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Keywords: meta, periodontitis, polymorphisms, susceptibility, tumor necrosis factor-alpha
Abstract
The association between tumor necrosis factor-alpha (TNF-α-308G/A, -238G/A, -863C/A, -1031T/C, and -857C/T) polymorphism and either chronic (CP) or aggressive (AgP) periodontitis susceptibility was conflicting. This meta-analysis aimed to quantitatively estimate the association.
A total of 52 studies involving 5519 patients and 7260 controls were identified through a search of multiple electronic databases. Odds ratios (ORs) and their 95% confidence intervals using allele, homozygous, heterozygous, dominant, and recessive genetic models were computed to assess the strength of the association.
The TNF-α-308G/A polymorphism was significantly associated with decreased risks of CP (GG vs AA: OR = 0.353, P < .001; GG+GA vs AA: OR = 0.480, P < .001) and AgP (G vs A: OR = 0.651, P < .001; GG vs AA: OR = 0.306, P < .001; GG+GA vs AA: OR = 0.384, P < .001) in Asians. There were no associations between TNF-α-238G/A, -863C/A, -1031T/C, -857C/T polymorphism and susceptibility to AgP. No associations were also found between CP susceptibility and TNF-α-238G/A, -857C/T polymorphism.
These findings supported that TNF-α-308G/A polymorphism might be the protective factors of CP and AgP in Asians, and TNF-α-238G/A, -863C/A, -1031T/C, -857C/T polymorphism is not linked to AgP susceptibility.
1. Introduction
Periodontal disease is a group of inflammatory disorders, primarily initiated by a chronic bacterial infection and related to the host response.[1] It is one of the causes of tooth loss and can be correlated with systemic diseases, such as arthritis and diabetes.[2] Majority of the population have experienced some levels of gingival inflammation worldwide, and 5% to 8% of the population suffering from severe forms of periodontitis.[3] Periodontitis is divided into chronic periodontitis (CP) and aggressive periodontitis (AgP).[4] There are many factors that cause periodontitis, including bacterial infection, genetic factors, and environmental factors. Common causes include stimulation of plaque, tartar, and smoking. Among them, plaque is considered to be the initiating factor for periodontitis.[5,6] Plaques colonized in periodontal tissues can trigger the host's autoimmune and inflammatory responses, thereby affecting the progress and severity of the disease. In addition, some genetic factors can cause changes in the expression of encoded proteins and their levels, alter the host's immune and inflammatory response, and then affect the development of periodontitis.[7]
Numerous studies have shown that nearly half of the clinical differences in periodontal disease stem from genetic polymorphisms.[8] Among these genes, tumor necrosis factor-alpha (TNF-α) has been considered as an important contributor to the pathogenesis of periodontal diseases. Bacterial pathogens in dental plaque can stimulate TNF-α secretion, cause osteoclast differentiation and bone resorption.[9] TNF-α is produced by diverse kinds of cells including macrophages, neutrophils, keratinocytes, fibroblasts, T and B cells after stimulation.[10] It is a potent proinflammatory cytokine and immune modulator with wide-ranging biological effects including protection from infection, surveillance against tumors, and stimulation of inflammatory responses.[11–14] It also can trigger various immune and inflammatory process, including adhesion of polymorphonuclear leukocytes to endothelial cells,[15] phagocyte a ctivation, and intercellular cell adhesion molecule-1 expression,[16] as well as having roles in necrosis and apoptosis.
TNF-α gene is located in 6p21.3 and has several functional polymorphism sites. Single-nucleotide polymorphisms (SNP) within TNF-α have the potential to affect the function or regulation of TNF-α production.[17] Several SNPs have been identified in its promoter. The TNF-α-308G/A (rs1800629), -238G/A (rs361525), and -863C/A(rs1800630) in the promoter region of the TNF-α gene are 3 common functional polymorphisms that have been demonstrated to be associated with the production level of the cytokine.[18] The TNF-α-1031T/C (rs1799964), -857C/T(rs1799724) are newly discovered gene polymorphism that affect periodontitis susceptibility in recent years.[19,20] A recent meta-analysis of TNF-α gene polymorphisms and susceptibility to periodontitis suggested that the TNF-α-308G/A and -863C/A AA genotypes contribute to susceptibility to CP, while the -308G/A polymorphism is connected with increased risk of AgP.[18] During the past few years, the number of original studies linking TNF-α gene polymorphism to periodontitis has doubled. However, not all researchers confirmed the previous findings, and the controversy on this topic continues. In addition, no one has done a meta-analysis of the relationship between TNF-α-1031T/C, -857C/T gene polymorphism, and susceptibility to periodontitis. With accumulating evidence, we therefore aimed to examine the associations between TNF-α gene polymorphisms and periodontitis susceptibility by conducting an updated meta-analysis of original studies.
2. Materials and methods
Since all analyses were based on previously published studies, no ethical approval and patient consent were required.
2.1. Search strategy
Four electronic databases, namely, PubMed, Web of Science, Embase, and the Chinese National Knowledge Infrastructure databases, were searched in May 2019 by 2 independent reviewers (LX and ZZ). The following terms were used in this search: (Tumor Necrosis Factor-alpha OR TNF-alpha OR TNF-α OR rs1800629 OR rs361525 OR rs1800630 OR rs1799964 OR rs1799724) AND (polymorphism OR mutation OR variant) AND (periodontitis OR periodontal disease OR periodontal pocket OR alveolar bone loss OR attachment loss OR attachment level OR tooth mobility). Furthermore, references in related studies or reviews were also reviewed by hand searching to identify additional eligible studies.
2.2. Inclusion and exclusion criteria
The included studies must meet the following 5 criterias: All published case-control studies and cohort studies of TNF-α-308G/A, -238G/A, -863C/A, -1031T/C, and -857C/T gene polymorphisms related to susceptibility to periodontitis; For adults over 18 years of age, the clinical diagnosis was CP or AgP, the correct diagnostic criteria and methods of CP and AgP were clearly mentioned, and the control group was a normal healthy population; The original literature had the allele and genotype distribution data that was detailed or could calculate through the data provided in the article, and could calculate odds ratio (OR) and 95% confidence interval (95%CI); Included studies were research reports published in English or Chinese with full text.
The exclusion criteria were as follows: Nonmedical case-control literature; Duplicate publication; Data was incomplete, genotype frequency couldn’t be calculated, and experimental results were unclear; There were obvious design flaws, and the quality of the literature was poor.
2.3. Quality assessment
The quality of each study was evaluated independently by 2 reviewers (LX and ZZ) according to the criteria described by Nibali.[21] The categories in scoring system used for assessing study quality were as follows: selection, comparability, exposure, study methodology/design, and genetic analyses. The details of each methodological item were listed in Supplementary Table S1. Scores ranged from 0 (lowest) to 20 (highest), and studies with scores ≥10 were classified as high-quality studies, whereas studies with scores < 10 were classified as low-quality studies.
2.4. Data extraction
Two investigators (LX and ZZ) individually checked the titles and abstracts, and then selected the relevant full-text articles, according to the inclusion criteria. Any disagreement was resolved via discussion or adjudicated by a third author. The following information was collected from each study: first author, publication year, country/region, the number of cases and controls, the racial descent-Caucasian, Asian and Mixed (If the authors did not clearly report the ethnic information or we could not separate them according to genotypes distribution, the ethnicity was classified as “Mixed”), clinical types of periodontitis, genotyping method, and genotype/allele distribution in both cases and controls, and evidence of Hardy-Weinberg equilibrium (HWE). A P value less than .05 of HWE was considered significant.
2.5. Statistical analysis
Statistical analysis was performed by using Stata software (Version 12.0, Stata Corp, College Station, TX). The associations of the TNF-α gene polymorphisms and susceptibility to periodontitis were estimated by calculating the pooled ORs and 95% CIs. This study used Bonferroni correction method, and the adjusted significance threshold was set at 0.01 (0.05/5) for single polymorphism since 5 polymorphisms were analyzed. Heterogeneity was tested by the Q test and I2 statistics. If the result of the Q test was P value > .05 and I2 < 50%, indicating the absence of heterogeneity, then a fixed-effects model was used to estimate the summary ORs; otherwise, the random-effects model was used. The rank correlation method of Begg[22] and Egger[23] linear regression method were used to evaluate potential publication bias. P value < .05 was used as an indication for the presence of potential publication bias.
3. Results
3.1. Literature search
A total of 303 published articles were identified from 4 databases, and 3 articles were found by hand research. When we removed the duplicates, 156 articles were selected. After reading the title and abstract, 87 of these articles were excluded, leaving 69 studies for full publication review. Finally, 52 studies containing a total of 5519 patients and 7260 controls were included in this meta-analysis (Supplementary Figure S1).
3.2. Study characteristics
The main characteristics of the included studies were summarized in Supplementary Table S2. Among these studies, 45 studies investigated the -308G/A polymorphism, 10 studies investigated the -238G/A polymorphism, 8 studies investigated the -863C/A polymorphism, 5 studies investigated the -1031T/C polymorphism, 7 studies investigated the -857C/T polymorphism. Twenty-three studies were performed in Asians, 21 studies were performed in Caucasians, and 8 studies were performed in Mixed. In terms of the type of periodontitis, 31 studies focused on CP, 10 studies focused on AgP and 11 studies focused on both CP and AgP. In the 52 included studies, 41 studies were in accordance with HWE for the genotype distribution, whereas 7 studies represented a significant departure from HWE.
3.3. TNF-α-308G/A(rs1800629) polymorphism
Significant association of the -308G/A polymorphism with protective factors for CP was only detected in Asians under homozygous model and dominant model (GG vs AA: OR=0.353, 95% CI: 0.241–0.515, P < .001; GG+GA vs AA: OR = 0.480, 95% CI: 0.338–0.684, P < .001) (Table 1 and Supplementary Figure S2). Significant heterogeneity was seen in Asians under the allele and recessive models. To explore potential source of heterogeneity across the studies, we performed sensitivity analyses. The results indicated that 3 studies[24–26] might be the major source of the heterogeneity in Asians. When we excluded these studies and repeated the analysis, heterogeneity was no longer present, and significant association was also found in Asians under the allele and recessive models (G vs A: OR = 0.587, 95% CI: 0.445–0.774, P < .001; GG vs GA+AA: OR = 0.466, 95% CI: 0.361–0.602, P < .001) (Supplementary Figure S4-S5). After exclusion of the studies that deviated from HWE, significantly correlations were found in Asians in 4 genetic models tested (G vs A: OR = 0.491, 95% CI: 0.395–0.609, P < .001; GG vs AA: OR = 0.292, 95% CI: 0.145–0.590, P = .001; GG vs GA+AA: OR = 0.468, 95% CI: 0.367–0.596, P < .001; GG+GA vs AA: OR = 0.337, 95% CI: 0.164–0.693, P = .003) (Table 1).
Table 1.
Meta-analysis of the association between TNF-α-308G/A(rs1800629) polymorphism and chronic periodontitis.
The results showed significant associations of the -308G/A polymorphism with AgP in Asians under the allele (G vs A: OR = 0.651, 95% CI: 0.526–0.806, P < .001), homozygous (GG vs AA: OR = 0.306, 95% CI: 0.169–0.551, P < .001), recessive (GG vs GA+AA: OR = 0.677, 95% CI: 0.523–0.876, P = .003), and dominant (GG+GA vs AA: OR = 0.384, 95% CI: 0.227–0.650, P < .001) models, but not in Caucasians and Mixed (Table 2 and Supplementary Figure S6, S7, S8 & S9). And there was no evidence of statistical heterogeneity in all populations. After exclusion of the studies that deviated from HWE, significantly correlations were found in Asians in 4 genetic models (G vs A: OR = 0.717, 95% CI: 0.565–0.909, P = .006; GG vs AA: OR = 0.317, 95% CI: 0.143–0.699, P = .004; GA vs AA: OR = 0.315, 95% CI: 0.138–0.716, P = .006; GG+GA vs AA: OR = 0.318, 95% CI: 0.146–0.693, P = .004) and in Caucasians (G vs A: OR = 0.606, 95% CI: 0.417–0.880, P = .009) (Table 2).
Table 2.
Meta-analysis of the association between TNF-α-308G/A (rs1800629) polymorphism and aggressive periodontitis.
3.4. TNF-α-238G/A(rs361525) polymorphism
The results of the associations between TNF-α-238G/A polymorphism and CP susceptibility were that no model was statistically significant in Asians and Caucasians. And there were greater heterogeneity in the 2 races, when we performed sensitivity analysis, the exclusion of the studies[27,28] with heterogeneity did not change the results significantly. After excluding the HWE violation study, the results were still not statistically significant (Table 3). The relations of TNF-α-238G/A polymorphism and AgP susceptibility were also no statistical correlation (Table 4).
Table 3.
Meta-analysis of the association between TNF-α-238G/A (rs361525) polymorphism and chronic periodontitis.
Table 4.
Meta-analysis of the association between TNF-α-238G/A (rs361525) polymorphism and aggressive periodontitis.
3.5. TNF-α-863C/A(rs1800630) polymorphism
The results of the associations between TNF-α-863C/A polymorphism and CP susceptibility were that no model was statistically significant. And the exclusion of the studies[29] with heterogeneity did not change the results significantly. And after exclusion of the studies that deviated from HWE, significantly correlations were found in Asians in 2 genetic models tested (C vs A: OR = 0.661, 95% CI: 0.515–0.849, P = .001; CC vs CA+AA: OR = 0.654, 95% CI: 0.488–0.877, P = .005) (Table 5). The relations of TNF-α-863C/A polymorphism and AgP susceptibility were also no statistical correlation (Table 6).
Table 5.
Meta-analysis of the association between TNF-α-863C/A (rs1800630) polymorphism and chronic periodontitis.
Table 6.
Meta-analysis of the association between TNF-α-863C/A (rs1800630) polymorphism and aggressive periodontitis.
3.6. TNF-α-1031T/C(rs1799964) polymorphism
In Asians, significant association was found between the TNF-α-1031T/C polymorphism and CP susceptibility under the homozygous model (TT vs CC: OR = 0.557, 95% CI: 0.388–0.798, P = .001) (Table 7 and Supplementary Figure S10). And the results of the relation of TNF-α-1031T/C polymorphism and AgP susceptibility were that no model was statistically significant (Table 8). When we performed sensitivity analysis, the exclusion of the studies[20,26] with heterogeneity did not change the results significantly. In addition, when stratified by HWE studies, all findings were negative.
Table 7.
Meta-analysis of the association between TNF-α-1031T/C (rs1799964) polymorphism and chronic periodontitis.
Table 8.
Meta-analysis of the association between TNF-α-1031T/C (rs1799964) polymorphism and aggressive periodontitis.
3.7. TNF-α-857C/T(rs1799724) polymorphism
Five studies[20,26,30–32] investigated TNF-α-857C/T polymorphism and its associations with CP. Another 5 studies[19,20,26,30,33] investigated -857C/T polymorphism and its associations with Agp. Heterogeneity tests showed that the associations of -857C/T gene polymorphisms with CP and AgP in Asians were derived from stable results. So we used fixed-effects models and no model was statistically significant (Tables 9 and 10). When stratified by HWE studies, all findings were negative.
Table 9.
Meta-analysis of the association between TNF-α-857C/T (rs1799724) polymorphism and chronic periodontitis.
Table 10.
Meta-analysis of the association between TNF-α-857C/T (rs1799724) polymorphism and aggressive periodontitis.
3.8. Publication bias
Begg funnel plot and Egger test were performed to assess the publication bias of included studies. As shown in Supplementary Figure S11, the shapes of the funnel plots did not reveal any indication of publication bias. Besides, Egger test was used to provide statistical evidence of funnel plot symmetry, and the results did not show any evidence of publication bias. All P values from the Egger test were > .05 (data not shown).
4. Discussion
TNF-α, also known as cachexia or TNFSF1A, is a prototype ligand of the TNF superfamily. It is a pleiotropic molecule that plays an important role in inflammation, immune system development, apoptosis, and lipid metabolism.[34] It is also a pro-inflammatory cytokine with immunoregulatory function. It has extensive biological effects on leukocytes, vascular endothelial cells, and other cells in connective tissue. TNF-α can lead to the destruction of connective tissue and enhance the formation and activity of osteoclasts, finally limiting the repair of periodontal tissue.[35]
To date, numerous studies evaluated the association between TNF-α gene polymorphisms and periodontitis susceptibility have been published, but the results were inconsistent. A meta-analysis first published by Nikolopoulos GK in 2008[36] (involving15 studies) showed that there was no association of the TNF-α-308G/A gene polymorphism with periodontitis. Other meta-analysis published in 2013[37] (involving 17 studies for -308G/A,3 studies for -238G/A) found that TNF-α-308G/A A allele was associated with periodontitis in Brazilian, Asian, and Turkish populations, no association between the TNF-α-238G/A gene polymorphism and periodontitis. The recent meta-analysis published in 2014[18] (31 studies for -308G/A, 7 studies for -238G/A, and 6 studies for -863C/A) concluded that the TNF-α-308G/A and -863C/A AA genotypes contributed to susceptibility to CP, while the -308G/A polymorphism was associated with increased risk of AgP. No considerable association was identified between TNF-α-238G/A polymorphism and CP. Recently, many new studies subsequent to these meta-analyses have emerged, but a consensus has not been reached. Therefore, there is a need to carry out this updated meta-analysis to summarize the latest relationship between TNF-α gene polymorphism and periodontitis susceptibility.
To our knowledge, this meta-analysis is so far the largest that had evaluated TNF-α polymorphisms with periodontitis susceptibility. Thus, the results of our meta-analysis were more reliable than those of previous studies. In this meta-analysis, we collected all the related studies up to date and re-evaluated the association between -308G/A polymorphism and periodontitis. We found that the genotype GG and the GG + GA in the dominant model (GG+GA vs AA) were the protective factors of CP. After conducting a sensitivity analysis to remove the study of greater heterogeneity and reanalysis, we found that the allele G was also the protective factor of CP in Asians. When limited to HWE studies, associations were also found in 4 genetic models in Asians.
In the AgP study, it was also found that there was a statistical correlation between the TNF-α-308G/A gene polymorphism and the susceptibility to AgP in the Asians. This indicated that the allele G, GG genotype, and the GG+GA in dominant model (GG+GA vs AA) were the protective factors of AgP. When limited to HWE studies, associations were also found in 4 genetic models in Asians. For both CP and AgP, we observed the effects of TNF-α gene polymorphisms and susceptibility to periodontitis for Asians were stronger than Caucasians and Mixed. Therefore, we speculated that there may be ethnic differences in the correlation between the TNF-α-308G/A gene polymorphism and the susceptibility to periodontitis.
For the TNF-α-238G/A gene polymorphism, we saw no model was statistically significant in the original study and HWE study in CP and AgP. This indicated that -238G/A gene polymorphism had no connection with periodontitis susceptibility. This result was the same as the meta-analysis which in 2014.[18] Shungin et al[38] and Masumoto et al[39] also recently reported no association between the -238G/A gene polymorphism and CP susceptibility as reported in the genome-wide association study. In the future, we still need a lot of time and data to explore the relationship between -238G/A gene polymorphism and susceptibility to periodontitis.
There were many studies on the correlation between -863C/A gene polymorphism and disease. In 1999, Skoog et al[40] found that -863C/A was associated with the disease severity. A SNP at position -863 was involved in NF-κB binding affecting the transcriptional regulation. TNF-863A allele lessened the NF-κB p50/p50 binding that directed the enhanced TNF production in human monocytes.[41] In 2003, Soga's study demonstrated that −863C/A A allele was a risk factor for CP.[32] These meaned -863C/A gene polymorphism may have impact on disease. However, we observed no relationship between the TNF-α-863C/A gene polymorphism and susceptibility to CP and AgP in this meta-analysis. The results were completely opposite to the previous analysis. It may be because we included much more studies than the previous ones. As new researches accumulated, the correlation changes from significant to nonsignificant. Thus, more researches are still required to verify the association between -863C/A gene polymorphism and periodontitis.
Our study was the first meta-analysis documented an association between TNF-α-1031T/C gene polymorphisms and periodontitis susceptibility. Our data showed that TT genotype may be an important protective factor for CP patients in Asians. A recent study showed[42] in -1031T/C gene polymorphisms, homogeneous risk allele -1031C genotype had remarkably higher TNF expression than homogeneous reference allele -1031T genotype, this finding was confirmed in our meta-analysis. In addition, some studies have shown that TNF-α-863C/A and TNF-α-1031T/C could stimulate expression and protein secretion of TNF RNA.[43–46] Therefore, we speculated that TNF-α-1031T/C may also control the progression of periodontitis by increasing RNA expression and cytokine levels.
To our knowledge, the present study was also the first meta-analysis which assessed the possible influence of TNF-α-857C/T gene polymorphism on susceptibility to periodontitis. Based on analysis results, our study suggested that -857C/T gene polymorphisms were not related to periodontitis. Due to the small sample size and single ethnicity included, this result was unstable. We need to conduct high-quality research in large populations to get more accurate results.
Several limitations of this meta-analysis should be noticed. First, studies included in our meta-analysis were mainly English and Chinese published articles, which may have caused a selection bias. Second, we did not think out gene–gene and gene–environmental interactions in the case-control study. Third, the number of included studies in the meta-analysis was still small, we could not perform a more precise analysis based on adjusted information. Fourth, the authors observed the presence of elevated heterogeneity in some comparisons herein presented. Beyond the statistical heterogeneity, there was also the clinical heterogeneity. Periodontitis and its diagnosis were characterized by variations since severity and forms of disease until diagnosis, what may be a potential bias in studies. Therefore, the results should be interpreted with caution.
5. Conclusions
In spite of the limitations mentioned above, the results of this meta-analysis suggested that TNF-α-308G/A polymorphism might be the protective factors of CP and AgP in Asians, and TNF-α-238G/A, -863C/A, -1031T/C, -857C/T polymorphism is not linked to AgP susceptibility. However, given the limitations of this meta-analysis, we cannot obtain a conclusive result. In future, additional well-designed studies are necessary to clarify these relationships and thus reinforce our findings.
Author contributions
Data curation: Lishuo Xu.
Methodology: Lishuo Xu, Youli Zheng.
Project administration: Chenguang Liu.
Writing – original draft: Lishuo Xu, Chenguang Liu.
Writing – review & editing: Youli Zheng.
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Footnotes
Abbreviations: AgP = aggressive periodontitis, CI = confidence interval, CP = chronic periodontitis, HWE = Hardy–Weinberg equilibrium, OR = odds ratio, SNP = single-nucleotide polymorphisms, TNF-α = tumor necrosis factor-alpha.
How to cite this article: Xu L, Liu C, Zheng Y, Huang Y, Zhong Y, Zhao Z, Ma N, Zhang Z, Zhang L. Association of TNF-α-308G/A, -238G/A, -863C/A, -1031T/C, -857C/T polymorphisms with periodontitis susceptibility: evidence from a meta-analysis of 52 studies. Medicine. 2020;99:36(e21851).
LX, CL, and YZ contributed equally to this work.
This study was supported by the Traditional Chinese Medicine Science and Technology Project of Jilin Province (2020129), the Appropriate Health Technology Promotion Project of Jilin Province (2019FP018), and the Science and Technology Foundation of Tianjin Stomatological Hospital (No. 2019BSZD02).
Funding Source: Health Promotion Administration, Ministry of Health and Welfare (TW); Award ID: 2019FP018; Recipient: Li Zhang.→Funding Source: The Appropriate Health Technology Promotion Project of Jilin Province; Award ID: 2019FP018.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
- [1].Cavalla F, Biguetti CC, Colavite PM, et al. TBX21-1993T/C (rs4794067) polymorphism is associated with increased risk of chronic periodontitis and increased T-bet expression in periodontal lesions, but does not significantly impact the IFN-g transcriptional level or the pattern of periodontophatic bacterial infection. Virulence 2015;6:293–304.. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].Loos BG, John RP, Laine ML. Identification of genetic risk factors for periodontitis and possible mechanisms of action. J Clin Periodontol 2005;32:159–79.. [DOI] [PubMed] [Google Scholar]
- [3].Hugoson A, Norderyd O. Has the prevalence of periodontitis changed during the last 30 years? J Clin Periodontol 2008;35:338–45.. [DOI] [PubMed] [Google Scholar]
- [4].Highfield J. Diagnosis and classification of periodontal disease. Aust Dent J 2009;54:S11–26.. [DOI] [PubMed] [Google Scholar]
- [5].Ozturk A, Vieira AR. TLR4 as a risk factor for periodontal disease: a reappraisal. J Clin Periodontol 2009;36:279–86.. [DOI] [PubMed] [Google Scholar]
- [6].Zhang JC, Sun X, Xiao LM, et al. Gene polymorphisms and periodontitis. Periodontology 20002011;56:102–24.. [DOI] [PubMed] [Google Scholar]
- [7].Pretzl B, El Sayed N, Cosgarea R, et al. IL-1-polymorphism and severity of periodontal disease. Acta Odontol Scand 2012;70:1–6.. [DOI] [PubMed] [Google Scholar]
- [8].Michalowicz BS, Diehl SR, Gunsolley JC, et al. Evidence of a substantial genetic basis for risk of adult periodontitis. J Periodontol 2000;71:1699–707.. [DOI] [PubMed] [Google Scholar]
- [9].Taylor PC, Williams RO, Feldmann M. Tumour necrosis factor alpha as a therapeutic target for immune-mediated inflammatory diseases. Curr Opin Biotechnol 2004;15:557–63.. [DOI] [PubMed] [Google Scholar]
- [10].Górska R, Gregorek H, Kowalski J, et al. Relationship between clinical parameters and cytokine profiles in inflamed gingival tissue and serum samples from patients with chronic periodontitis. J Clin Periodontol 2003;30:1046–52.. [DOI] [PubMed] [Google Scholar]
- [11].Feng RN, Liu GY, Wang C, et al. TNF polymorphisms and cancer. Asian Pac J Cancer Prev 2012;13:3007. [DOI] [PubMed] [Google Scholar]
- [12].Pan F, Tian J, Ji CS, et al. Association of TNF-alpha-308 and -238 polymorphisms with risk of cervical cancer: a meta-analysis. Asian Pac J Can Pre 2012;13:5777–83.. [DOI] [PubMed] [Google Scholar]
- [13].Shaker OG, Sadik NA, El-Hamid NA. Impact of single nucleotide polymorphism in tumor necrosis factor-alpha gene 308G/A in Egyptian asthmatic children and wheezing infants. Hum Immunol 2013;74:796–802.. [DOI] [PubMed] [Google Scholar]
- [14].Zhang BZ, Liu TC, Wang ZP. Association of tumor necrosis factor-alpha gene promoter polymorphisms (-308G/A, -238G/A) with recurrent spontaneous abortion: a meta-analysis. Hum Immunol 2012;73:574–9.. [DOI] [PubMed] [Google Scholar]
- [15].Hoffmann SC, Stanley EM, Cox ED, et al. Association of cytokine polymorphic inheritanc and in vitro cytokine production in anti-CD3/CD28-stimulated peripheral blood lymphocytes. Transplantation 2001;72:1444–50.. [DOI] [PubMed] [Google Scholar]
- [16].Meistrell ME, Botchkina GI, Wang H, et al. Tumor necrosis factor is a brain damaging cytokine in cerebral ischemia. Shock 1997;8:341–8.. [PubMed] [Google Scholar]
- [17].Koss K, Satsangi J, Fanning GC, et al. Cytokine (TNF alpha, LT alpha and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies. Genes Immun 2000;1:185–90.. [DOI] [PubMed] [Google Scholar]
- [18].Ding C, Ji X, Chen X, et al. TNF-alpha gene promoter polymorphisms contribute to periodontitis susceptibility: evidence from 46 studies. J Clin Periodontol 2014;41:748–59.. [DOI] [PubMed] [Google Scholar]
- [19].Barnea TV, Sava A, Gentimir C, et al. Genetic polymorphisms of TNFA and IL-1A and generalized aggressive periodontitis. Rom J Morphol Embryol 2015;56:459–64.. [PubMed] [Google Scholar]
- [20].Majumder P, Thou K, Bhattacharya M, et al. Association of tumor necrosis factor-alpha (TNF-alpha) gene promoter polymorphisms with aggressive and chronic periodontitis in the eastern Indian population. Biosci Rep 2018;38:1–4.. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [21].Nibali L. Suggested guidelines for systematic reviews of periodontal genetic association studies. J Clin Periodontol 2013;40:753–6.. [DOI] [PubMed] [Google Scholar]
- [22].Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088–101.. [PubMed] [Google Scholar]
- [23].Egger M, Smith GD, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34.. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [24].Ho YP, Lin YC, Yang YH, et al. Analysis of tumor necrosis factor-α−308 and lymphotoxin-α+252 gene polymorphisms in Taiwanese patients with periodontitis. J Dent Sci 2015;10:316–22.. [Google Scholar]
- [25].Qian W, Zhang JC, YH Z. The relationship between tumor necrosis factor A-308 gene polymorphism and susceptibility of severe periodontitis in adults. Chin J Stomatol 2002;37:126–8.. [PubMed] [Google Scholar]
- [26].Yang WW, Jia Y, Wu HK. Four tumor necrosis factor alpha genes polymorphisms and periodontitis risk in a Chinese population. Hum Immunol 2013;74:1684–7.. [DOI] [PubMed] [Google Scholar]
- [27].Loo WTY, Fan CB, Bai LJ, et al. Gene polymorphism and protein of human proand anti-inflammatory cytokines in Chinese healthy subjects and chronic periodontitis patients. J Transl Med 2012;10:S8–18.. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [28].Schulz S, Reichert S, Streetz K, et al. Tumor necrosis factor-alpha and oral inflammation in patients with Crohn disease. J Periodontol 2014;85:1424–31.. [DOI] [PubMed] [Google Scholar]
- [29].Li LM, Cao ZZ. Association of TNF-A-863 and CGRP979 gene polymorphisms with susceptibility to severe chronic periodontitis in Chinese Han nationality. Acad J Second Military Med Univ 2009;30:541–4.. [Google Scholar]
- [30].Kobayashi T, Murasawa A, Ito S, et al. Cytokine gene polymorphisms associated with rheumatoid arthritis and periodontitis in Japanese adults. J Periodontol 2009;80:792–9.. [DOI] [PubMed] [Google Scholar]
- [31].Kobayashi T, Nagata T, Murakami S, et al. Genetic risk factors for periodontitis in a Japanese population. J Dent Res 2009;88:1137–41.. [DOI] [PubMed] [Google Scholar]
- [32].Soga Y, Nishimura F, Ohyama H, et al. Tumor necrosis factor-alphagene (TNF-a)-1031/-863,-857 single-nucleotide polymorphisms (SNPs) are associated with severe adult periodontitis in Japanese. J Clin Periodontol 2003;30:524–31.. [DOI] [PubMed] [Google Scholar]
- [33].Endo M, Tai H, Tabeta K, et al. Analysis of single nucleotide polymorphisms in the 5-flanking region of tumor necrosis factor-alpha gene in Japanese patients with early-onset periodontitis. Periodontology 2001;72:1554–9.. [DOI] [PubMed] [Google Scholar]
- [34].Singh P, Gupta ND, Bey A, et al. Salivary TNF-alpha: a potential marker of periodontal destruction. J Indian Soc Periodontol 2014;18:306–10.. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [35].Wei XM, Chen YJ, Wu L, et al. Tumor necrosis factor-α G-308A (rs1800629) polymorphism and aggressive periodontitis susceptibility: a meta-analysis of 16 case-control studies. Sci Rep 2016;6:1–8.. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [36].Nikolopoulos GK, Dimou NL, Hamodrakas SJ, et al. Cytokine gene polymorphisms in periodontal disease: a meta-analysis of 53 studies including 4178 cases and 4590 controls. J Clin Periodontol 2008;35:754–67.. [DOI] [PubMed] [Google Scholar]
- [37].Song GG, Choi SJ, Ji JD, et al. Association between tumor necrosis factor-alpha promoter -308 A/G, -238 A/G, interleukin-6-174 G/C and -572 G/C polymorphisms and periodontal disease: a meta-analysis. Mol Biol Rep 2013;40:5191–203.. [DOI] [PubMed] [Google Scholar]
- [38].Shungin D, Haworth S, Divaris K. Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data. Nat Commun 2019;10:2773. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [39].Masumoto R, Kitagaki J, Fujihara C, et al. Identification of genetic risk factors of aggressive periodontitis using genomewide association studies in association with those of chronic periodontitis. J Periodontal Res 2019;54:199–206.. [DOI] [PubMed] [Google Scholar]
- [40].Skoog T, van’t Hooft FM, Kallin B, et al. A common functional polymorphism (C → A substitution at position− 863) in the promoter region of the tumour necrosis factor-alpha (TNF-alpha) gene associated with reduced circulating levels of TNF-alpha. Hum Mol Genet 1999;8:1443–9.. [DOI] [PubMed] [Google Scholar]
- [41].Sadaf T, John P, Bhatti A, et al. Lack of association of -863C/A (rs1800630) polymorphism of tumor necrosis factor-a gene with rheumatoid arthritis. Arch Med Sci 2019;15:531–6.. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [42].Yousefian-Jazi A, Jung J, Choi JK, et al. Functional annotation of noncoding causal variants in autoimmune diseases. Genomics 2019;7:1–6.. [DOI] [PubMed] [Google Scholar]
- [43].Nourian M, Chaleshi V, Pishkar L, et al. Evaluation of tumor necrosis factor (TNF)-alpha mRNA expression level and the rs1799964 polymorphism of the TNF-alpha gene in peripheral mononuclear cells of patients with inflammatory bowel diseases. Biomed Rep 2017;6:698–702.. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [44].Piosik ZM, Goegebeur Y, Klitkou L, et al. Plasma TNF-alpha levels are higher in early pregnancy in patients with secondary compared with primary recurrent miscarriage. Am J Reprod Immunol 2013;70:347–58.. [DOI] [PubMed] [Google Scholar]
- [45].Rodríguez-Reyes SC. Increased expression of TNF-A gene in Mexican patients with acute myocardial infarction and its relationship with-857 C > T and-863 C>A polymorphisms. Int J Clin Exp Med 2016;9:17596–603.. [Google Scholar]
- [46].Wu SQ, Wang MG, Wang Y, et al. Polymorphisms of cytokine genes and tuberculosis in two independent studies. Sci Rep 2019;9:2507. [DOI] [PMC free article] [PubMed] [Google Scholar]
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