Abstract
Objectives
The purpose of this study was to investigate whether the genetic variations which could regulate inflammatory responses were associated with the risk of peri-implantitis.
Materials and methods
We evaluated three genetic variants including tumor necrosis factor-alpha (TNF-α) − 308G/A, interleukin-1 alpha (IL-1A) − 889C/T, and IL-1 beta (IL-1B) + 3954C/T, as risk factors for peri-implantitis, in a total of 144 patients with peri-implantitis and 174 healthy controls in a Chinese non-smoking population.
Results
Logistic regression analyses revealed that subjects carrying the T allele of IL-1A − 889C/T and IL-1B + 3954C/T had a significant 2.27–2.47-fold (CT, OR [95% CI] = 2.27 [1.12–4.58], p = 0.021; TT, OR [95% CI] = 2.47 [1.32–4.69], p = 0.006) and 1.9–1.99-fold (CT, OR [95% CI] = 1.99 [1–3.93], p = 0.041; TT, OR [95% CI] = 1.9 [1.08–3.43], p = 0.03) increased risk of peri-implantitis, respectively, when using the CC genotype as a reference point. And subjects carrying the TT genotype of IL-1A − 889C/T or IL-1B + 3954C/T also had significantly higher periodontal variables including peri-implant pocket depth (PPD), bleeding on probing (BOP), gingival index (GI), plaque index (PI), calculus index (CI), and clinical attachment level (CAL) (p < 0.05). However, no associations were found between the TNF-α − 308G/A polymorphism and the risk of peri-implantitis.
Conclusions
Our results suggest that the IL-1A − 889C/T or IL-1B + 3954C/T genetic polymorphisms were associated with the risk of peri-implantitis and periodontal status.
Clinical relevance
Genetic polymorphisms are constant and can be measured before disease onset, thus it could be of great benefit for treatment planning and prognosis in an early stage.
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Introduction
Nowadays, dental implants have become the most chosen option for edentulous patients to repair some or all of their missing teeth and yielded promising results. However, implant failures do occur despite adequate surgical and medical treatments [1]. There have been studies that show the presence of peri-implantitis, which represents a destructive inflammation occurring in the tissues surrounding osseointegrated dental implants and resulting in loss of supporting bone [2], is closely related to the occurrence of implants loss [3, 4]. Many systemic and local factors, such as pathogenic bacteria, lack of oral hygiene, smoking, and alcohol consumption, have been related to the development of peri-implantitis [5, 6]. Also, gene susceptibility has been considered as one of the common etiologies of peri-implantitis, which is revealed by the fact that implant losses tend to cluster in subsets of individuals when exposed to similar risk factors, and patients with one implant failure likely suffer from additional failures [7, 8]. Genetic variations are differences in DNA sequence which may affect the function of genes. Based on the inflammatory nature of peri-implantitis, genetic variations which could influence inflammatory cytokine secretion and regulate inflammatory responses have been extensively investigated.
The variations of tumor necrosis factor-alpha (TNF-α) gene and interleukin-1 (IL-1) gene cluster, including IL-1 alpha (IL-1A) and IL-1 beta (IL-1B) genes, are most commonly studied functional polymorphisms for dental implant loss, peri-implantitis, and marginal bone loss [9, 10]. Both the TNF-α and IL-1 are pro-inflammatory cytokines which play significant roles in inflammatory processes [11]. The expression of TNF-α, which is mainly produced by macrophages, has been found to be associated with periodontitis [12, 13], and increases the local secretion and activity of metalloproteinase, resulting in peri-implant tissue destruction and bone resorption by activating osteoclast maturation [14]. Similarly, IL-1 is considered as a major mediator of the osseointegration process [15] and plays an important role in the process of bone destruction and resorption by regulating the production of matrix metalloproteinase (MMP) [16].
Thus, functional polymorphisms in these genes, which could affect the expression levels and protein functions, may influence the development of peri-implantitis. Single-nucleotide polymorphisms (SNPs) are the most common type of genetic variation among people. Many studies have investigated different SNPs in the TNF-α and IL-1 genes as risk factors for dental implant failure and peri-implantitis. Among them, the TNF-α − 308G/A (rs1800629), IL-1A − 889C/T (rs1800587), and IL-1B + 3954C/T (rs1143634) have been mostly investigated [9, 10], because these SNPs have been demonstrated to be associated with directly changed levels of gene expression and secreted cytokines [17, 18]. However, studies have yielded conflicting results on this issue [19,20,21,22,23].
In the present study, we aimed to investigate whether the three functional variants (TNF-α − 308G/A, IL-1A − 889C/T, and IL-1B + 3954C/T) were associated with the risk of peri-implantitis in a Chinese non-smoking population.
Materials and methods
Patients and controls
The present study is a hospital-based case-control study. It was approved by the ethics committee of West China Hospital of Stomatology (81400549). All participants provided written informed consent to approve the use of their oral samples for research purposes. All procedures performed in the study were in accordance with the Helsinki declaration. A total of 144 patients diagnosed with peri-implantitis (TEST group) and 174 individuals with peri-implant health (control group) were recruited between January 2016 and September 2018. All participants were genetically unrelated to ethnic Han Chinese.
The clinical parameters for the subject population were collected, including age, sex, peri-implant pocket depth (PPD), bleeding on probing (BOP), gingival index (GI), plaque index (PI), calculus index (CI), clinical attachment level (CAL), and dental mobility (present or absent). For peri-implantitis patients, inclusion criteria were as follows: (1) PPD ≥4 mm; (2) positive BOP; (3) positive GI; (4) positive PI; (5) recorded radiographic signs of pathologic bone loss involving ≥ 2 threads compared with the radiograph taken at the time of prosthetic replacement. For peri-implant health individuals, inclusion criteria were as follows: (1) healthy peri-implant tissue and implant-supported restorations after at least 2 years of loading; (2) PPD <3 mm; (3) no BOP; (4) no radiographically evidenced bone loss. Moreover, the exclusion criteria were as follows: (1) smokers; (2) pregnancy and lactation; (3) general health problems including diabetes mellitus, HIV infection, and other chronic diseases; (4) intake of any antibiotics and anti-inflammatory drugs in the past 3 months.
DNA collection, purification, and polymorphism detection
A total of 318 buccal epithelial cell samples from 144 patients and 174 healthy controls were collected and used in the present study. For each subject, a sterile wood spatula was used to scrape oral mucosa, after a mouthwash with 3% glucose solution. The tip of the spatula was immediately shaken into the mouthwash solution. Buccal epithelial cells were pelleted by centrifugation at 2000×g for 10 min. The supernatant was discarded. And genomic DNA was isolated from the cell pellet using the QIAamp DNA Mini Kit (QIAGEN, Germany), in accordance with the manufacturer’s protocol. After that, the genomic DNA was either stored at − 80 °C or SNP genotyping was conducted on it immediately.
The polymorphisms of three selected genetic variants were determined by the TaqMan SNP Genotyping Assay (Thermo Fisher, USA), Briefly, 30–60 ng of DNA was amplified using TaqMan Genotyping Master Mix (Thermo Fisher, USA) and commercial probes (Thermo Fisher, USA) for TNF-α − 308G/A (rs1800629), IL-1A − 889C/T (rs1800587), and IL-1B + 3954C/T (rs1143634) in a final volume of 25 μL. PCR thermal cycling conditions were as follows: 10 min at 95 °C for AmpliTaq Gold, UP Enzyme activation, and then 40 cycles of denaturation at 95 °C for 15 s, and annealing/extension at 65 °C for 1 min.
Statistical analysis
The statistical analyses were performed using the SPSS version 19.0 software. Differences in genotype distribution between groups were evaluated using Pearson’s chi-squared test. Risks for developing peri-implantitis were estimated by calculating the odds ratio (OR) and the 95% confidence interval (CI) from logistic regression analyses. Continuous variables were expressed as mean and standard deviation (SD). The Mann-Whitney U test was used to determine the differences for continuous variables. A p value of less than 0.05 was considered statistically significant. In addition, the sample size required to achieve statistically significant associations were calculated using the G*Power version 3.1.7 software. The parameters used in sample size calculations were as follows: power of 80%, α of 0.05, and degrees of freedom of 1. It estimated a sample size of < 100 cases. Thus, our sample size was sufficient to identify significance towards three selected genetic variants in association with peri-implantitis.
Results
Characteristics of the study population
The baseline information of all sampled subjects is summarized in Table 1. A total of 318 unrelated subjects who had at least one dental implant inserted were recruited in this study. The mean age was 44.7 ± 8.6 years (range 30–60 years). No statistical differences were found in age, gender, alcohol consumption, dental implant platform type and position, peri-implant phenotype, and hygiene habits between the two groups (p > 0.05). However, positive history of periodontitis was significantly more frequent in the TEST group than in the control group (54.2% . 33.3%, p = 0.0002). Evaluating the periodontal status, all variables including GI, PI, CI, PPD, and CAL were significantly higher in peri-implantitis when compared with peri-implant health (p < 0.05), except for the presence of dental implant mobility (Table 2).
Allele frequencies
As shown in Table 3, the distribution of allele frequencies did not differ for TNF-α − 308G/A between the TEST and control groups (17.7% vs. 12.6%, p = 0.0745). However, statistically significant differences were observed in the distribution of the mutated allele for IL-1A − 889C/T and IL-1B + 3954C/T, in which the frequencies of the T allele (29.9% vs. 15.8%, p < 0.0001 and 31.2% vs. 20.1%, p = 0.0013, respectively) were higher in the TEST group. These deviations could have been due to genetic associations with the risk of peri-implantitis.
Association of TNF-α and IL-1 polymorphisms with a risk of peri-implantitis
The associations between the risk of peri-implantitis and the genotypes for the TNF-α − 308G/A, IL-1A − 889C/T, and IL-1B + 3954C/T were evaluated (Table 4). Dominant and recessive models are tests for the minor allele with two of the classes pooled. In the single-locus analyses, the genotype frequencies of IL-1A − 889C/T were 62.5% (CC), 15.3% (CT), and 22.2% (TT) in the TEST group and 79.9% (CC), 8.6% (CT), and 11.5% (TT) in the control group; the difference was significant for the CT and TT genotypes (p = 0.021 and p = 0.004 respectively), when using the CC genotype as a reference point. Logistic regression analyses revealed that subjects carrying the T allele of IL-1A − 889C/T had a significant 2.27–2.47-fold (CT vs. CC, OR 2.27, 95% CI 1.12–4.58; TT vs. CC, OR 2.47, 95% CI 1.32–4.69) increased risk of peri-implantitis. Also, the IL-1A − 889C/T was significant in both dominant (CT + TT vs. CC, OR 2.38, 95% CI 1.43–3.96, p = 0.0006) and recessive (CC + CT vs. TT, OR 2.2, 95% CI 1.2–4.11, p = 0.01) models. Moreover, subjects carrying the T allele of IL-1B + 3954C/T had a significant 1.9–1.99-fold increased risk of peri-implantitis (CT vs. CC, OR 1.99, 95% CI 1–3.93, p = 0.041; TT vs. CC, OR 1.9, 95% CI 1.08–3.43, p = 0.03), and it was also significant in the dominant model (CT + TT vs. CC, OR 1.94, 95% CI 1.21–3.15, p = 0.006). However, the TNF-α − 308G/A did not exhibit a statistically significant difference in the genotype distributions between the two groups.
Association of analyzed gene polymorphisms with periodontal status
We investigated the association between the three gene variants and the periodontal index (Table 5). Our results suggest that subjects carrying the TT genotype of IL-1A − 889C/T or IL-1B + 3954C/T had a significantly higher GI, PI, CI, PPD, and CAL (p < 0.05), when using the CC genotype as a reference point. There were also significantly higher GI and CAL for subjects carrying the CT genotype of IL-1A − 889C/T (1.78 ± 1.04 vs. 1.25 ± 1.13, p = 0.007, and 3.54 ± 1.9 vs. 2.66 ± 1.82 mm, p = 0.014, respectively), and PI for subjects carrying the CT genotype of IL-1B + 3954C/T (1.76 ± 1.02 vs. 1.38 ± 1.03, p = 0.027). In addition, no associations were found between the TNF-α − 308G/A polymorphism and the periodontal status.
Discussion
Any intense inflammatory response is supposed to stimulate the resorption of supporting bones and damage the process of osseointegration, leading to implant failure [14,15,16]. TNF-α and IL-1 play critical roles in the immune-inflammatory response. And in vitro study has demonstrated that the A allele of TNF-α − 308G/A, which was located in the promoter region of human TNF-α gene, was a strong transcription activator, resulting in a sevenfold increase of TNF-α levels [18]. Similarly, the polymorphic IL-1A − 889C/T is also located in the promoter region of human IL-1A gene, and the T allele of this polymorphism significantly enhances the transcriptional activity of the gene [17]. The T to C substitution of IL-1B + 3954C/T, which is located in exon five of human IL-1B gene, could lead to a synonymous change, and it has been demonstrated that T allele was associated with a significantly increased production of IL-1B in vitro [24]. Thus, many studies have investigated the association between these genetic variations and the development of dental implant disease including implant failure, peri-implantitis, and marginal bone loss. However, most of the studies focused on Caucasian populations and the results are still controversial [9, 10]. These differences in results between studies might be caused by limited sample size, various defined inclusion/exclusion criteria, ethnicity of subjects, potential gene-environment interactions, and confounders such as age, sex, and smoking. To the best of our knowledge, the present study is the first to provide reliable evidence about the association between these gene polymorphisms and the risk of peri-implantitis in a Chinese non-smoking population. Genetic polymorphisms are constant and can be measured before disease onset, thus it could be of great benefit for individuals who are at high risk of peri-implantitis, because clinicians could suggest targeted risk reduction strategies in an early stage.
The presence or history of periodontitis is one of the most studied risk factors for peri-implantitis. Previous studies have demonstrated that peri-implantitis-related biofilm was similar to that of periodontitis, comprising high levels of periodontal pathogens [25, 26]. And it has been reported that the microflora present in the oral cavity before implantation determines the composition of the newly establishing microflora on implants [27], suggesting that patients with a history of periodontitis might be at high risk for peri-implantitis. In a recent meta-analysis, Ferreira et al. evaluated 19 eligible studies and found that the presence or history of periodontitis was significantly associated with the occurrence of peri-implantitis [28]. In the present study, our results also demonstrated that there was a significant association between the history of periodontitis and peri-implantitis. For TNF-α − 308G/A polymorphism, two previous studies have investigated the association of this genetic variant with the risk of peri-implantitis [19, 20]. Cury et al. demonstrated that the TNF-α − 308G/A polymorphism was not associated with an increased risk of peri-implantitis in Caucasian non-smoking Brazilian patients (49 cases and 41 controls) [19], while another study by Rakic et al. which includes 369 Southeastern Europe Caucasians (180 cases and 189 controls) demonstrated that AG genotype was associated with peri-implantitis and a fivefold increased risk [20]. Although the number of relevant studies is small, in a recent meta-analysis, the results showed that the pooled ORs did not reveal a significant relationship between the TNF-α − 308G/A polymorphism and risk of peri-implantitis (OR 1.13, 95% CI 0.72–1.78, p = 0.509), as well as implant failure [10]. Consistently, our results demonstrated that the TNF-α − 308G/A polymorphism was not strongly associated with the risk of peri-implantitis and any variable of individuals’ periodontal conditions in a Chinese non-smoking population.
The IL-1A − 889C/T and IL-1B + 3954C/T are two of the most widely studied genetic variants in the issue of implant failure and peri-implant disease [9]. But there were only four studies that have investigated its associations with the risk of peri-implantitis, in which one obtained positive results [22], and the 3 others yielded negative results [21, 23, 29]. Hamdy et al. demonstrated that having T allele at both IL-1A − 889C/T and IL-1B + 3954C/T in patients with inflamed periodontal or peri-implant tissues was a risk factor that leads to greater tissue destruction [22], while Laine et al. reported that no associations were found between the two gene polymorphisms and the risk of peri-implantitis in 120 North Caucasian individuals [21]. Lachmann et al. found that the composite genotype of IL-1A − 889C/T and IL-1B + 3954C/T was not associated with peri-implant crevicular fluid volume and concentrations of crevicular inflammatory mediators [29]. And there was also no significant difference in the concentration of IL-1B detected in the crevicular sulcular fluid between the peri-implantitis patients and controls [23]. However, in a meta-analysis by Liao et al., the results showed that the composite genotype of IL-1A − 889C/T and IL-1B + 3954C/T was significantly associated with an increased risk of peri-implantitis in European descents (OR 2.34, 95% CI 1.03–5.33) [9]. Similar to that, in the present study, we found that subjects carrying the T allele of IL-1A − 889C/T or IL-1B + 3954C/T had a significantly increased risk of peri-implantitis and higher periodontal variables including GI, PI, CI, PPD, and CAL.
There are several limitations that should be acknowledged. The sample size was not large enough to achieve nominal significance, which is often in the 1000 to 10,000 range [30]. And the recruited subjects may not be representative of the general population, because it was a hospital-based case-control study. Further studies are required to confirm the present findings. In conclusion, our results demonstrated that the IL-1A − 889C/T or IL-1B + 3954C/T genetic polymorphisms were associated with the risk of peri-implantitis and periodontal status in a Chinese non-smoking population.
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This work was supported by the grants from the National Natural Science Foundation of China (No.81400549).
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He, K., Jian, F., He, T. et al. Analysis of the association of TNF-α, IL-1A, and IL-1B polymorphisms with peri-implantitis in a Chinese non-smoking population. Clin Oral Invest 24, 693–699 (2020). https://doi.org/10.1007/s00784-019-02968-z
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DOI: https://doi.org/10.1007/s00784-019-02968-z