Abstract
The association between TGF-β1 rs1800469 polymorphism and the risk of periodontitis was controversial and inconclusive. This meta-analysis aimed to evaluate the association between the TGF-β1 rs1800469 polymorphism and periodontitis risk. The electronic databases PubMed, EMBASE, and Web of Science were searched for studies to include in the present meta-analysis. Odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of association between the TGF-β1 rs1800469 polymorphism and periodontitis risk. A total of 8 publications involving 923 cases and 892 controls met the inclusion criteria and were ultimately analyzed. In this meta-analysis, a significant association was detected between TGF-β1 rs1800469 polymorphism and periodontitis risk (OR=1.21; 95% CI, 1.05-1.39; P=0.008). In the subgroup analysis by ethnicity, the significant association was only found among Asians (OR=1.23; 95% CI, 1.05-1.44; P=0.01), while no significant association was found among Caucasians (OR=1.16; 95% CI, 0.90-1.49; P=0.25). In the subgroup analysis by type and periodontitis, the significant association was only found among CP patients (OR=1.18; 95% CI, 1.02-1.37; P=0.03), while no significant association was found among AP patients (OR=1.27; 95% CI, 0.98-1.65; P=0.07). In addition, no significant association was found among non-smokers (OR=1.28; 95% CI, 0.93-1.76; P=0.13). In conclusion, this meta-analysis suggests that the TGF-β1 rs1800469 polymorphism is associated with periodontitis risk. Further studies analyzing gene-gene and gene-environment interactions are required.
Keywords: Periodontitis, TGF-β1, meta-analysis, genetic
Introduction
Periodontitis is a complex, multifactorial disease that may be classified as two main types, chronic periodontitis (CP) and aggressive periodontitis (AP) [1]. The destruction of periodontal tissues occurs by a complex interaction of the bacterial biofilm and host response and is also influenced by genetic, systemic and environmental factors.
Transforming growth factor β1 (TGF-β1) is a member of a highly pleiotrophic family of growth factors that are involved in the regulation of numerous immunomodulatory processes [2]. Vikram et al. suggested that TGF-β1 may play a role in the pathogenesis and diagnosis of periodontal disease and could be considered as a disease predictive biomarker [3]. Mize et al. found that the gingival expression levels of TGFβ1 mRNA in individuals with periodontitis are upregulated and correlated [4]. In addition, Khalaf and coworkers indicated that the ease of sampling and analyzing cytokine expression profiles, including TGF-β1, in saliva and gingival crevicular fluid (GCF) may serve to predict the progression of periodontitis and associated systemic inflammatory diseases [5].
The location of TGF-β1 is on chromosome 19q13.1-13.3 and some polymorphic areas have been recognized in this gene. Rs1800469 is one of the main TGF-β1 signal sequence polymorphism. The association between TGF-β1 rs1800469 polymorphism and the risk of periodontitis was controversial and inconclusive [6-13]. This meta-analysis aimed to evaluate the association between the TGF-β1 rs1800469 polymorphism and periodontitis risk.
Materials and methods
Publication search
The electronic databases PubMed, EMBASE, and Web of Science were searched for studies to include in the present meta-analysis, using the terms: “Transforming growth factor β1” or “TGF-β1”, “rs1800469”, “polymorphism” and “periodontitis”. An upper date limit of Apr 2015 was applied; no lower date limit was used. The search was performed without any restrictions on language and was focused on studies that had been conducted in humans. Concurrently, the reference lists of reviews and retrieved articles were searched manually. Only full-text articles were included. When the same patient population appeared in several publications, only the most recent or complete study was included in this meta-analysis.
Inclusion criteria
The included studies have to meet the following criteria: (1) evaluating the TGF-β1 rs1800469 polymorphism and periodontitis risk; (2) case-control studies; and (3) provided sufficient data of allele and genotype frequencies of SNP or required information could be calculated. The exclusion criteria were as follows: (1) studies not evaluating the correlation between TGF-β1 rs1800469 polymorphism and periodontitis risk; (2) animal or cellular studies; (3) reviews, comments, meta-analysis or abstracts; (4) studies that lack a control group.
Qualitative assessment
Two authors completed the quality assessment independently. The Newcastle-Ottawa Scale (NOS) was used to evaluate the methodological quality, which scored studies by the selection of the study groups, the comparability of the groups, and the ascertainment of the outcome of interest. We considered a study awarded 0-3, 4-6, or 7-9 as a low-, moderate-, or high-quality study, respectively.
Data extraction
Information from the publications that met the above criteria was carefully extracted by two independent investigators. A third investigator subsequently reviewed the results. The following items were extracted from each article: first author’s name, publication year, ethnicity, gender, type of disease, smoking status, numbers of case and control patients, and Hardy-Weinberg equilibrium (HWE).
Statistical analysis
Odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of association between the TGF-β1 rs1800469 polymorphism and periodontitis risk. The pooled OR for the risk was calculated in allele model. Subgroup analyses were done by ethnicity, type of disease, and smoking status. Heterogeneity assumption was checked by the chi-square-based Q-test. A P value greater than 0.10 for the Q-test indicates a lack of heterogeneity among studies, so the pooled OR estimate of the each study was calculated by the fixed-effects model (the Mantel-Haenszel method). Otherwise, the random-effects model (the DerSimonian and Laird method) was used. One-way sensitivity analyses were performed to assess the stability of the results, namely, a single study in the meta-analysis was deleted each time to reflect the influence of the individual data-set to the pooled OR. An estimate of potential publication bias was carried out by the funnel plot, in which the standard error of log (OR) of each study was plotted against its log (OR). An asymmetric plot suggests a possible publication bias. Funnel plot asymmetry was assessed by the method of Egger’s linear regression test, a linear regression approach to measure the funnel plot asymmetry on the natural logarithm scale of the OR. The significance of the intercept was determined by the t-test suggested by Egger (P<0.05 was considered representative of statistically significant publication bias). All of the calculations were performed using RevMan5.1 software and STATA version 11.0 (STATA Corporation, College Station, TX, USA).
Results
Study selection and study characteristics
After screening 113 records for eligibility, 8 case-control studies were included in the meta-analysis. The most common reasons for study exclusion included animal or cellular studies, review or abstract. A flow diagram of study identification and selection is shown in Figure 1. A total of 8 publications involving 923 cases and 892 controls met the inclusion criteria and were ultimately analyzed. Table 1 presents the main characteristics of these studies. All but one study were published in English. The sample sizes ranged from 50 to 626. There were 4 studies of Asians and 4 studies of Caucasian population.
Figure 1.
Flow chart for the literature search strategy.
Table 1.
Characteristics of the included studies in this meta-analysis
| First author/Year | Ethnicity | Gender | Type of disease | Smoking status | Case number | Control number | HWE | Study quality |
|---|---|---|---|---|---|---|---|---|
| Holla 2002 | Caucasian | Mixed | CP | Mixed | 98 | 108 | Yes | 7 |
| de Souza 2003 | Caucasian | Mixed | CP | Non-smoker | 50 | 37 | Yes | 6 |
| Komatsu 2008 | Asian | Mixed | CP | Non-smoker | 113 | 108 | Yes | 7 |
| Kobayashi-a 2009 | Asian | Mixed | CP | Mixed | 117 | 108 | Yes | 7 |
| Kobayashi-b 2009 | Asian | Mixed | CP, AP | Mixed | 319 | 303 | Yes | 7 |
| Zhao 2010 | Asian | Mixed | CP | Non-smoker | 102 | 102 | Yes | 8 |
| Arab 2012 | Caucasian | Mixed | AP | Non-smoker | 24 | 26 | Yes | 5 |
| Heidari 2013 | Caucasian | Mixed | CP | Non-smoker | 100 | 100 | Yes | 7 |
HWE, Hardy-Weinberg equilibrium; CP, chronic periodontitis; AP, aggressive periodontitis.
Meta-analysis results
In this meta-analysis, a significant association was detected between TGF-β1 rs1800469 polymorphism and periodontitis risk (OR=1.21; 95% CI, 1.05-1.39; P=0.008; Figure 2). In the subgroup analysis by ethnicity, the significant association was only found among Asians (OR=1.23; 95% CI, 1.05-1.44; P=0.01), while no significant association was found among Caucasians (OR=1.16; 95% CI, 0.90-1.49; P=0.25). In the subgroup analysis by type and periodontitis, the significant association was only found among CP patients (OR=1.18; 95% CI, 1.02-1.37; P=0.03), while no significant association was found among AP patients (OR=1.27; 95% CI, 0.98-1.65; P=0.07). In addition, no significant association was found among non-smokers (OR=1.28; 95% CI, 0.93-1.76; P=0.13). Table 2 listed the main results of this meta-analysis.
Figure 2.
Meta-analysis for TGF-β1 rs1800469 polymorphism and periodontitis risk.
Table 2.
The effect of TGF-β1 rs1800469 polymorphism on periodontitis
| OR (95% CI) | P Value | Model | |
|---|---|---|---|
| Overall | 1.21 (1.05-1.39) | 0.008 | F |
| Asian | 1.23 (1.05-1.44) | 0.01 | F |
| Caucasian | 1.16 (0.90-1.49) | 0.25 | F |
| CP | 1.18 (1.02-1.37) | 0.03 | F |
| AP | 1.27 (0.98-1.65) | 0.07 | F |
| Non-smoker | 1.28 (0.93-1.76) | 0.13 | R |
F, fixed-effects model; R, random-effects model; CP, chronic periodontitis; AP, aggressive periodontitis.
Sensitivity analysis of the positive results was performed to determine the influence of each study on the pooled ORs by sequentially removing one study. No significant change was found, indicating that the results were reliable (Figure 3). In addition, when the low quality studies were excluded, the result was not changed (OR=1.23; 95% CI, 1.06-1.42; P=0.007). When the studies with small sample size were excluded, the result was also not altered (OR=1.21; 95% CI, 1.03-1.42; P=0.02). Table 3 listed the main results of sensitivity analysis.
Figure 3.
Sensitivity analysis for TGF-β1 rs1800469 polymorphism and periodontitis risk.
Table 3.
Sensitivity analysis of this study
| OR (95% CI) | P Value | Model | |
|---|---|---|---|
| High quality study | 1.23 (1.06-1.42) | 0.007 | F |
| Large sample size | 1.21 (1.03-1.42) | 0.02 | F |
F, fixed-effects model.
Funnel plot and Egger’s test were performed to access the publication bias of literatures. Egger test was not significant (P=0.711). The funnel plots for publication bias (Figure 4) also did not show asymmetry. These results did not indicate a potential for publication bias.
Figure 4.
Funnel plot for TGF-β1 rs1800469 polymorphism and periodontitis risk.
Discussion
Gürkan et al. found that AP and CP groups had significantly elevated GCF TGF-β1 total amount compared to healthy group [14]. Stein and colleagues suggested that Smokers exhibited a higher mean concentration of GCF TGF-β1 at baseline compared to non-smokers. After initial therapy, smokers exhibited significantly less reduction in mean GCF volume compared to non-smokers [15]. Therefore, high level of TGF-β1 might be associated with periodontitis risk. This meta-analysis summarizes all the available data on the association between TGF-β1 rs1800469 polymorphism and periodontitis risk, including a total of 923 cases and 892 controls. Our results indicated that TGF-β1 rs1800469 polymorphism contributes to risk of periodontitis among Asian population, but not for Caucasian population. Furthermore, TGF-β1 rs1800469 polymorphism increases the risk of CP but not for AP.
The effect of any single gene might have a limited impact on periodontitis risk than have so far been anticipated. The knowledge of environmental determinants and large studies with detailed exposure information are crucial to evaluate reliably any moderate genetic effects. Many controversial data are present in literature. Positive associations were found in certain populations and not confirmed in others. Gene–environment interactions could be a confounding factor in these studies, with controversial findings on periodontitis risk.
Some limitations of this meta-analysis should be acknowledged. Firstly, our results were based on unadjusted estimates, while a more precise analysis should be conducted if individual data were available, which would allow for the adjustment by other covariates including age, ethnicity, family history, environmental factors and lifestyle. Secondly, due to the limited original data, potential gene-gene and gene-environment interactions which have an important impact on periodontitis risk were not evaluated in this study. Thirdly, the data included in this meta-analysis did not have a sufficiently large sample size for a comprehensive analysis because of the limited number of published studies and samples.
In conclusion, this meta-analysis suggests that the TGF-β1 rs1800469 polymorphism is associated with periodontitis risk. Further studies analyzing gene-gene and gene-environment interactions are required. Such studies may eventually lead to have a better, comprehensive understanding of the association between the TGF-β1 rs1800469 polymorphism and periodontitis risk.
Disclosure of conflict of interest
None.
References
- 1.Armitage GC. Development of a classification system for periodontal diseases and conditions. Northwest Dent. 2000;79:31–5. [PubMed] [Google Scholar]
- 2.Verrecchia F, Mauviel A. Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. J Invest Dermatol. 2002;118:211–5. doi: 10.1046/j.1523-1747.2002.01641.x. [DOI] [PubMed] [Google Scholar]
- 3.Vikram V, Ramakrishnan T, Anilkumar K, Ambalavanan N. Changes in Transforming Growth Factor-β1 in Gingival Crevicular Fluid of Patients with Chronic Periodontitis Following Periodontal Flap Surgery. J Clin Diagn Res. 2015;9:ZC13–6. doi: 10.7860/JCDR/2015/11039.5539. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Mize TW, Sundararaj KP, Leite RS, Huang Y. Increased and correlated expression of connective tissue growth factor and transforming growth factor beta 1 in surgically removed periodontal tissues with chronic periodontitis. J Periodontal Res. 2015;50:315–9. doi: 10.1111/jre.12208. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Khalaf H, Lönn J, Bengtsson T. Cytokines and chemokines are differentially expressed in patients with periodontitis: possible role for TGF-β1 as a marker for disease progression. Cytokine. 2014;67:29–35. doi: 10.1016/j.cyto.2014.02.007. [DOI] [PubMed] [Google Scholar]
- 6.Holla LI, Fassmann A, Benes P, Halabala T, Znojil V. 5 polymorphisms in the transforming growth factor-beta 1 gene (TGF-beta 1) in adult periodontitis. J Clin Periodontol. 2002;29:336–41. doi: 10.1034/j.1600-051x.2002.290409.x. [DOI] [PubMed] [Google Scholar]
- 7.de Souza AP, Trevilatto PC, Scarel-Caminaga RM, de Brito RB, Line SR. Analysis of the TGF-beta1 promoter polymorphism (C-509T) in patients with chronic periodontitis. J Clin Periodontol. 2003;30:519–23. doi: 10.1034/j.1600-051x.2003.00323.x. [DOI] [PubMed] [Google Scholar]
- 8.Komatsu Y, Galicia JC, Kobayashi T, Yamazaki K, Yoshie H. Association of interleukin-1 receptor antagonist +2018 gene polymorphism with Japanese chronic periodontitis patients using a novel genotyping method. Int J Immunogenet. 2008;35:165–70. doi: 10.1111/j.1744-313X.2008.00757.x. [DOI] [PubMed] [Google Scholar]
- 9.Kobayashi T, Murasawa A, Ito S, Yamamoto K, Komatsu Y, Abe A, Sumida T, Yoshie H. Cytokine gene polymorphisms associated with rheumatoid arthritis and periodontitis in Japanese adults. J Periodontol. 2009;80:792–9. doi: 10.1902/jop.2009.080573. [DOI] [PubMed] [Google Scholar]
- 10.Kobayashi T, Ito S, Kuroda T, Yamamoto K, Sugita N, Narita I, Sumida T, Gejyo F, Yoshie H. The interleukin-1 and Fcgamma receptor gene polymorphisms in Japanese patients with rheumatoid arthritis and periodontitis. J Periodontol. 2007;78:2311–8. doi: 10.1902/jop.2007.070136. [DOI] [PubMed] [Google Scholar]
- 11.Zhao XZ, Guan ZM, Zhang YM. Relationship between transforming growth factor beta-1 gene-509C/T polymorphism and severe chronic periodontitis. Zhonghua Kou Qiang Yi Xue Za Zhi. 2010;45:610–3. [PubMed] [Google Scholar]
- 12.Arab HR, Afshari JT, Radvar M, Taghavi AM, Sargolzaee N, Mokhtari MR, Farazi F. Association between TGF- β1-509 Gene Polymorphism with Aggressive Periodontitis. International Journal of Genetic Engineering. 2012;2:33–37. [Google Scholar]
- 13.Heidari Z, Mahmoudzadeh-Sagheb H, Hashemi M, Rigi-Ladiz MA. Quantitative analysis of interdental Gingiva in patients with chronic periodontitis and transforming growth factor-β1 29C/T gene polymorphisms. J Periodontol. 2014;85:281–9. doi: 10.1902/jop.2013.130087. [DOI] [PubMed] [Google Scholar]
- 14.Gürkan A, Emingil G, Cinarcik S, Berdeli A. Gingival crevicular fluid transforming growth factor-beta1 in several forms of periodontal disease. Arch Oral Biol. 2006;51:906–12. doi: 10.1016/j.archoralbio.2006.04.008. [DOI] [PubMed] [Google Scholar]
- 15.Stein SH, Green BE, Scarbecz M. Augmented transforming growth factor-beta1 in gingival crevicular fluid of smokers with chronic periodontitis. J Periodontol. 2004;75:1619–26. doi: 10.1902/jop.2004.75.12.1619. [DOI] [PubMed] [Google Scholar]