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Gene Polymorphisms and the Prevalence of Key Periodontal Pathogens
L. Nibali1,
D.R. Ready2,
M. Parkar1,
P.M. Brett1,
M. Wilson3,
M.S. Tonetti4 and
G.S. Griffiths1,5,*
1 Periodontology Unit, Eastman Dental Hospital, University College London (UCL), London, UK;
2 Eastman Dental Hospital, UCLH NHS Foundation Trust, London, UK;
3 Division of Microbial Diseases, Eastman Dental Institute, UCL, London, UK;
4 Division of Periodontology, Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, University of Connecticut Health Science Center, Farmington, USA; and
5 Department of Adult Dental Care, School of Clinical Dentistry, Claremont Crescent, Sheffield S10 2TA, UK
Correspondence: * corresponding author, g.s.griffiths{at}sheffield.ac.uk
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ABSTRACT
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Growing evidence suggests that individual genetic susceptibility may influence the host’s response to infections. The aim of this project was to study whether gene polymorphisms of inflammatory markers are associated with the presence of viable periodontopathogenic bacteria. We extracted genomic DNA from 45 young adults diagnosed with generalized aggressive periodontitis to study Fc receptors, formyl peptide receptor, Interleukin-6, tumor necrosis factor- , and vitamin D receptor polymorphisms. The presence and viable numbers of Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, and Tannerella forsythensis were determined by culture, and their identities confirmed by PCR. Multiple logistic regressions revealed that both Fc receptor and IL-6 -174 polymorphisms were associated with increased odds of detecting A. actinomycetemcomitans, P. gingivalis, and T. forsythensis after adjustment for age, ethnicity, smoking, and periodontitis extent. These findings support the hypothesis that complex interactions between the microbiota and host genome may be at the basis of susceptibility to aggressive periodontitis.
Key Words: aggressive periodontitis • genetic polymorphisms • bacteria • interleukin-6 • Fc receptors
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INTRODUCTION
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Response to infections varies enormously between individuals, and genetic factors may explain these individual variations (Wang, 2005). For example, genetic variants in the promoter region of the CC chemokine receptor 5 gene have been shown to confer protection against HIV infection (Cooke and Hill, 2001). Moreover, genetic polymorphisms of inflammatory markers and neutrophil receptors have recently been associated with the prevalence of bacterial infections and malaria (Omi et al., 2002; Sutherland et al., 2005). Understanding the molecular basis for these different responses may improve our understanding of infectious disease pathogenesis and help in the treatment and control of these infections (Cooke and Hill, 2001).
Aggressive periodontitis is an infectious disease of the periodontium which affects young adults, causing damage to the supporting apparatus of the teeth, leading to bone resorption and tooth loss (Papapanou, 1999; Tonetti and Mombelli, 1999). In aggressive periodontitis, host responses (genetically determined) and microbiological factors seem to be deterministic components, which may trigger or cause the onset of this disease (Loos et al., 2005; Tonetti et al., 2005). This concept leads to speculation that the predominant periodontal pathogenetic microbiota—such as A. actinomycetemcomitans, P. gingivalis, and T. forsythensis—preferably develop in persons with a specific susceptibility profile. In a study of persons with chronic periodontitis (Socransky et al., 2000), some evidence emerged on how a particular genotype could render host defense mechanisms more selective against specific periodontal pathogens.
In the present study, we hypothesized that the host genotype can possibly be related to the composition of the subgingival microbiota in persons with aggressive periodontitis. The aim of this study was to investigate whether, in a population diagnosed with generalized aggressive periodontitis, polymorphisms in genes coding for important inflammation-associated molecules may influence the presence of A. actinomycetemcomitans, P. gingivalis, and T. forsythensis.
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MATERIALS & METHODS
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Study Population
Forty-five patients diagnosed with untreated generalized aggressive periodontitis were identified among the population referred for treatment to the Periodontal Department of the Eastman Dental Hospital. All persons gave written informed consent, and the study had been reviewed and approved by the Eastman/UCLH joint ethics committee.
Clinical and radiographic periodontal examination confirmed the diagnosis of aggressive periodontitis (Armitage, 1999). Individuals were excluded from the study if they (i) were pregnant or lactating, (ii) had received antibiotic treatment in the previous 3 mos, (iii) were taking long-term anti-inflammatory or immunosuppressive drugs, or (iv) had received periodontal treatment within the preceding 6 mos. Part of the population included in this study has already been described elsewhere (Guerrero et al., 2005). The demographic and clinical characteristics of the population are presented in Table 1 .
Clinical Examination
Persons with a suspected diagnosis of aggressive periodontitis were examined by a single experienced clinician. Full-mouth measures of probing pocket depth (PPD), recessions, and lifetime cumulative attachment levels (LCAL) were obtained at 6 points per tooth. Radiographic examination was also performed for each person.
Persons were diagnosed with generalized aggressive periodontitis when presenting with interproximal PPD and LCAL  5 mm and radiographic bone loss of 30% of root length affecting at least 3 permanent teeth other than first molars and incisors. Following informed patient consent, blood samples were collected via venipuncture and stored at –70°C. Before periodontal probing, plaque samples were collected by means of sterile curettes in the deepest site in each quadrant (Mombelli et al., 1991). These were pooled by immediate placement in a sterile container with 1 mL of reduced transport fluid (Syed and Loesche, 1972).
DNA Extraction and Genotyping
DNA was extracted from leukocytes as described previously (Brett et al., 2005). A 10-ng quantity of DNA was subsequently used for polymerase chain-reaction (PCR) analysis. Allelic discrimination assays were performed with use of the Applied Biosystems 7300/7500 Real Time PCR System (Warrington, Cheshire, UK). The panel of genetic polymorphisms to be tested was selected because they had either been associated previously with the periodontitis phenotype (Loos et al., 2005), or because they are genes coding for important inflammation-associated molecules that may be involved in the process of managing the bacterial challenge associated with aggressive periodontitis. This panel included FcR, FcRIIa, FcRIIb, FcRIIIa, FcRIIIb, FPR, IL-6 -174, TNF-, and VDR polymorphisms. The primers and probes were designed with the Assay-by-Design service offered by Applied Biosystems, while others were obtained from Applied Biosystems from their Assays-on-Demand products (Table 2). Genotyping was performed in 25-µL reactions consisting of 10 ng of genomic DNA, 12.5 µL of 2X Taqman Universal PCR Master Mix, and either 0.625 µL (40X) or 1.25 µL (20X) primer/probe sets. The 7300/7500 SDS software plotted the results of the allelic discrimination run on a scatter plot of Allele X vs. Allele Y and automatically identified genotypes dependent on fluorescence intensities of VIC and FAM reporter dyes.
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Table 2. Gene Polymorphism Real-time Probe/Primer Combinations Designed with Assay-by-Design Service from Applied Biosystems or Inventoried SNP Genotyping Assay Products from Applied Biosystems
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Microbiological Analysis
Samples were processed immediately by vortex-mixing for 30 sec or until the plaque was dispersed, serially diluted in reduced transport fluid, and inoculated onto fastidious anaerobic agar (FAA) containing 5% defibrinated horse blood (E and O Laboratories, Bonnybridge, UK), for isolation of P. gingivalis and determination of the total number of cultivable bacteria present. T. forsythensis was investigated by culture on FAA supplemented with 7% horse blood and 10 mg/L N-acetyl muramic acid (Sigma, Poole, UK). All FAA plates were incubated aerobically at 37°C for 5 days. A. actinomycetemcomitans was determined by culture on tryptone soy agar (Oxoid Ltd., Basingstoke, UK) plus 0.1% yeast extract and 10% horse serum with bacitracin (75 mg/L; Sigma, Poole, UK) and vancomycin (5 mg/L; Sigma; Slots, 1982), and incubated at 37°C for 5 days in air supplemented with 5% CO2. All potential pathogenic bacteria were enumerated and subcultured for further identification. DNA was extracted by means of the PuregeneTM DNA isolation Kit, (Gentra Systems, Minneapolis, MN, USA), and bacterial species identification was confirmed by PCR (Gafan et al., 2004). The PCR results were confirmed by DNA sequencing of the amplicons, which was carried out with an ABI310 Genetic Analyser (PE Biosystems, Warrington, UK). We analyzed sequences using the Ribosomal Database project II (Maidak et al., 2000) and BLAST at the National Centre for Biotechnological Information (Altschul et al., 1997).
Statistical Analysis
The SPSS 12.0 package was used for statistical analysis, and the alpha value was set at 0.01, to compensate for multiple variable testing (Altman, 1991). Continuous, normally distributed variables were reported as means ± standard deviations (SD). Comparisons of continuous and categorical data between groups were analyzed with ANOVA and the Chi-square test, respectively, on all tested polymorphisms. Associations between genotype and the presence of periodontopathogenic bacteria (A. actinomycetemcomitans, P. gingivalis, and T. forsythensis) were analyzed by multiple logistic-regression analysis. We used a backward likelihood-ratio elimination algorithm, entering age, gender, smoking, ethnicity, number of periodontal pockets 5 mm, and genotype as variables. SLE (significance level for entry into the model) and SLS (significance level to stay in the model) were set at 0.05 and 0.1, respectively. The results of the final models are reported. We performed further analysis to investigate the prevalence of the concomitant presence of A. actinomycetemcomitans and P. gingivalis, and A. actinomycetemcomitans, P. gingivalis, and T. forsythensis.
We performed WHAP analysis (http://pngu.mgh.harvard.edu/~purcell/whap/) to detect possible FcR and FPR haplotype associations able to predict the presence of the studied bacteria or their combinations (Sham et al., 2004).
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RESULTS
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The allele distributions of all studied polymorphisms satisfied the Hardy-Weinberg equilibrium. A. actinomycetemcomitans, P. gingivalis, and T. forsythensis were detected in 22 (48.9%), 22 (48.9%), and 29 (64.4%) persons, respectively. A. actinomycetemcomitans and P. gingivalis were concomitantly detected in 16 persons (35.6%), while all 3 bacteria were present together in 10 persons (22.2%). No statistically significant differences were observed in bacterial detection for age, gender, ethnicity, smoking, and disease severity, indicated by the number of probing pocket depths 5 mm (data not presented). Average log counts for A. actinomycetemcomitans, P. gingivalis, and T. forsythensis were 4.43 ± 1.18, 6.02 ± 1.34, and 6.23 ± 0.48 cfu/sample, respectively.
Of the candidate polymorphisms studied, only the IL-6 polymorphism showed association with the presence of A. actinomycetemcomitans (Table 3). FcIIIRb NA also showed a tendency for an association with the presence of A. actinomycetemcomitans (Table 3). For ease of presentation in the Table, only selected gene polymorphisms and bacterial combinations studied were included.
Logistic regression, adjusted for age and smoking, revealed a statistically significant difference (p = 0.003, OR = 13.7, 95% CI = 2.4–77.1) between the detection of A. actinomycetemcomitans in IL-6 -174 homozygous GG individuals 17/26 (65%) compared with the homozygous CC 3/7 (42.9%) and heterozygous CG 2/12 (16.7%) individuals. In homozygous GG individuals, smaller differences, which were not statistically significant, were noted for the detection of A. actinomycetemcomitans combined with P. gingivalis (p = 0.019), and the detection of all 3 organisms (p = 0.042). Tendencies for association, although not statistically significant, were observed for FcIIIb NA, FcIIIb SH antigen, and FcIIa polymorphisms (see Table 3 ). No differences between genotypes were observed for average log counts of bacteria in positive individuals.
WHAP analysis revealed that FcR haplotypes were associated with the presence of A. actinomycetemcomitans (p = 0.010, adjusted for gender, smoking, and ethnicity). The highest p values were observed for constrained models, including FcRIIa, IIIb NA, and IIIb SH (p = 0.003 and 0.006, respectively, for A. actinomycetemcomitans and the combined presence of all 3 bacteria), and IIIb NA and IIIb SH (p = 0.008, 0.006, and 0.02, respectively, for A. actinomycetemcomitans, A. actinomycetemcomitans combined with P. gingivalis, and all 3 studied bacteria).
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DISCUSSION
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In this study, polymorphisms of genes encoding for neutrophil receptors (FcR) and pro-inflammatory cytokines (IL-6) were associated with the presence of pathogenic bacteria in the periodontal pockets of persons with aggressive periodontitis. This was independent of age, smoking, ethnic origin, and disease severity. This study supported the hypothesis that the host genotype can influence the composition of the subgingival microbiota and data from previous studies suggesting that individual genetic susceptibility may influence the host response to infections (Cooke and Hill, 2001).
In particular, our findings suggest that IL-6 -174 polymorphism may be important in determining susceptibility to colonization with periodontopathogenic bacteria. IL-6 is a multifunctional cytokine with a central role in host defense (Ishihara et al., 1997). IL-6 has been shown to be crucial in the inflammatory response to infectious agents (especially Gram-negative bacteria) (Dalrymple et al., 1996), and its presence has been shown in endothelial cells, fibroblasts, and macrophages of persons affected by periodontitis, but not in cells from healthy individuals (Takahashi et al., 1994). Homozygosity for the G allele at position -174 in the promoter region has been linked to increased serum concentration of IL-6 and increased construct expression upon stimulation with LPS (Fishman et al., 1998), and suspected as a susceptibility factor for periodontitis (Trevilatto et al., 2003; Brett et al., 2005).
In our study, -174 G homozygous patients exhibited higher detection rates of periodontopathogenic bacteria. A possible explanation for this is that bacteria such as A. actinomycetemcomitans and P. gingivalis are known to stimulate the inflammatory cascade and the production of IL-6 from gingival fibroblasts (Belibasakis et al., 2005). Therefore, the presence of periodontopathogenic bacteria in IL-6 -174 G homozygous individuals may act over an already "primed" individual, excessively amplifying the local inflammatory response, resulting in the characteristic tissue destruction seen in aggressive periodontitis. Consequently, detection rates of these pathogenic bacteria and G homozygosity cluster in the same group of persons. In addition, increased inflammatory response to plaque accumulation in persons carrying specific gene polymorphisms may increase the chance of overgrowth of particular components of the microbiota that grow well in inflamed areas.
Recently, a haplotype with possible functional relevance has been discovered in a region of the IL-6 gene extending upstream of the previously known promoter region (Terry et al., 2000; Fife et al., 2005), implying the possibility that the real functional polymorphism may be elsewhere in the IL-6 gene and in linkage equilibrium with the one we tested.
The other finding was that FcRIIIb NA1 individuals exhibited higher detection rates of periodontopathogenic bacteria. Neutrophils recognize bacteria opsonized by immunoglobulins (Ig) through specific FcR, and their binding activates important effector functions (van Sorge et al., 2003). The NA2 isoforms of the FcRIIIb receptor allotype exhibit lower affinity for immune-complexed IgG3, and therefore decreased phagocytosis (Salmon et al., 1990; Kobayashi et al., 2000), and has been suspected to be involved in susceptibility to periodontitis (Kobayashi et al., 2001). NA1 homozygous individuals are likely to have hyperactive neutrophils. Consequently, NA1 homozygosity in combination with the presence of A. actinomycetemcomitans may lead to the disease severity characteristic of aggressive periodontitis. However, the only statistically significant association was with FcR haplotypes, pointing toward the functional importance of the interaction between the different FcR loci studied.
While this represents interesting preliminary information, we must accept the limitations within the existing study. In particular, microbiological analysis was performed by culture, which is generally considered to have a lower sensitivity than molecular techniques. However, molecular techniques themselves are considered less specific than culture techniques, and may therefore lead to false-positive results. Furthermore, recent publications have suggested that all methodologies have some degree of bias (Pratten et al., 2003). Whether the sites were "active" or merely evidence of previous disease should also be considered. The temporal association between the defect and its microbiological status is yet to be resolved, but our results on the prevalence of A. actinomycetemcomitans (49%) and P. gingivalis (49%) are in accordance with data reported in the literature (Mombelli et al., 2002). In studies including localized and generalized cases of aggressive periodontitis, Mombelli et al.(2002) found 62% and 71% of persons, respectively, to be positive to A. actinomycetemcomitans and P. gingivalis. Smaller percentages are usually reported when only generalized cases are considered (Mullally et al., 2000).
Thus, within the limitations of a small sample size of mixed ethnicities, and with the limitation of bacterial culture analysis, the results of this study support the hypothesis that complex interactions between the microbiota and host genome are at the basis of susceptibility to aggressive periodontitis. Further studies with larger sample sizes and haplotype analyses are now required to test these hypotheses. Periodontal disease, being one of the most common multibacterial diseases in developed countries, may represent a useful model for the study of the pathways and mechanisms of microbe-genetic interactions.
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ACKNOWLEDGMENTS
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This study was supported by funds from the Periodontal Research Fund of the Eastman Dental Hospital and Institute. LN was additionally supported by a fellowship from the Italian Society of Periodontology. Dr. Adrian Guerrero and the clinical staff of the Department of Periodontology, University College London, assisted in the recruitment of participants.
Received for publication January 25, 2006.
Revision received December 4, 2007.
Accepted for publication January 14, 2007.
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Journal of Dental Research, Vol. 86, No. 5,
416-420 (2007)
DOI: 10.1177/154405910708600505
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ABSTRACT
INTRODUCTION