around each tooth.
Inclusion criteria for patients suffering 951C, 40 s 531C, 40 s 701C; and 8 min.
Fisher’s exact test was performed.
teeth, at least three of the affected teeth –Smirnov test (test of normal distribu- hybridization were included in the test.
tion). For the statistical evaluation, the mally distributed values) and the Mann– Clinical details of the patient groups are covariates for periodontitis such as age, sity Clinic of Heidelberg, Germany).
ethical guidelines of the ‘‘Declaration of All individuals involved in the study were Helsinki’’ and its amendment in ‘‘Tokyo evaluated according to their age, gender, patient groups with the periodontitis-free healthy controls, no statistically signifi- cant differences in age, gender and smok- subgingival scaling was carried out.
r 2008 The AuthorsJournal compilation r 2008 Blackwell Munksgaard Table 2. Influence of genotype, allele and haplotype distribution of tumour necrosis factor a Table 3. Association of the individual geno- (TNFa) SNPs c. À 308G4A and c. À 238G4A in dependence on the occurrence of chronic and type/haplotype distribution and the occurrence of five subgingival periodontal bacteria inthe total study group. Only for Prevotella intermedia could a significant association beproven nAn almost two-fold increase in the prevalence of genotype and haplotype carriers among healthy subjects compared with patients suffering from periodontitis.
be proven in the entire study group.
CP, chronic periodontities; AP, aggressive periodontities.
outcome of periodontitis, namely BOP,and the TNFa haplotype could be their clinical status (AP and CP groups), detected in the group of patients suffer- of patients, there was an increase in the no significant association could be found no significant difference with respect to (1 À b) of the corresponding evaluations patients with CP and the control group.
mutant alleles (BOP %): 77.4 Æ 18.9).
factors, known to affect periodontitis, on prevalence of P. intermedia. (Table 3).
investigated by means of logistic regres- sion analysis. Because there is a correla- Journal compilation r 2008 Blackwell Munksgaard Genetic variants of TNFa in periodontitis Table 4. Forward stepwise binary logistic regression analyses investigating the impact of the genetic background of tumour necrosis factor a(TNFa) (haplotype combinations GG–GG versus GG–AG1GG–GA1AG–AG) on periodontitis considering the occurrence of periodontal bacteria(a) and age, gender, smoking and approximal plaque index (b) (a) Patients with periodontitis versus healthy subjects Patients with chronic periodontitis versus healthy subjectsPrevotella gingivalis Patients with aggressive periodontitis versus healthy subjectsPorphyromonas gingivalis (b) Patients with periodontitis versus healthy subjects Patients with chronic periodontitis versus healthy subjectsAPI Patients with aggressive periodontitis versus healthy subjectsAPI p 5 0.001), two separate statistical ana- lyses were performed. In the initial step, gingival crevicular fluid of patients with periodontal tissues (Loos et al. 2005).
tics is considered to be a candidate gene for periodontitis. In this study, the influ- established results (Pihlstrom et al.
predictor for periodontitis in this model.
(Cortelli et al. 2005). The most interest- dontal bacteria among healthy controls.
tures, the influence of the genetic back- subjects have no clinical signs of perio- dontitis despite bacterial colonization.
well-characterized periodontitis patients with generalized CP or generalized AP.
dontitis. Because periodontitis increases plex diseases including periodontitis.
with age and usually occurs after the age study in order to investigate the associa- r 2008 The AuthorsJournal compilation r 2008 Blackwell Munksgaard the occurrence of periodontitis including not detect a statistically significant influ- dontal bacteria were investigated. It was causal role, the variant is in close vici- to the occurrence of periodontal bacteria association is only caused by a stratifi- carriers, it was not possible to detect a highly selected unrelated individuals.
This requires high attention in selecting (Palmer et al. 2005, Pihlstrom et al.
controls (according to statistical evalua- assess the importance of the functionally gated in the present study (Yoshie et al.
clinical association study addressing the first time, we investigated the influence et al. 1999, Soga et al. 2003, Lin et al.
2003; for a review, see Shapira et al.
Folwaczny et al. 2004, Donati et al.
2005, Loos et al. 2005), many researchers more substantiated results, our prelimin- variants and periodontitis (Endo et al.
ary results should be indicative for pro- Folwaczny et al. 2004, Donati et al.
statistical settings as well as by ethnic differences in genotype distributions.
et al. 2007). In our multivariate models, tribution were reported by others (Cuenca et al. 2001). In contrast to other studies (Craandijk et al. 2002, D’Aiuto et al.
Despite the limitations of clinical asso- loss of power due to ethnic variability.
paid to the clinical selection criteria of patients and controls. Only patients with host’s bacterial defence mechanism.
basis is yet to be clarified. In previous were taken into consideration, the genetic Journal compilation r 2008 Blackwell Munksgaard Genetic variants of TNFa in periodontitis Gonzalez, S., Rodrigo, L., Martinez-Borra, J., polymorphisms and susceptibility to human Lopez-Vazquez, A., Fuentes, D., Nino, P., papillomavirus 16-associated cervical cancer.
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