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CD14 and TLR4 Gene Polymorphisms in Adult Periodontitis

¹ Department of Periodontology, Section of Oral Microbiology, Academic Centre for Dentistry Amsterdam, Van der Boechorsstraat 7, 1081 BT Amsterdam, The Netherlands;
² Laboratory of Immunogenetics, VU University Medical Center, Amsterdam, The Netherlands; and
³ Department of Gastroenterology, VU University Medical Centre, Amsterdam, The Netherlands;

Correspondence: ^* corresponding author, ML.Laine{at}vumc.nl

	ABSTRACT

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Bacterial deposits, smoking, and host genetic factors play a major role in an individual’s predisposition to periodontitis. Bacterial components are recognized by CD14 and toll-like receptor 4 (TLR4), resulting in a NF-B-based inflammatory response. We hypothesized that functional CD14 and TLR4 polymorphisms contribute to periodontitis susceptibility. We aimed to investigate the occurrence of CD14-260C>T, TLR4 299Asp>Gly, and 399Thr>Ile gene polymorphisms in adult periodontititis. DNA was collected from 100 patients with severe periodontitis and from 99 periodontally healthy controls. The gene polymorphisms were determined by the PCR technique. The presence of the periodontal pathogens Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans, and whether the subjects smoked, was included in the analyses. The CD14-260T/T genotype was found in 34.0% of periodontitis patients and in 20.2% of controls. Logistic regression analysis adjusted for gender, age, smoking, and prevalence of P. gingivalis and A. actinomycetemcomitans showed an association between the CD14-260T/T genotype and periodontitis (P = 0.004, OR 3.0, 95% CI 1.4–6.9). We conclude that the CD14-260T/T genotype contributes to the susceptibility to severe periodontitis in Dutch Caucasians.

Key Words: CD14 • TLR4 • gene polymorphisms • periodontitis • innate immunity.

	INTRODUCTION

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Adult periodontitis is a chronic inflammatory disease of the tooth-supporting tissues and the alveolar bone. Specific micro-organisms of the subgingival plaque, including Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans, and many other mainly Gram-negative strict anaerobic rods initiate the disease (Haffajee and Socransky, 1994). In addition to the microbial component, behavioral factors such as smoking and stress are risk factors for periodontitis (Bergström, 1989; Genco et al., 1999). Immune responses against microbiological agents are partly genetically determined (Girardin et al., 2003) and appear to be important in an individual’s susceptibility to periodontitis (Michalowicz, 1994; Laine et al., 2001).

CD14 is a co-receptor involved in the recognition of bacterial lipopolysaccharide (LPS). CD14 forms a complex with LPS and the LPS-binding protein. A membrane-anchored CD14 can be cleaved to a soluble serum protein (sCD14). CD14 is involved in the phagocytosis of bacteria (Grunwald et al., 1996) and LPS-mediated bone resorption (Amano et al., 1997). Increased serum levels of sCD14 have been associated with periodontitis (Hayashi et al., 1999).

Toll-like receptors (TLRs) mediate intracellular signaling and antimicrobial responses upon recognition of pathogen-associated molecular patterns (PAMPs) of micro-organisms, and play a central role in innate immunity (Medzhitov et al., 1997).

Candidate gene approaches investigating the effects of functional polymorphisms in genes involved in an immune response against microbiological agents have shown the importance of the IL-1 gene cluster in periodontitis (Kornman et al., 1997; Laine et al., 2001). TLR2 and TLR4, both with CD14 as a co-receptor, are involved in Gram-positive and Gram-negative PAMP recognition, making them interesting targets for the candidate gene approach. Activation of these receptors results in the activation of NF-B, followed by the transcription of various pro-inflammatory cytokine genes, such as TNF-A, IL-1A, and IL-1B, which code for proteins that have been associated with periodontitis (Wang et al., 2003). Expression of CD14, TLR4, and TLR2 in periodontal tissues supports the importance of these receptors in periodontitis (Wang et al., 2003).

Although TLR2 has been reported to recognize LPS of P. gingivalis (Werts et al., 2001), and polymorphisms in the TLR2 gene have been described (Lorenz et al., 2000; Kang and Chae, 2001), they either do not exist in the Caucasian population or occur at very low frequencies. However, both CD14 and TLR4 functional gene polymorphisms have frequently been described in Caucasian populations (Agnese et al., 2002; Holla et al., 2002).

The CD14-260C>T promoter polymorphism enhances the transcriptional activity of the CD14 gene (Hubacek et al., 1999). Individuals carrying the T/T genotype have significantly higher serum levels of sCD14 and increased density of CD14 in monocytes than those carrying the C/C or C/T genotype (Hubacek et al., 1999).

The TLR4 299Asp>Gly gene polymorphism (+896A>G) has been correlated with hyporesponsiveness to inhaled lipopolysaccharide (Arbour et al., 2000), sepsis, and infections caused by Gram-negative bacteria (Agnese et al., 2002). The TLR4 299Asp>Gly polymorphism is in close linkage with the TLR4 399Thr>Ile gene polymorphism (+1196C>T), a point mutation that results in threonine-to-isoleucine substitution.

We have recently shown that simultaneous carriage of the rare alleles of the IL-1 cluster genes is associated with periodontitis (Laine et al., 2001) in non-smoking patients without detectable P. gingivalis and A. actinomycetemcomitans. This makes the present study of the PAMP-sensing system, by analyses of the functional CD14 and TLR4 gene polymorphisms, relevant in relation to periodontitis susceptibility. We hypothesized that patients with CD14-260T, TLR4 299Gly, and 399Ile polymorphisms have an enhanced inflammatory response to LPS or other components of Gram-negative bacteria, contributing to the development of periodontitis. The obtained genetic information may give more insight into the pathogenesis of adult periodontitis and may identify genetic markers for susceptibility and progression of destructive periodontal disease.

	MATERIALS & METHODS

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Subjects
The study was performed in unrelated Dutch Caucasian adult patients with severe periodontitis (n = 100) and in periodontally healthy controls (n = 99) (Table 1). Patients who were current smokers, or had stopped smoking 1 yr previously, were defined as ‘smokers’, and patients who had never smoked, or had stopped smoking > 1 yr previously, were defined as ‘non-smokers’. The study was approved by the Medical Ethical Committee of the VUMC, Amsterdam, and all participants gave informed consent to participate in the study.

For the microbiological examination, subgingival paper-point samples were taken from the deepest subgingival site in each quadrant of the dentition, and from the mesio-buccal sulcus of each first molar of the controls. The samples were analyzed for the presence of A. actinomycetemcomitans, with the use of trypticase soy-serum-bacitracin-vancomycin agar plates (Slots, 1982), and for P. gingivalis with the use of non-selective blood agar plates (van Winkelhoff et al., 1986).

DNA Isolation
Mouthwash samples were obtained, and DNA was isolated by the mouthwash method, as described previously (Laine et al., 2000).

Analysis of Polymorphisms in Genes
PCR of 35 cycles was performed on a thermal cycler GeneAmp9700 (Perkin-Elmer Cetus, Norwalk, CT, USA). Primers were synthesized (Invitrogen Life Technologies, Breda, The Netherlands), and enzymes were obtained (New England Biolabs, Herts, UK). Overnight-restricted fragments were analyzed on a 4% agarose gel (2% Invitrogen + 2% Nusieve low melting agarose, Tebu-bio, Heerhoevaar, The Netherlands).

CD14-260C>T Gene Polymorphism
Genotyping (NCBI SNP CLUSTER ID: rs2569190) was performed with forward primer 5'-TCACCTCCCCACCTCTCTT-3' and reverse primer 5'-CCTGCAGAATCCTTCCTGTT-3'. The cycle program consisted of 30 sec at 95°C, 30 sec at 59°C, and 1 min at 72°C. HaeIII digestion resulted in two fragments of 83 bp and 24 bp (C allele) or 107 bp (T allele).

TLR4 896A>G (299Asp>Gly) Gene Polymorphism
Genotyping (NCBI SNP CLUSTER ID: rs4986790) was performed with forward primer 5'-TTTACCCTTTCAATAGT CACACTCA-3' and reverse primer 5'-AGCATACTTAGACTAC TACCTCCATG-3'. The cycle program consisted of 94°C for 30 sec, 55°C for 30 sec, and 72°C for 30 sec. NcoI digestion resulted in two fragments of 80 bp and 22 bp (G allele) or 102 bp (A allele).

TLR4 1196C>T (399The>Ile) Gene Polymorphism
Genotyping (NCBI SNP CLUSTER ID: rs4986791) was performed with forward primer 5'- GCTGTTTTCAAAGTGA TTTTGGGAGAA-3' and reverse primer 5'-CACTCATTTGTTT CAAATTGGAATG-3'. The cycle program consisted of 95°C for 30 sec, 60°C for 30 sec, and 72°C for 45 sec. HinfI digestion resulted in two fragments of 121 bp and 25 bp (T allele) or 146 bp (C allele).

Statistical Methods
The CD14-260C>T, TLR4 299Asp>Gly, and 399The>Ile allele, genotype, and carrier frequencies were compared between the control and periodontitis groups by Fisher’s two-tailed exact test. Subsequently, we performed logistic regression analysis to assess the association of different genotypes with periodontitis, adjusting for gender, age, smoking, and prevalence of P. gingivalis and A. actinomycetemcomitans. Since prevalence of P. gingivalis and A. actinomycetemcomitans and smoking have been strongly associated with periodontitis, we investigated whether there was an interaction between these variables and different genotypes. The significant determinants were determined, and adjusted OR and CI were calculated. Differences in genotype frequencies between patient and control subgroups were explored. A p-value < 0.05 was considered statistically significant. Statistical analysis was performed with the use of SPSS version 10.0 for Windows (SPSS Inc., Chicago, IL, USA).

	RESULTS

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Study Population Characteristics
The mean age of the patients was 46.4 yrs (n = 100; range, 28–66 yrs), and that of the control population was 40.5 yrs (n = 99; range, 25–75 yrs) (Table 1).

One hundred patients and 99 periodontally healthy individuals were typed for the CD14-260C>T, the TLR4 299Asp>Gly, and 399The>Ile gene polymorphisms (Table 2). Each individual allele for each locus of CD14-260C>T, TLR4 299Asp>Gly, and 399The>Ile gene polymorphisms was in Hardy-Weinberg equilibrium in the control group.

No significant differences were found in the genotype and allele frequencies for the TLR4 299Asp>Gly and 399The>Ile gene polymorphisms in any of the subgroups. Furthermore, logistic regression analysis showed no association between the TLR4 genotypes and periodontitis.

	DISCUSSION

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The major finding of the present study is the association between the CD14-260T/T genotype and severe periodontitis. The association was found without any corrections but was the strongest when adjusted for age, gender, smoking, and presence of P. gingivalis and A. actinomycetemcomitans. We found the CD14-260T/T genotype to be a risk factor for periodontitis, with the odds ratio 3.0, which was comparable with that of smoking (OR 2.1). The observed CD14-260T/T genotype odds ratio is high in comparison with other published genetic risk factors in multifactorial diseases (OR 1.1–1.5) (Ioannidis et al., 2003). No associations between the TLR4 polymorphisms analyzed and periodontitis were found.

We compared our findings with those from another investigation on the prevalence of the CD14-260T/T genotypes in a Dutch Caucasian population (Murillo, 2003). In this control population (N = 169), with unknown periodontal status, 23.7% were homozygous for the CD14-260T allele, which is similar to findings in our periodontally healthy group (20.2%), and further validates the reported association with periodontitis.

The frequency of the CD14-260T/T genotype in our periodontitis population is comparable with that in Japanese patients (25.0%) (Yamazaki et al., 2003) but higher than in Czech patients (19.2%) (Holla et al., 2002), in whom no association was found between this polymorphism and periodontitis. The frequency of the T/T genotype in our periodontally healthy group (20.2%) was comparable with that found in other control populations (15.6%-34.6%) (Hubacek et al., 1999; Holla et al., 2002; Yamazaki et al., 2003).

The two previous studies did not find any association between the CD14-260T/T genotype and periodontitis (Holla et al., 2002; Yamazaki et al., 2003). The different clinical selection criteria, the ethnic background of the study populations, and the age range of subjects may explain the discrepancies. For example, the age limit of the present study was 25 yrs, whereas the previous studies had a limit of 35 yrs for periodontitis. Moreover, the previous studies did not take into account the presence of the periodontal pathogens P. gingivalis and A. actinomycetemcomitans. Finally, since a specific SNP frequency, as for CD14-260, might also be different in various ethnic populations, differences in linkage disequilibrium with other genetic markers may explain the contradictory results between reported studies.

Variation in the CD14 gene at the interface between the environment and host may skew the immune response by modulating the impact of pathogen exposure. This impact, however, might be modulated by both the time of first exposure and the bacterial load associated with the exposure, variables which might differ greatly in different ethnic, geographic, and urban vs. rural populations (Holla et al., 2002; Yamazaki et al., 2003).

The association found for the CD14-260T/T genotype and periodontitis emphasizes the importance of the choice of functional gene polymorphisms. However, the possible causality of the reported association needs to be established in further studies. We hypothesized that, in periodontitis, the CD14-mediated signaling is involved in a pro-inflammatory pathway through the release of cytokines.

A role for TLR4 signaling has been suggested in periodontal disease (Wang et al., 2003). However, our study demonstrated that the TLR4 polymorphisms studied are not associated with periodontitis. The prevalence of the 299Gly and the 399Ile polymorphisms was 5.0% among Dutch periodontitis patients and controls. In a recent study on these polymorphisms in a Caucasian population, a comparable prevalence for these polymorphisms was reported for periodontitis patients (4.1 to 4.5%) and periodontally healthy controls (3.3% to 3.7%) (Folwaczny et al., 2004). The lack of association could be due to the fact that the heterozygous genotype presents no deficit in the recognition of LPS (Erridge et al., 2003), although the homozygous genotype is functional (Arbour et al., 2000). In our study, we found no patients homozygous for the TLR4 299/399 mutant allele.

We have previously genetically identified a patient group with increased prevalence of certain IL-1 cluster and CARD15 genotypes (Laine et al., 2001, 2004), characterized by the absence of P. gingivalis and A. actinomycetemcomitans and by non-smoking habits. The present study provides a new genetic risk marker for severe periodontitis in adults. In agreement with results from our previous studies, the highest prevalence of the CD14-260T/T genotype was found in a group of patients without two major risk factors for adult periodontitis, i.e., smoking and the presence of P. gingivalis and A. actinomycetemcomitans (50.0% vs. 22.9% in controls). We speculate that the patients with the CD14-260T/T genotype are more susceptible to developing periodontal infections caused by opportunistic pathogens, which otherwise display little pathogenicity.

We hypothesize that periodontitis susceptibility is partly given by the CD14-260T/T genotype. In polygenic diseases such as periodontitis, one genetic variation may be insufficient to cause disease. However, a combination of certain environmental factors and gene polymorphisms may determine the susceptibility and resistance to, and the severity of, an inflammatory process. The additive effect of different gene polymorphisms and environmental factors has previously been reported for severe periodontitis (Laine et al., 2001, 2004).

In conclusion, this is the first report to show that a gene polymorphism of the CD14 receptor, which is involved in LPS recognition, is associated with severe periodontitis in adults. CD14-260 gene polymorphism and our previously identified genetic markers in the IL-1 gene cluster (Laine et al., 2001) may be useful to identify a group of at-risk periodontitis patients.

	ACKNOWLEDGMENTS

 
The present study was supported by The Netherlands Institute for Dental Sciences. L.S. Murillo was a fellow from Prous Science Foundation, Barcelona, Spain, until 12.12.2003. S.A. Morré is supported by the Department of Internal Medicine (VUMC), Tramedico BV, the Netherlands, and by the Falk Foundation, Germany. We thank Laboral Diagnostics for providing patient material, the Dental Clinic of Zaandam, E.G. Winkel, L.J. van Dijk, and A.J. Ham for recruiting patients, A.A.M. Hart for statistical assistance, and Jolein Pleijster for technical assistance.

Received for publication April 20, 2004. Revision received April 28, 2005. Accepted for publication July 13, 2005.

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Journal of Dental Research, Vol. 84, No. 11, 1042-1046 (2005)
DOI: 10.1177/154405910508401114


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