key: cord-0025859-og77kj7f
authors: Liu, Xin; Li, Hui
title: A Systematic Review and Meta-Analysis on Multiple Cytokine Gene Polymorphisms in the Pathogenesis of Periodontitis
date: 2022-01-03
journal: Front Immunol
DOI: 10.3389/fimmu.2021.713198
sha: cfc622a8e740ada4ba31c0dd8335b0b2818f23e4
doc_id: 25859
cord_uid: og77kj7f

AIM: Periodontitis is an inflammatory disease that destroys both soft and hard periodontal tissues. However, a complex periodontal cytokine network remains unclear. This systematic review explored multiple cytokine gene polymorphisms in the pathogenesis of periodontitis. MATERIAL AND METHODS: A systematic search was performed using the databases from previous publications, which indicated the association between cytokine polymorphisms and periodontitis pathogenesis. Meta-analysis was conducted using fixed or randomized models to calculate the significance of multiple cytokine polymorphisms. A total of 147 articles were analyzed with polymorphisms in 12 interleukins [Th1 (IL-2, IFN-γ, and TNF-α), Th2 (IL-4 and IL-13), Th17 (IL-1α, IL-1β, IL-6, and IL-17), and Treg cytokines (IL-10 and TGF-β)]. Doi plot was used to probe the occurrence of publication bias. RESULTS: The polymorphisms of IL-2 and TNF-α of Th1 cytokine family may be associated with the pathogenesis or the prevention of periodontitis risk, while the polymorphism of IFN-γ is not related to periodontitis risk. The polymorphisms for IL-4 and IL-13 of Th2 cytokine family are not found to be associated with the pathogenesis of periodontitis. For the polymorphisms of the members of Th17 cytokine family, different IL-1α polymorphisms may have inverse actions in the pathogenesis of periodontitis. IL-1β is a noteworthy cytokine biomarker in periodontitis development and progression. IL-6 may have a protective function in the inflammatory responses of periodontitis, and IL-17 has a weak relationship the inflammatory responses. The polymorphisms for the members of Treg cell cytokines may have a protective function against periodontitis risk. LFK indexes show the major asymmetry due to publication bias. CONCLUSION: IL-1β is a notable cytokine biomarker in periodontitis risk. Treg cytokines favor an anti-inflammatory and protective environment. Further data are needed to confirm the present conclusion due to publication bias.

Periodontitis is a chronic destructive inflammatory disease that destroys the tooth-supporting structures and results in tooth loss (1) . The cytokine network plays an important role in periodontitis development and immune responses (2) , and its association with periodontitis remains widely unclear. Cytokine expression profiles are closely related to Th1, Th2, Th17, and Treg cells, which play an immunoregulatory role (3) . Interferon-g (IFN-g), tumor necrosis factor a (TNF-a), and IL-2 belong to Th1 cytokines (4) ; and T follicular helper cells have been shown to be a significant source of IL-4 and IL-13 in the lymph nodes during the Th2 activity (5) . Th17 cells are the major source of interleukin-17 (6) , TGF-b (7), IL-1 and IL-6 (8), and IL-23 (9) . Anti-inflammatory IL-10 (10) and TGF-b (11) are secreted by B cell-endowed Tregs, involved in the suppressive function of regulatory T cells, and play critical roles in maintaining immune homeostasis.

Many studies have proven gene polymorphisms in cytokines such as IL-1a (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) , IL-1b (12, 16, 18, 24, , IL-2 (56) (57) (58) (59) (60) , IL-4 (61-73), IL-6 (74-86), IL-23 (87) , IL-10 (16, 42, (84) (85) (86) , IL-13 (66, 111, 112) , IL-17 (60, 73, 87, (113) (114) (115) (116) (117) , TNFa (16, 35, 38, 44, 48, 85, (118) (119) (120) (121) (122) (123) (124) (125) (126) (127) (128) (129) (130) (131) (132) , IFN (70, 85, 102, (133) (134) (135) (136) , and TGF (42, (137) (138) (139) (140) (141) (142) (143) , which often play various vital roles in periodontitis immune pathogenesis or in the prevention of periodontitis immune responses.

However, the genetic polymorphisms of these cytokines were often analyzed separately and seldom compared together. The significant differences remain unclear. Therefore, in the current meta-analysis, a total of 147 studies were included to further identify the contributions of these genetic polymorphisms using a broader collection of patients and races.

The criteria for inclusion in our meta-analysis were as follows: 1) case-control studies; 2) the case groups consisted of patients diagnosed with periodontitis, and the control groups consisted of periodontally healthy individuals; 3) the genetic polymorphisms were detected, and sufficient data supporting the genotype distribution were provided for the calculation of odds ratios (ORs) and corresponding 95% confidence intervals (CIs); and 4) studies with no repeated data. Studies that did not fit any of the criteria were excluded.

A systematic literature search was performed using the databases PubMed, the Cochrane Library, Medical Abstracts, TOXLINE, OVID, EMBASE, Web of Science, EBSCO, VIP Full Text, CNKI, and Wanfang, including studies published up to January 31, 2021. In addition, the reference lists of the selected manuscripts and related reviews were also manually searched and screened to ensure that a comprehensive search was performed. Furthermore, no language restriction was applied. Two authors independently searched all the databases. The following key terms were used for searching; "interleukin-1", "interleukin 1", "IL-1", "IL1", "interleukin-2", "interleukin 2", "IL-2", "IL2", "interleukin-4", "interleukin 4", "IL-4", "IL4", "interleukin-6", "interleukin 6", "IL-6", "IL6", "interleukin-10", "interleukin 10", "IL-10", "IL10", "interleukin-13", "interleukin 13", "IL-13", "IL13", "interleukin-17", "interleukin 17", "IL-17", "IL17", "interferon-gamma", "interferon gamma", "IFNgamma", "IFN gamma", "interferon-g", "interferon g", "IFN-g", "IFN g", "tumor necrosis factor-alpha", "tumor necrosis factor alpha", "TNF-alpha", "TNF alpha", "tumor necrosis factor-a", "tumor necrosis factor a", "TNF-a", "TNF a", "transforming growth factor-beta", "transforming growth factor beta", "TGF-beta", "TGF beta", "transforming growth factor-b", "transforming growth factor b", "TGF-b", "TGF b", "polymorphism", "periodontal diseases", "periodontitis", and their combined phrase.

During the data selection, duplicate researches were removed using Endnote. The abstracts of selected papers were further screened, and the full text was checked based on the selection criteria ( Figure 1 ). The results were examined by two authors, and an expert was referred if inconsistencies appeared. Two authors obtained the following characteristics, and inconsistencies were determined via discussion: 1) the first author name and publication years; 2) nationality and/or ethnicity; 3) population size; 4) genetic polymorphism; and 5) Hardy-Weinberg equilibrium (HWE) in these populations.

ORs and 95% CIs were analyzed to evaluate the relationship between genetic polymorphisms in 12 interleukins [Th1 (IL-2, IFN-g, and TNF-a), Th2 (IL-4 and IL-13), Th17 (IL-1 a, IL-1b, IL-6, TGF-b, and IL-17), and Treg cytokines (IL-10 and TGF-b)] and periodontitis. The interstudy heterogeneity was estimated using I 2 , where I 2 > 50% and p < 0.05 were regarded as significant heterogeneity. Subsequently, the random-effects model (Mantel-Haenszel method) was performed in this study. I 2 < 50% and p > 0.05, and the fixed-effects model (Mantel-Haenszel method) was performed to confirm collective effectiveness. One or all the following genetic polymorphisms were analyzed: 1) genetic specific allele; 2) dominant model; and/or 3) recessive model. Statistical analyses were carried out using MetaXL (https://www. epigear.com/index_files/metaxl.html).

Publication bias is a major problem in meta-analysis, which affects the strength of the final conclusion and remains suboptimal, and impedes the cogency and explanation of meta-analysis discoveries. When bias occurs, it typically differentially affects studies manifesting as an association between precision and effect size, and photographic asymmetry of common funnel plots. However, the asymmetry is quantified using Egger's regression, and the sensitivity of Egger's regression is difficult to detect such asymmetry when the amounts of studies are limited. A new graphical method, the Doi plot, to visualize asymmetry using the LFK index can detect the asymmetry of study effects well. The LFK index also has a higher sensitivity than Egger's regression (144) . Therefore, publication bias was assessed using LFK index test proposed by Furuya-Kanamori et al. LFK index zero represents complete symmetry, and the limits of symmetry were set at ±1, and values beyond ±1 were inconsistent with symmetry.

According to the study flowchart ( Figure 1 ), a total of 147 articles were included in the final meta-analysis on genetic polymorphism in the 12 cytokine genes (Th1 (IL-2, IFN-g, and TNF-a), Th2 (IL-4 and IL-13), Th17 (IL-1a, IL-1b, IL-6, TGF-b, and IL-17), and Treg cytokines (IL-10 and TGF-b)), including IL-1a (12-28), IL-1b (12, 16, 18, 24, , IL-2 (56-60), IL-4 (61-73), IL-6 (74-85, 145), IL-10 (16, 42, 84-86, 88-107, 109, 110, 118, 146, 147) , IL-13 (66, 111, 112) , IL-17 (60, 73, 87, (113) (114) (115) (116) (117) , TNF-a (16, 35, 38, 44, 48, 85, (118) (119) (120) (121) (122) (123) (124) (125) (126) (127) (128) (129) (130) (131) (132) , IFN (70, 85, 102, (133) (134) (135) (136) , and TGF (42, (137) (138) (139) (140) (141) (142) (143) . These studies encompassed various periodontitis cases and healthy controls, which were involved in the analysis of the gene polymorphism and play important roles in promoting or preventing either chronic or aggressive periodontitis. We explored the relationship between the genetic polymorphism and the occurrence of periodontitis risk or prevention of periodontitis development using these studies (Tables S1-S12), in which the data were used to test the association of alleles and genotype with periodontitis risk.

Th1 cytokines are structurally related to IL-2, IFN-g, and TNF-a, whose polymorphisms are possibly associated with periodontitis risk. IL-2 −330G allele had a weak relationship with the periodontitis development with OR (95% CI), 0.96 (0.72-1.20) (Figure 2A) . LFK index showed that there was major asymmetry and significant publication bias for the result of IL-2 −330G allele ( Figure 2B ). In contrast, IL-2 −330T allele had a strong relationship with the periodontitis risk with OR (95% CI), 0.80 (0.35-1.24) ( Figure 2C ). However, a higher level of LFK FIGURE 1 | Flowchart of trial search and selection for meta-analysis. RCT, randomized and controlled trial; IL-1, interleukin-1; IL-2, interleukin-2; IL-4, interleukin-4; IL-6, interleukin-6; IL-8, interleukin-8; IL-10, interleukin-10; IL-13, interleukin-13; IL-17, interleukin-17; IFN-g, interferon gamma; TNF-a, tumor necrosis factor alpha; TGF-b, transforming growth factor beta.

index also indicated that there was major asymmetry and publication bias for the result of IL-2 −330T allele ( Figure 2D ).

IFN-g 874 A/T dominant model had a weak relationship with the periodontitis risk with OR (95% CI), 0.92 (0.66-1.17) ( Figure 2E ). LFK index showed that there was minor asymmetry and publication bias for the result of IFN-g 874 A/ T dominant model ( Figure 2F ). Similarly, IFN-g 874 A/T recessive model also had a weak relationship with the periodontitis development with OR (95% CI), 0.94 (0.73-1.15) ( Figure 2G ). LFK index also indicated that there was minor asymmetry and publication bias for the result of IFN-g 874 A/T recessive model ( Figure 2H ).

TNF-a 308 G/A polymorphism had a significant relationship in the prevention of periodontitis risk with OR (95% CI), 1.13 (0.88-1.39) ( Figure 2I ). LFK index showed that there was major asymmetry and significant publication bias for the result of TNFa 308 G/A polymorphism ( Figure 2J ). Taken together, these results suggest that the members IL-2 and TNF-a of Th1 cytokine family may be associated with the pathogenesis of periodontitis or prevention of periodontitis risk, and their polymorphism can affect periodontitis risk while the polymorphism of IFN-g is not associated with periodontitis risk.

IL-4 and IL-13 are the members of Th2 cell cytokines. IL-4 −590 C/T T allele had a weak relationship with the periodontitis risk with OR (95% CI), 0.92 (0.72-1.11) ( Figure 3A) . LFK index showed that there was major asymmetry and significant publication bias for the result of IL-4 −590 C/T T allele ( Figure 3B ). IL-13 −1112C/T C allele had a weak relationship with the periodontitis risk with OR (95% CI), 0.91 (0.62-1.21) ( Figure 3C) . LFK index showed that there was major asymmetry and publication bias for the result of IL-13 −1112C/T C allele model ( Figure 3D) . Similarly, IL-13 −1112C/T T allele also had a weak relationship with the periodontitis development with OR (95% CI), 0.92 (0.45-1.39) ( Figure 3E ). LFK index indicated that there was no asymmetry or publication bias for the result of IL-13 −1112C/T T allele model ( Figure 3F ). Taken together, these results suggest that the members IL-4 and IL-13 of Th2 cytokine family may not be associated with the pathogenesis of periodontitis.

IL-1 a, IL-1b, IL-6, and IL-17 belong to the members of Th17 cell cytokine family. IL-17A, secreted by Th17 cells, was found upregulated in human inflammatory and autoimmune disease (148) . IL-1a −889C/T T allele had a favorable relationship in the prevention of periodontitis risk with OR (95% CI), 1.12 (0.99-1.25) ( Figure 4A) . LFK index showed that there was major asymmetry and publication bias for the result of IL-1a −889C/T T allele model ( Figure 4B ). In contrast, IL-1a −889C/T C allele also had a strong relationship with the periodontitis development with OR (95% CI), 0.75 (0.66-0.85) ( Figure 4C ). LFK index indicated that there was major asymmetry and publication bias for the result of IL-1a −889C/T C allele model ( Figure 4D ). IL-1b −511C>T polymorphism had a very strong relationship in the periodontitis risk with OR (95% CI), 0.50 (0.30-0.71) ( Figure 4E) . LFK index showed that there was major asymmetry and publication bias for the result of IL-1b −511C>T polymorphism ( Figure 4F) . Similarly, IL-1b 3954C>T polymorphism also had a very strong relationship with the periodontitis development with OR (95% CI), 0.66 (0.52-0.80) ( Figure 4G ). LFK index indicated that there was major asymmetry and publication bias for the result of IL-1b 3954C>T polymorphism ( Figure 4H) .

IL-6 −174G/C G allele model had a weak relationship in the prevention of periodontitis risk with OR (95% CI), 1.10 (0.82-1.38) ( Figure 4I) . LFK index showed that there was major asymmetry and publication bias for the result of IL-6 −174G/C G allele model ( Figure 4J) . Similarly, IL-6 −174G/C C allele model also had a weak relationship in the prevention of periodontitis development with OR (95% CI), 1.09 (0.81-1.36) ( Figure 4K ). LFK index indicated that there was major asymmetry and publication bias for the result of IL-6 −174G/C C allele model ( Figure 4L ).

IL-17 rs2275913 polymorphism had a weak relationship in the periodontitis risk with OR (95% CI), 0.92 (0.45-1.39) ( Figure 4M) . LFK index showed that there was no asymmetry or publication bias for the result of IL-17 rs2275913 polymorphism ( Figure 4N ). Taken together, in the members of Th17 cytokine family, different IL-1 a polymorphisms may have inverse functions in the pathogenesis of periodontitis. IL-1b is a significant cytokine biomarker in the periodontitis development. IL-6 may have protective function in the inflammatory responses of periodontitis, and IL-17 has a weak relationship with the inflammatory responses.

Treg cell cytokines include TGF-b; and the IL-10 family, and TGF-b and IL-10 are the most relevant members for immune regulation. IL-10 592C>A A allele model had a strong relationship in the prevention of periodontitis risk with OR (95% CI), 1.21 (1.03-1.39) ( Figure 5A) . LFK index showed that there was major asymmetry and publication bias for the result of IL-10 592C>A A allele model ( Figure 5B ). IL-10 1082A>G A allele model also had a weak relationship with the periodontitis development with OR (95% CI), 1.04 (0.81-1.28) ( Figure 5C ). LFK index indicated that there was major asymmetry and publication bias for the result of L-10 1082A>G A allele model ( Figure 5D ). TGF-b rs1800469 polymorphism had a relationship in the prevention of periodontitis risk with OR (95% CI), 1.13 (0.93-1.34) ( Figure 5E ). LFK index showed that there was major asymmetry and publication bias for the result of TGF-b rs1800469 polymorphism ( Figure 5F ). Taken together, the members of Treg cell cytokines may have a protective function in the periodontitis risk by reducing the inflammatory responses.

Pro-inflammatory CD4+ T helper cells mainly belong to the Th1, Th2, Th17, and Treg cells, which secrete various cytokines and are closely associated with periodontal diseases (Figure 6) (149) . The present meta-analysis showed that the polymorphisms of the members IL-2 and TNF-a of Th1 cytokine family may be associated with the pathogenesis of periodontitis or the prevention of periodontitis risk, while the polymorphism of IFN-g is not related to periodontitis risk. The result is consistent with previous meta-analysis that IFN-g may not contribute to periodontitis susceptibility (150) . Cytokine receptors also can induce inflammatory signals by binding specifically to certain types of cytokines. The activity of IL-2 receptor in the periodontitis patients was also found to be higher than that in the control subjects (151) . Previous report also could not find any evidence to support that polymorphisms in an IFNg receptor-1 contributes to periodontitis risk either (152) .

TNF-a, one of the essential pro-inflammatory cytokines in periodontitis patients, has been regarded as a potential biomarker for diagnosis of a periodontal disease (153) . Anti-TNF-a will be a potential way to prevent periodontitis risk (154) . Apical periodontitis patients were treated with anti-TNF-a biologic medications and showed faster healing than the controls (155) .

The polymorphisms for the members IL-4 and IL-13 of Th2 cytokine family are not found to be associated with the pathogenesis of periodontitis. The statistical differences for IL-4 receptor polymorphism were insignificant among mild, moderate, and severe chronic periodontitis subjects (156) . Further work also did not show that the polymorphisms of IL-4 receptor were associated with the risk of severe chronic periodontitis (157) .

For the polymorphisms of the members of Th17 cytokine family, different IL-1a polymorphisms may have inverse actions in the pathogenesis of periodontitis. IL-1b is a noteworthy cytokine biomarker in periodontitis development and progression. IL-6 may have a protective function in the inflammatory responses of periodontitis, and IL-17 has a weak relationship the inflammatory responses. The relationship between interleukin-1 receptor and periodontitis risk was seldom reported. The polymorphism (rs2234663) of interleukin-1 receptor antagonist (IL-1ra), an agent that binds to interleukin-1 receptor, was found to contribute to serious periodontitis susceptibility (158) . Salivary level of IL-1Ra was also reported to be statistically higher in the periodontitis patients than the controls (159) . Gingival crevicular fluid-soluble IL-6 receptor was also higher in the inflammatory sites than in the healthy controls in periodontitis patients (160) . Clinical evidence shows that IL-1b, a pro-inflammatory cytokine, is raised and contributes to periodontitis susceptibility. Evaluated levels of IL-1b initiate a chain of inflammatory responses and increase bone resorption (161) . Therefore, IL-1b is an important therapeutic target for periodontitis. The application of IL-1ra (a natural inhibitor of IL-1b) suggests the possible function of IL-1ra in controlling periodontal inflammation in an experimental periodontitis model (162) .

The present study showed that IL-2 −330T allele had a strong relationship with the periodontitis risk ( Figure 2C) , which was consistent with the previous report that the expression of IL-2 was increased in the tenacity stage of periodontitis and that IL-2 exerts an inhibitory function in the development of periodontitis (163) . IL-2 −330T allele may affect its normal protective function. Preclinical experiments indicated that IL-2/anti-IL-2antibody complexes activated the percent of Treg cells and reduced the inflammatory responses in various diseases (164, 165) .

The present findings showed that the members IL-4 and IL-13 of Th2 cytokine family may not be associated with the pathogenesis of periodontitis. The results are inconsistent with the previous report that IL-4 has been found to be decreased in chronic periodontitis subjects and increased after therapy, which implies that IL-4 in Th2 cells may have protective effects in the prevention of periodontitis (166) . Furthermore, it has been also reported that IL-4 can control pro-inflammatory cytokine levels (167) and restrain the occurrence of osteoclastogenesis (168) .

The present findings showed that the members of Treg cell cytokines may have protective function in the periodontitis risk by reducing the inflammatory responses, which are consistent with popular reports. TGF-b and IL-10 are the main effector cytokines in Treg cells and may have synergetic functions (169, 170) . Treg cells might gather at infecting sites of dental infection and might reduce immune actions and bone resorption in the periodontal area (171) . The upregulation of TGF-b results in collagen production and reduces collagen-destroying MMP-1 production, which will be beneficial to protect against periodontitis (172) . IL-10 polymorphism is of high clinical relevance and a valuable marker to recognize patients who are at higher risk for periodontitis (173) . On the other hand, regulatory T cells play an important role in modulating the immunity in periodontitis patients by defending against inflammation and autoimmunity (174) . Modulating the Th17/ Treg imbalance during periodontitis may be a promising approach to cure periodontitis (175, 176) by affecting the levels of TGF-b and IL-10 (177).

This meta-analysis has several strengths, including an unrestricted search process and duplicate review procedures for the search and strict assessments of the risk of bias and the quality of literature.

There are some limitations in the present paper. First, although a broad search in different databases of various cytokines was carried out, it is difficult to approve that whether all the studies for exploring the relationship between these genetic polymorphisms of various cytokines and periodontitis risk were included in the present study. Second, there were obvious heterogeneities and potential publication biases in these metaanalyses. To reduce some potential heterogeneities, the related literatures were removed; however, some heterogeneities still existed. Third, we used Doi plot to probe the occurrence of publication bias in the studies used for our meta-analysis, and the results showed that all LFK indexes showed the major asymmetry due to publication bias. Therefore, to understand whether the different Th cell cytokines were associated with periodontitis, more unbiased data are required. IL-23 plays a critical role in the development of periodontitis (9, (178) (179) (180) (181) . However, the present research focuses on the relationship between cytokine polymorphisms and periodontitis and not between the cytokine level and periodontitis. We have tried to investigate the relationship between IL-23 polymorphisms and periodontitis. Unfortunately, the related contents were seldom reported, and the meta-analysis was not performed.

Within the limitations of this study, the present meta-analysis indicated that genetic polymorphism of Th17 cytokines might be a risk factor for the development of periodontitis, while Treg cells may show protective function in the prevention of periodontitis inflammation. Further studies on larger population will be needed to verify these findings. 

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

XL and HL contributed to conception, design of the study, collect all literatures, analyze all data and wrote the manuscript. All authors contributed to the article and approved the submitted version.

The present project was supported by the Department of Science and Technology of Jilin Province (Grant No. 20200201519JC).

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021. 713198/full#supplementary-material

Local Sustained Delivery of Anti-IL-17a Antibodies Limits Inflammatory Bone Loss in Murine Experimental Periodontitis

Central Regulatory Role of Cytokines in Periodontitis and Targeting Options

Simultaneous Analysis of Multiple T Helper Subsets in Leprosy Reveals Distinct Patterns of Th1, Th2, Th17 and Tregs Markers Expression in Clinical Forms and Reactional Events

The Diagnostic Accuracy of Th1 (IFN-g, TNF-a, and IL-2) and Th2

Cytokines Response in AFB Microscopy Smear Negative PTB-HIV Co-Infected Patients

IL-4 Is a Key Requirement for IL-4-and IL-4/IL-13-Expressing CD4 Th2 Subsets in Lung and Skin

Cytokine Profile and Disease Severity in Patients With COVID-19

TGF-Beta/atRA-Induced Tregs Express a Selected Set of microRNAs Involved in the Repression of Transcripts Related to Th17 Differentiation

Critical Regulation of Th17 Cell Differentiation by Serum Amyloid-A Signalling in Behcet's Disease

Th17 Cells and the IL-23/IL-17 Axis in the Pathogenesis of Periodontitis and Immune-Mediated Inflammatory Diseases

Interleukin-10 Producing Regulatory B Cells Transformed CD4+ CD25-Into Tregs and Enhanced Regulatory T Cells Function in Human Leprosy

Transforming Growth Factor-b Signaling in Regulatory T Cells Controls T Helper-17 Cells and Tissue-Specific Immune Responses

Interleukin-1 Two-Locus Haplotype is Strongly Associated With Severe Chronic Periodontitis Among Yemenis

Polymorphisms in the Interleukin-1 Gene Locus and Chronic Periodontitis in Patients With Atherosclerotic and Aortic Aneurysmal Vascular Diseases

Association Analysis of the IL-1 Gene Cluster Polymorphisms With Aggressive and Chronic Periodontitis in the Algerian Population

Analysis of IL1 Gene Polymorphisms and Transcript Levels in Periodontal and Chronic Kidney Disease

Functional Gene Polymorphisms in Aggressive and Chronic Periodontitis

Investigation of the Interleukin-1 Gene Cluster Polymorphisms in Jordanian Patients With Chronic and Aggressive Periodontitis

Polymorphisms of the Interleukin-1 Gene Family, Oral Microbial Pathogens, and Smoking in Adult Periodontitis

Association of Interleukin-1

Polymorphisms With Periodontal Disease

Interleukin-1 Gene Cluster Polymorphisms Associated With Periodontal Disease in Type 2 Diabetes

Association of Interleukin-1 Alpha (-889) Gene Polymorphism in Patients With Generalized Aggressive and Chronic Periodontitis

Do Interleukin-1 Polymorphisms Predict the Development of Periodontitis or the Success of Dental Implants?

Single Nucleotide Polymorphisms in Interleukin-1gene Cluster and Subgingival Colonization With Aggregatibacter Actinomycetemcomitans in Patients With Aggressive Periodontitis

Polymorphisms in the IL-1A Gene Are Correlated With Levels of Interleukin-1alpha Protein in Gingival Crevicular Fluid of Teeth With Severe Periodontal Disease

Association of IL1 Gene Polymorphisms With Chronic Periodontitis in Brazilians

Gene and Susceptibility to Chronic Periodontitis: A Genetic Association Study

Role of Familiarity Versus, Interleukin-1 Genes Cluster Polymorphisms in Chronic Periodontitis

Assessment of Single Nucleotide Polymorphism at IL-1A+ 4845 and IL-1B+ 3954 as Genetic Susceptibility Test for Chronic Periodontitis in Maharashtrian Ethnicity

Distribution of Interleukin-1beta(+3954) and IL-1alpha(-889) Genetic Variations in a Thai Population Group

Analysis of Interleukin-1beta Gene Polymorphism and Its Association With Generalized Aggressive Periodontitis Disease

Association Between Interleukin-1 Gene Polymorphism and Severity of Chronic Periodontitis in a South Indian Population Group

Polymorphism in Interleukin-1beta Gene and the Risk of Periodontitis in a Polish Population

The Association Between IL-1 Gene Polymorphisms and Susceptibility to Severe Periodontitis. Hua xi kou qiang yi xue za zhi= Huaxi kouqiang yixue zazhi=

Gene Polymorphisms of TNF-a and IL-1b are Not Associated With Generalized Aggressive Periodontitis in an Iranian Subpopulation

Allele, Genotype, and Composite Genotype Effects of IL-1A +4845 and IL-1B +3954 Polymorphisms for Chronic Periodontitis in an Indian Population

Comparison of Interleukin-1 Genotypes in Two Populations With Aggressive Periodontitis

Interleukin-1 and Tumor Necrosis Factor-Alpha Gene Polymorphisms in Turkish Patients With Localized Aggressive Periodontitis

Polymorphisms Within the IL-1 Gene Cluster: Effects on Cytokine Profiles in Peripheral Blood and Whole Blood Cell Cultures of Patients With Aggressive Periodontitis, Juvenile Idiopathic Arthritis, and Rheumatoid Arthritis

Investigation on the Association of Interleukin-1

Genotype Polymorphism With Chronic Periodontitis. Hua xi kou qiang yi xue za zhi= Huaxi kouqiang yixue zazhi=

Analysis of the Association Between Interleukin-1beta (+3954) Gene Polymorphism and Chronic Periodontitis in a Sample of the South Indian Population

Cytokine Gene Polymorphisms Associated With Rheumatoid Arthritis and Periodontitis in Japanese Adults

Study on the Correlation of Cytokine Gene Polymorphism With Chronic

Correlation Study on Polymorphisms of the Interleukin-1 and Tumor Necrosis Factoralpha Gene in Hui Patients With Chronic Periodontitis in Ningxia

Evaluation of Interleukin -1B (+3954) Gene Polymorphism in Patients With Chronic and Aggressive Periodontitis: A Genetic Association Study

A Functional Interleukin-1b Gene Polymorphism Is Associated With Chronic Periodontitis in a Sample of Brazilian Individuals

Association of Interleukin-1 Polymorphisms With Aggressive Periodontitis

No Correlation of Five Gene Polymorphisms With Periodontal Conditions in a Greek Population

Linkage Disequilibrium Analysis of Case-Control Data: An Application to Generalized Aggressive Periodontitis

Association of Single Nucleotide Gene Polymorphism at Interleukin-1b+ 3954,-511, and-31 in Chronic Periodontitis and Aggressive Periodontitis in Dravidian Ethnicity

Analysis of IL-1alpha(-889) and IL-1b (+3953) Gene Polymorphism in Syrian Patients With Aggressive Periodontitis: A Pilot Study

Association of Interleukin-1 Receptor Antagonist Gene Polymorphisms With Early Onset Periodontitis in Japanese

The Relationship of IL-1beta Expressed in Buccal Cells and the Polymorphisms of IL-1beta (+ 3953) With Chronic Periodontitis

A Study of Association Between the Interleukin-1 Single Nucleotide Polymorphism and Risk of Chronic Periodontitis Among the Hui and Dongxiang Minorities in Gansu Province

The Association of Interleukin

Gene Polymorphisms With the Susceptibility to Chronic Periodontitis in Uighur

Interleukin Gene Polymorphisms in Chronic Periodontitis: A Case-Control Study in the Indian Population

Association of Matrix Metalloproteinase (MMP)-1, 3, 9, Interleukin (IL)-2, 8 and Cyclooxygenase (COX)-2 Gene Polymorphisms With Chronic Periodontitis in a Chinese Population

Interleukin-2 -330 and 166 Gene Polymorphisms in Relation to Aggressive or Chronic Periodontitis and the Presence of Periodontopathic Bacteria

Investigation of an IL-2 Polymorphism in Patients With Different Levels of Chronic Periodontitis

Interleukin-2, -16, and -17 Gene Polymorphisms in Iranian Patients With Chronic Periodontitis

Polymorphisms and Haplotypes in the Interleukin-4 Gene Are Associated With Chronic Periodontitis in a Brazilian Population

IL4 Gene Polymorphisms and Their Relation to Periodontal Disease in a Macedonian Population

Two Polymorphisms of Interleukin-4 Gene in Korean Adult Periodontitis

Analysis of Correlation Between IL-6, IL-6R and IL-4 Single Nucleotide Polymorphism and the Susceptibility of Chronic Periodontitis Among Shanghai Patients of Han Nationality

Interleukin-4 Gene Polymorphisms in Japanese and Caucasian Patients With Aggressive Periodontitis

Single-Nucleotide Polymorphisms in the IL-4 and IL-13 Promoter Region in Aggressive Periodontitis

The Association of Interleukin-4 Haplotypes With Chronic Periodontitis in a Czech Population

Interleukin-4 (C-590T) and Interferon-Gamma (G5644A) Gene Polymorphisms in Patients With Periodontitis

Association of the Polymorphisms in Promoter and Intron Regions of the Interleukin-4 Gene With Chronic Periodontitis in a Turkish Population

Et Al: Gene Polymorphism and Protein of Human Pro-and Anti-Inflammatory Cytokines in Chinese Healthy Subjects and Chronic Periodontitis Patients

Investigation of IL4 Gene Polymorphism in Individuals With Different Levels of Chronic Periodontitis in a Brazilian Population

Association Between Polymorphisms in Interleukins 4 and 13 Genes and Chronic Periodontitis in a Han Chinese Population

Association of Interleukin-4 and Interleukin-17F Polymorphisms in Periodontitis in Dravidian Ethnicity

Interleukin-6 C.-174G> C Polymorphism and Periodontitis in a Brazilian Population

Expression, Polymorphism and Methylation Pattern of Interleukin-6 in Periodontal Tissues

Implant Disease and Chronic Periodontitis: Is Interleukin

Gene Promoter Polymorphism the Common Risk Factor in a Brazilian Population

Interleukin-6 (G-174C) and Tumour Necrosis Factor-Alpha (G-308A) Gene Polymorphisms in Geriatric Patients With Chronic Periodontitis

and IFN-Gamma Gene Polymorphisms as Risk Factors for Brucellosis

Interleukin-6 Promoter Polymorphism (-174 G/C) in Indian Patients With Chronic Periodontitis

Association Among Interleukin-6 Gene Polymorphisms, Type 2 Diabetes Mellitus, and Chronic Periodontitis: A Pilot Study

Coronary Heart Disease and Chronic Periodontitis: Is Polymorphism of Interleukin-6 Gene the Common Risk Factor in a Chinese Population

Analysis of the Interleukin-6 Gene Promoter Polymorphisms in Czech Patients With Chronic Periodontitis

Analysis of IL-6, IL-10 and NF-kB Gene Polymorphisms in Aggressive and Chronic Periodontitis

Interleukin-6 Gene Polymorphism Modulates the Risk of Periodontal Diseases

Variations in Inflammatory Genes Are Associated With Periodontitis

IL-6 and IL-10 Gene Polymorphisms in Patients With Aggressive Periodontitis: Effects on GCF, Serum and Clinic Parameters

Evaluation of IL17A Expression and of IL17A, IL17F and IL23R Gene Polymorphisms in Brazilian Individuals With Periodontitis

IL10 -1082, IL10 -819 and IL10 -592 Polymorphisms are Associated With Chronic Periodontitis in a Macedonian Population

The Broad Effects of the Functional IL-10 Promoter-592 Polymorphism: Modulation of IL-10, TIMP-3, and OPG Expression and Their Association With Periodontal Disease Outcome

The Use of Chronic Gingivitis as Reference Status Increases the Power and Odds of Periodontitis Genetic Studies-A Proposal Based in the Exposure Concept and Clearer Resistance and Susceptibility Phenotypes Definition

Interleukin-10 (-592 C/A) and Interleukin-12B (+16974 A/C) Gene Polymorphisms and the Interleukin-10 ATA Haplotype are Associated With Periodontitis in a Taiwanese Population

Association of Interleukin-10 Gene Promoter Polymorphisms With Chronic and Aggressive Periodontitis

Interleukin-10 Gene Promoter Polymorphism in Chinese Patients With Generalized Aggressive Periodontitis

Effect of Ancestry on Interleukin-10 Haplotypes in Chronic Periodontitis

Analysis of Interleukin-10 Gene Polymorphisms in Patients With Chronic Periodontitis and Healthy Controls

The Interleukin-10 Promoter Haplotype ATA is a Putative Risk Factor for Aggressive Periodontitis

IL6 and IL10 Are Genetic Susceptibility Factors of Periodontal Disease

Interleukin 10 Gene Promoter Polymorphisms Are Associated With Chronic Periodontitis

Analysis of Polymorphisms in Interleukin 10, NOS2A, and ESR2 Genes in Chronic and Aggressive Periodontitis

Association of Interleukin-10 Gene Polymorphisms With Severe Generalized Chronic Periodontitis

Correlation Between Interleukin-10 Polymorphisms and Susceptibility to Chronic Periodontitis Among Uygur Adults in the Moyu Area

Analysis of Tumor Necrosis Factor-Alpha, Transforming Growth Factor-Beta, Interleukin-10, IL-6, and Interferon-Gamma Gene Polymorphisms in Patients With Chronic Periodontitis

Association of the -1087 IL 10 Gene Polymorphism With Severe Chronic Periodontitis in Swedish Caucasians

Association of -1082 Interleukin-10 Gene Polymorphism in Peruvian Adults With Chronic Periodontitis

Single Nucleotide Polymorphism at-1087 Locus of Interleukin

Gene Promoter Is Associated With Severe Chronic Periodontitis in Nonsmoking Patients

A Comparative Study of the Role of Cytokine Polymorphisms Interleukin-10 and Tumor Necrosis Factor Alpha in Susceptibility to Implant Failure and Chronic Periodontitis

Association Between IL-10-1082G/ A Gene Polymorphism and Susceptibility of Recurrent Oral Ulcer: Meta Analysis

Gene Polymorphism and Protein of Human Pro-and Anti-Inflammatory Cytokines in Chinese Healthy Subjects and Chronic Periodontitis Patients

Analysis of -1082 IL-10 Gene Polymorphism in Iranian Patients With Generalized Aggressive Periodontitis

A Case-Control Study on Interleukin-10 Genetic Polymorphisms and Susceptibility to Chronic Periodontitis

Gene Polymorphisms in Individuals With Chronic and Generalized Aggressive Periodontitis in a Taiwanese (Chinese) Population

Interleukin-13 -1112 C/T Promoter Polymorphism Confers Risk for COPD: A Meta-Analysis

Interleukin-17a Gene Variability in Patients With Type 1

Its Correlation With IL-17 Levels and the Occurrence of Periodontopathic Bacteria

Association of Interleukin-17 Polymorphism (-197G/A) in Chronic and Localized Aggressive Periodontitis

Association Between Polymorphisms in Interleukin-17A and-17F

The Influence of Interleukin 17A and IL17F Polymorphisms on Chronic Periodontitis Disease in Brazilian Patients

Interleukin (IL)-17F (H161R) and IL-23R (R381Q) Gene Polymorphisms in Turkish Population With Periodontitis

TNFA and IL10 Gene Polymorphisms Are Not Associated With Periodontitis in Brazilians

Association of Cytokines Polymorphisms With Chronic Peridontitis and Rheumatoid Arthritis in a Mexican Population

Analysis of Single Nucleotide Polymorphisms in the 5'-Flanking Region of Tumor Necrosis Factor-Alpha Gene in Japanese Patients With Early-Onset Periodontitis

Polymorphisms in the +252(A/G) Lymphotoxin-Alpha and the -308(A/G) Tumor Necrosis Factor-Alpha Genes and Susceptibility to Chronic Periodontitis in a Czech Population

Lack of Association Between the Tnfa G-308 A Promoter Polymorphism and Periodontal Disease

Association of the Tumour Necrosis Factor-a 308

Gene Polymorphism and Susceptibility to Severe Chronic Periodontitis

YA-ping P. A Study of Frequency of TNF Alpha Gene With Type 2 Diabetes Mellitus With Chronic Periodontitis

Association of Tumor Necrosis Factor-Alpha (TNF-Alpha) Gene Promoter Polymorphisms With Aggressive and Chronic Periodontitis in the Eastern Indian Population

Analysis of TNF-Alpha (-308) Polymorphism and Gingival Crevicular Fluid TNF-Alpha Levels in Aggressive and Chronic Periodontitis: A Preliminary Report

Association of TNFA-308 Gene Polymorphisms With Susceptibility to Chronic Periodontitis in Chinese Patients

Tumor Necrosis Factor-Alpha and Oral Inflammation in Patients With Crohn Disease

Cytokine Gene Polymorphism (Interleukin-1beta +3954, Interleukin-6 [-597/-174] and Tumor Necrosis Factor-Alpha -308) in Chronic Periodontitis With and Without Type 2 Diabetes Mellitus

Tumor Necrosis Factor-Alpha-308G/A Single Nucleotide Polymorphism and Red-Complex Periodontopathogens Are Independently Associated With Increased Levels of Tumor Necrosis Factor-a in Diseased Periodontal Tissues

Four Tumor Necrosis Factor Alpha Genes Polymorphisms and Periodontitis Risk in a Chinese Population

Association Between Tumour Necrosis Factor A-308 Genotype and Chronic Periodontitis of Uighur Patients

Association between IFN-g +874A/T and IFN-gR1 (-611A/G, +189T/G, and +95C/T) Gene Polymorphisms and Chronic Periodontitis in a Sample of Iranian Population

Interferon-g+ 874a/T Polymorphism in Relation to Generalized Chronic Periodontitis and the Presence of Periodontopathic Bacteria

Association Between TNF-Alpha, TGF-Beta1, IL-10, IL-6 and IFN-Gamma Gene Polymorphisms and Generalized Aggressive Periodontitis

Interferon-Gamma and Interleukin-12 Gene Polymorphisms and Their Relation to Aggressive and Chronic Periodontitis and Key Periodontal Pathogens

Analysis of the TGF-Beta1 Promoter Polymorphism (C-509T) in Patients With Chronic Periodontitis

Association of Interleukin-1 Receptor Antagonist +2018 Gene Polymorphism With Japanese Chronic Periodontitis Patients Using a Novel Genotyping Method

Quantitative Analysis of Interdental Gingiva in Patients With Chronic Periodontitis and Transforming Growth Factor-b1 29c/T Gene Polymorphisms

The Interleukin-1 and Fcgamma Receptor Gene Polymorphisms in Japanese Patients With Rheumatoid Arthritis and Periodontitis

5 Polymorphisms in the Transforming Growth Factor-Beta 1 Gene (TGF-Beta 1) in Adult Periodontitis

Relationship Between Transforming Growth Factor Beta-1 Gene-509C/T Polymorphism and Severe Chronic Periodontitis

Association Between TGF-b1-509 Gene Polymorphism With Aggressive Periodontitis

A New Improved Graphical and Quantitative Method for Detecting Bias in Meta-Analysis

IL-6 and IL-10 Gene Polymorphisms in Patients With Aggressive Periodontitis: Effects on GCF, Serum and Clinic Parameters

Polymorphisms in the CD14 and IL-6 Genes Associated With Periodontal Disease

Correlation of Interleukin-10-1082 G/A Single Nucleotide Polymorphism to the Risk of Severe Chronic Periodontitis in Chinese: A Case-Control Study

IL-17A Secreted by Th17 Cells Is Essential for the Host Against Streptococcus Agalactiae Infections

A New Inflammatory Cytokine on the Block: Re-Thinking Periodontal Disease and the Th1/Th2 Paradigm in the Context of Th17 Cells and IL-17

Is There an Association Between IFN-g+ 874a/T Polymorphism and Periodontitis Susceptibility?: A Meta-Analysis

Interleukin-2, Interleukin-2 Receptor and Interleukin-4 Levels Are Elevated in the Sera of Patients With Periodontal Disease

Polymorphisms in an Interferon-g Receptor-1 Gene Marker and Susceptibility to Periodontitis

Tumor Necrosis Factor-Alpha in Gingival Crevicular Fluid as a Diagnostic Marker for Periodontal Diseases: A Systematic Review

Tumor Necrosis Factor-a Antagonist Diminishes Osteocytic RANKL and Sclerostin Expression in Diabetes Rats With Periodontitis

Healing of Apical Periodontitis in Patients With Inflammatory Bowel Diseases and Under Anti-tumor Necrosis Factor Alpha Therapy

Association of Interleukin-4 Receptor Gene Polymorphism With Chronic Periodontitis

Association of the-159 CD14 Gene Polymorphism and Lack of Association of the-308 TNFA and Q551R IL-4RA Polymorphisms With Severe Chronic Periodontitis in Swedish Caucasians

Interleukin-1 Receptor Antagonist Polymorphism (Rs2234663) and Periodontitis Susceptibility: A Meta-Analysis

Assessment of Salivary Interleukin-1 Receptor Antagonist and Obesity Measures of Patients With Chronic Periodontitis in Comparison to Healthy Control

Clinical Significance of GCF sIL-6R and Calprotectin to Evaluate the Periodontal Inflammation

Interleukin-1b is a Potential Therapeutic Target for Periodontitis: A Narrative Review

Preparation and Evaluation of IL-1ra-Loaded Dextran/PLGA Microspheres for Inhibiting Periodontal Inflammation In Vitro

Cytokine Gene Expression Profiles During Initiation, Progression and Resolution of Periodontitis

Role of Cytokines in Thymus-Versus Peripherally Derived-Regulatory T Cell Differentiation and Function

Et Al: Interleukin-2/ Anti-Interleukin-2 Monoclonal Antibody Immune Complex Suppresses Collagen-Induced Arthritis in Mice by Fortifying Interleukin-2/STAT5 Signalling Pathways

Gingival Crevicular Fluid Levels of Cytokines/Chemokines in Chronic Periodontitis: A Meta-Analysis

Inflammatory and Immune Pathways in the Pathogenesis of Periodontal Disease

Revisiting the Page & Schroeder Model: The Good, the Bad and the Unknowns in the Periodontal Host Response 40 Years Later

Th17/Treg Cells Imbalance and Their Related Cytokines (IL-17, IL-10 and TGF-Beta) in Children With Autism Spectrum Disorder

Et Al: Human CD8(+) CD25 (+) CD127 (Low) Regulatory T Cells: microRNA Signature and Impact on TGF-Beta and IL-10 Expression

An Update of Knowledge on the Regulatory Role of Treg Cells in Apical Periodontitis

Effects of IL-13 on TGF-Beta and MMP-1 in Periodontitis

Association of IL-10 -1082a>G, -819c>T, and -592C>A Polymorphisms With Susceptibility to Chronic and Aggressive Periodontitis: A Systematic Review and Meta-Analysis

Evidence Revealing the Role of T Cell Regulators (Tregs) in Periodontal Diseases: A Review

Systemic Antibiotic Therapy Reduces Circulating Inflammatory Dendritic Cells and Treg-Th17 Plasticity in Periodontitis

Interleukin-35 Inhibits Alveolar Bone Resorption by Modulating the Th17/Treg Imbalance During Periodontitis

Regulatory T Cell Phenotype and Anti-Osteoclastogenic Function in Experimental Periodontitis

IL-23-Producing CD68(+) Macrophage-Like Cells Predominate Within an IL-17-Polarized Infiltrate in Chronic Periodontitis Lesions

Clinical Significance of IL-23 Regulating IL-17A and/or IL-17F Positive Th17 Cells in Chronic Periodontitis

The Involvement of IL-23 and the Th17 Pathway in Periodontitis

Role of Serum IL-23/ IL-17 Axis in the Relationship Between Periodontitis and Coronary Heart Disease

Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest