It was previously reported that specific genetic factors can account for as much as 50% of the overall onset risks of periodontal disease [
IL-10 is an anti-inflammatory cytokine and a B lymphocyte proliferation factor, having pleiotropic effects on both immune regulation and inflammation [
Meta-analyses exclusively on the association of IL-10-592 (-590, -597) C>A polymorphisms with periodontitis have not been extensively reported on, though two papers by Zhong et al. [
The meta-analysis was performed in accordance with the PRISMA-P (preferred reporting items for systematic reviews and meta-analysis protocols) statement which was recommended for the establishment of a systematic review and meta-analysis [
Is there an association between IL-10-592 (-590, -597) gene variations and CP or AgP?
The inclusion criteria that published studies need to meet to be included in the meta-analysis were as follows: (1) case-control studies; (2) the case groups consisted of patients diagnosed with CP or AgP, and the control groups consisted of periodontally healthy individuals; (3) IL-10-592 (-590, -597) C>A polymorphisms were detected, and sufficient data regarding genotype distributions were provided for the calculation of odds ratio (ORs) and corresponding 95% confidence intervals (95% CIs); and (4) studies with no repeated data. Studies that did not meet each of these criteria were excluded from the meta-analysis.
A systematic literature search for studies published up to January 31, 2018, was performed using the electronic databases, PubMed, Embase, Web of Science, and WANFAN. In addition, the reference lists of the selected manuscripts and related reviews were also manually screened for comprehensive results. The search strategies were presented as follows.
Number 1
TS = periodontal disease or
TS = periodontitis or TS = periodontal pocket or TS = periodontal tissue
Number 2
TS = interleukin-10 or TS = IL-10 or TS = interleukin 10 or TS = IL 10
Number 3
TS = polymorphism or
TS = polymorphisms or TS = genetic variation
Number 1 and Number 2 and Number 3
For study selection, duplicate studies or datasets were firstly removed from the included titles using EndNote software. Then titles and abstracts of the remaining results were screened, followed by full-text paper screening according to the inclusion criteria described above (Figure
Screening process of the included studies.
The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the included case-control studies, which was performed by two authors independently. The composition of NOS includes three sections for consideration, which were “Selection” (0–4 points), “Comparability” (0–2 points), and “Exposure” (0–3 points). For the “Comparability” chapter, smoking status, age, and sex were selected as the main confounding factors to be matched in the present study. If two out of three factors were matched, one point (asterisk) was scored; if all three factors were matched, two points were assigned. The final scores were calculated ranging from 0 to 9. Studies with scores of 0–3, 4–6, and 7–9 points were considered of low, moderate, and high quality, respectively [
The ORs and 95% CIs were calculated to evaluate the association between IL-10-592 (-590, -597) polymorphisms and susceptibility to chronic or aggressive periodontitis. Heterogeneity between studies was estimated by
A total of 18 articles were included in the current meta-analysis on the gene IL-10-592 (-590, -597) C>A (rs1800872) polymorphisms. The selection process for including publication articles is presented in the flowchart (Figure
Characteristics of the included studies on association of IL-10-592 (-590, -597) C>A gene polymorphisms with periodontitis.
Author (year) | Population | Study type | Cases/controls | Smoking status | Control type | Gender | Quality (NOS) | Locus of SNPs |
---|---|---|---|---|---|---|---|---|
Scarel-Caminaga et al. (2004) [ |
Brazilian Caucasian | Case-control | 48/36 | No smoke | HC | Matched | 7/9 | -592 |
Sumer et al. (2007) [ |
Turkish Caucasian | Case-control | 75/73 | No smoke | CC | Matched | 8/9 | -597 |
Claudino et al. (2008) [ |
Brazilian (mixed) | Case-control | 116/173 | No smoke | CC | Not Matched | 6/9 | -592 |
Reichert et al. (2008) [ |
German Caucasian | Case-control | 59/34 | Mixed | CC | Matched | 6/9 | -590 |
Hu et al. (2009) [ |
Taiwanese Han | Case-control | 210/126 | Mixed | HC | Matched | 5/9 | -592 |
Li et al. (2009) [ |
Chinese Han | Case-control | 30/30 | Unknown | HC | Matched | 6/9 | -592 |
Atanasovska-Stojanovska et al. (2012) [ |
Macedonian Caucasian | Case-control | 111/299 | No smoke | HC | Matched | 7/9 | -592 |
Garlet et al. (2012) [ |
Brazilian (mixed) | Case-control | 197/214 | No smoke | HC | Matched | 7/9 | -592 |
Jaradat et al. (2012) [ |
Jordanian | Case-control | 190/86 | No smoke | CC | Matched | 7/9 | -597 |
Scapoli et al. (2012) [ |
Italian Caucasian | Case-control | 182/230 | Mixed | Unknown | Unknown | 5/9 | -592 |
Scapoli et al. (2015) [ |
Italian Caucasian | Case-control | 182/230 | No smoke | Unknown | Matched | 6/9 | -592 |
Silveira et al. (2016) [ |
Brazilian | Case-control | 111/61 | No smoke | HC | Matched | 6/9 | -592 |
Gorgun et al. (2017) [ |
Turkish | Case-control | 53/50 | No smoke | HC | Matched | 7/9 | -597 |
Lopes et al. (2017) [ |
Brazilian | Case-control | 55/150 | Unknown | HC | Matched | 4/9 | -592 |
Toker et al. (2017) [ |
Turkish Caucasian | Case-control | 103/38 | No smoke | HC | Matched | 6/9 | -597 |
Zhang et al. (2017) [ |
Chinese Uygur | Case-control | 200/100 | Unknown | CC | Matched | 7/9 | -597 |
Moudi et al. (2018) [ |
Iranian | Case-control | 210/100 | No smoke | HC | Matched | 7/9 | -592 |
Toker et al. (2018) [ |
Turkish | Case-control | 52/50 | No smoke | HC | Matched | 7/9 | -592 |
HC/CC: hospital/community control; NOS: Newcastle-Ottawa scale; SNPs: single-nucleotide polymorphisms.
The scores of NOS ranged from 4 to 8. Nine studies were considered to be of high quality [
Distribution of IL-10-592 (-590, -597) C>A genotypes and allele frequency among periodontitis patients and control subjects.
First author | Year | Cases (CP/AgP) | Controls | Genotype distribution | Allele distribution | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Cases | Controls | Cases | Controls | |||||||||||
CC | AC | AA | CC | AC | AA | C | A | C | A | |||||
Scarel-Caminaga [ |
2004 | 48 (CP) | 36 | 12 | 34 | 2 | 19 | 14 | 3 | 58 | 38 | 52 | 20 | 0.85 |
Sumer [ |
2007 | 75 (CP) | 73 | 24 | 40 | 11 | 43 | 29 | 1 | 88 | 62 | 115 | 31 | 0.11 |
Claudino [ |
2008 | 116 (CP) | 173 | 33 | 65 | 18 | 84 | 69 | 20 | 131 | 101 | 237 | 109 | 0.32 |
Reichert [ |
2008 | 27 (CP) | 34 | 20 | 7 | 0 | 23 | 10 | 1 | 47 | 7 | 56 | 12 | 0.94 |
32 (AgP) | 18 | 8 | 6 | 44 | 20 | |||||||||
Hu [ |
2009 | 145 (CP) | 126 | 27 | 32 | 86 | 16 | 48 | 62 | 86 | 204 | 80 | 172 | 0.17 |
65 (AgP) | 6 | 21 | 38 | 33 | 97 | |||||||||
Li [ |
2009 | 30 (AgP) | 30 | 7 | 11 | 12 | 5 | 12 | 13 | 25 | 35 | 22 | 38 | 0.275 |
Atanasovska-Stojanovska [ |
2012 | 111 (CP) | 299 | 62 | 45 | 4 | 154 | 117 | 28 | 169 | 53 | 425 | 173 | 0.40 |
Scapoli [ |
2012 | 178 (CP) | 222 | 75 | 83 | 20 | 115 | 91 | 16 | 233 | 123 | 321 | 123 | 0.73 |
Garlet [ |
2012 | 197 (CP) | 214 | 57 | 107 | 33 | 106 | 80 | 28 | 221 | 173 | 292 | 136 | 0.04 |
Jaradat [ |
2012 | 105 (CP) | 86 | 60 | 32 | 13 | 63 | 19 | 4 | 152 | 58 | 145 | 27 | 0.13 |
Scapoli [ |
2015 | 279 (CP) | 213 | 143 | 109 | 27 | 114 | 83 | 16 | 395 | 163 | 311 | 115 | 0.87 |
Silveira [ |
2016 | 61 (CP) | 61 | 22 | 32 | 7 | 27 | 26 | 8 | 76 | 46 | 80 | 42 | 0.66 |
50 (AgP) | 20 | 21 | 9 | 61 | 39 | |||||||||
Gorgun [ |
2017 | 53 (AgP) | 50 | 7 | 34 | 12 | 3 | 45 | 2 | 48 | 58 | 51 | 49 | <0.001 |
Lopes [ |
2017 | 55 (CP) | 150 | 0 | 42 | 13 | 48 | 83 | 19 | 42 | 68 | 179 | 121 | 0.07 |
Toker [ |
2017 | 45 (CP) | 38 | 5 | 24 | 16 | 2 | 34 | 2 | 34 | 56 | 38 | 38 | <0.001 |
50 (AgP) | 6 | 38 | 14 | 50 | 66 | |||||||||
Zhang [ |
2017 | 199 (CP) | 100 | 54 | 95 | 50 | 29 | 52 | 19 | 203 | 195 | 110 | 90 | 0.96 |
Moudi [ |
2018 | 210 (CP) | 100 | 12 | 152 | 46 | 10 | 61 | 29 | 176 | 214 | 81 | 119 | 0.008 |
Toker [ |
2018 | 52 (CP) | 50 | 7 | 27 | 18 | 3 | 45 | 2 | 41 | 63 | 61 | 49 | <0.001 |
CP/AgP: chronic/aggressive periodontitis; HWE: Hardy–Weinberg equilibrium fulfillment.
Our literature search yielded 16 viable studies that had been conducted on the association between IL-10-592 (-590, -597) C>A polymorphisms and the risk of acquiring CP. The results are summarized in Table
IL-10-592 (-590, -597) C>A polymorphism and periodontitis.
Genetic model | Total/subgroup | Number of studies | Cases/controls | OR ( |
95% CI | Egger ( |
Model of meta-analysis | |
---|---|---|---|---|---|---|---|---|
IL-10-592 (-590, -597) C>A polymorphism and chronic periodontitis | ||||||||
A versus C | Total | 16 | 1903/1975 | 1.38 (<0.001) | 1.17–1.64 | 62.1 (0.001) | 0.071 | Random |
Total for HWEb | 12 | 1418/1580 | 1.38 (0.002) | 1.12–1.70 | 65.9 (<0.001) | 0.017 | Random | |
Caucasian | 7 | 763/915 | 1.31 (0.088) | 0.96–1.77 | 68.4 (0.004) | 0.047 | Random | |
Nonsmoker | 11 | 1299/1343 | 1.43 (0.002) | 1.15–1.79 | 68.0 (<0.001) | 0.294 | Random | |
AA versus CC+CA | Total | 16 | 1903/1975 | 1.49 (0.02) | 1.06–2.10 | 59.4 (0.001) | 0.243 | Random |
Total for HWE | 12 | 1399/1573 | 1.42 (0.002) | 1.13–1.78 | 31.0 (0.14) | 0.234 | Fixed | |
Caucasian | 7 | 763/915 | 1.50 (0.33) | 0.66–3.43 | 68.0 (0.005) | 0.647 | Random | |
Nonsmoker | 11 | 1299/1343 | 1.56 (0.10) | 0.91–2.66 | 71.0 (<0.001) | 0.993 | Random | |
CC versus AA+CA | Total | 16 | 1903/1975 | 0.69 (0.01) | 0.51–0.92 | 68.0 (<0.001) | 0.208 | Random |
Total for HWE | 12 | 1399/1573 | 0.68 (0.02) | 0.49–0.93 | 69.0 (<0.001) | 0.149 | Random | |
Caucasian | 7 | 763/915 | 0.74 (0.15) | 0.50–1.11 | 66.2 (0.007) | 0.676 | Random | |
Nonsmoker | 11 | 1299/1343 | 0.62 (0.006) | 0.44–0.87 | 68.0 (<0.001) | 0.450 | Random | |
IL-10-592 (-590, -597) C>A polymorphism and aggressive periodontitis | ||||||||
A versus C | Total | 6 | 288/399 | 1.29 (0.04) | 1.01–1.63 | 0.0 (0.69) | 0.28 | Fixed |
Caucasian | 2 | 90/72 | 1.55 (0.07) | 0.97–2.48 | 0.0 (0.35) | — | Fixed | |
Nonsmoker | 3 | 161/149 | 1.26 (0.157) | 0.92–1.74 | 0.0 (0.98) | — | Fixed | |
AA versus CC+CA | Total | 6 | 288/399 | 1.93 (0.001) | 1.30–2.89 | 47.5 (0.09) | — | Fixed |
Caucasian | 2 | 90/72 | 6.29 (0.004) | 1.78–22.21 | 0.0 (0.83) | — | Fixed | |
Nonsmoker | 3 | 161/149 | 3.24 (0.001) | 1.59–6.61 | 47.0 (0.15) | — | Fixed | |
CC versus AA+CA | Total | 6 | 288/399 | 0.98 (0.91) | 0.64–1.49 | 0.0 (0.52) | 0.43 | Fixed |
Caucasian | 2 | 90/72 | 0.88 (0.76) | 0.39–2.01 | 34.0 (0.22) | — | Fixed | |
Nonsmoker | 3 | 161/149 | 1.19 (0.58) | 0.65–2.17 | 5.6 (0.35) | — | Fixed |
OR: odds ratio; CI: confidence interval. a
Forest plot of the association between IL-10-592 (-590, -597) C>A polymorphisms and chronic periodontitis by excluding the studies deviated from HWE in the control. (a) A allele versus C allele model. (b) AA versus AC+CC model. (c) CC versus AC+AA model.
When we considered only the Caucasian subgroup, we found no significant differences in the A allele versus C allele model, in the AA versus CC+CA model, or in the CC versus CA+AA model (Table
Forest plot of the association between IL-10-592 (-590, -597) C>A polymorphisms and chronic periodontitis in nonsmoking population. (a) A allele versus C allele model. (b) AA versus AC+CC model. (c) CC versus AC+AA model.
Six studies were involved, comprising 288 cases and 399 controls. The results are summarized in Table
Forest plot of the association between IL-10-592 (-590, -597) A>C polymorphisms and aggressive periodontitis. (a) A allele versus C allele model. (b) AA versus AC+CC model. (c) AA versus AC+CC model in Caucasian population. (d) AA versus AC+CC model in nonsmoking population.
To assess the effect of an individual dataset on pooled ORs, a sensitivity analysis was performed through the sequential omission of each study. The results suggested that no single study greatly influenced the pooled estimations under any of the three genetic models for CP (e-Tables
Egger’s test proved that there was no significant publication bias except HWE fulfillment or Caucasian population subgroup analysis in the CP versus controls allele comparison (Table
The present meta-analysis included 18 studies with 2191 cases and 1975 controls. There are some conflicting results among the 18 studies included, which may be the result of variations in individual study characteristics, including the ethnic populations surveyed, different sample sizes, and key confounding variables such as smoking status. Therefore, the present meta-analysis increases the likelihood of identifying true correlations by further systematizing the existing information.
Investigations of the correlations between IL-10-592 (-590, -597) C>A polymorphisms and CP risk suggested that IL-10-592 (-590, -597) A allele and AA genotype may increase the risk of CP, while CC genotype provides increased protection against the risk of the disease. These results were expected because 11 out of 16 individual studies included in our meta-analysis presented these trends in their populations. Furthermore, sensitivity analysis revealed no quantitative changes for the interstudy heterogeneity, suggesting that these results were stable and trustworthy.
It was demonstrated that the associations between genetic polymorphisms and certain diseases varied with different geographical regions and ethnic groups [
For IL-10-592 (-590, -597) C>A polymorphisms and AgP, our meta-analysis results indicated that the A allele may confer a relative increase in the risk for developing AgP, especially in Caucasian individuals, as described in the meta-analysis results reported by Albuquerque et al. [
Smoking may increase the risk of periodontitis onset [
This meta-analysis has several strengths, including an unrestricted search process (including grey literature), duplicate review procedures for the search, sensitivity analysis, and assessments of the risk of bias and the quality of literature. But this meta-analysis has some limitations. As we know, interstudy heterogeneity and publication bias are main limitations associated with meta-analyses. Heterogeneity can be caused by many factors such as race, sample sizes, smoking habits, and deviations of allele distributions from the HWE [
Another factor that we considered in our analysis was publication bias. Publication bias stems from the fact that positive results are much more readily published by journals, whereas negative results tend to be poorly received by journals and are collectively known as “grey literature” [
Although a broad search in four different databases was used to find studies for inclusion in our meta-analysis, it is impossible to confirm that all available studies addressing the relationship between IL-10-592 (-590, -597) C>A polymorphisms and periodontitis were included, presenting another major limitation of the meta-analysis.
Three common single nucleotide polymorphisms (SNPs) in the IL-10 gene promoter (-1082 A>G, -819 C>T, and -592 C>A) show strong linkage disequilibrium and form two common haplotypes, designated as [ATA] and [GCC]. The [ATA] haplotype has been associated with decreased synthesis of IL-10 and is frequently associated with periodontitis [
Even considering the limitations of this study, the present meta-analysis supported the hypothesis that IL-10-592 (-590, -597) C>A polymorphisms may be associated with CP and AgP susceptibility. We not only identified that the IL-10-592 (-590, -597) A alleles and AA genotypes may be a risk factor for the development of CP and AgP but also found out that the IL-10-592 (-590, -597) CC genotype may play a protective role in preventing CP. It is noteworthy that the AA genotype was found to be more closely tied to the risk of AgP in Caucasian and nonsmoker population. Thus, IL-10-592 (-590, -597) A alleles or AA genotypes may be a putative biomarker for diagnosing CP and AgP. Large-scale studies to further validate our findings should be performed in the future.
The authors declare that there are no competing interests regarding the publication of this paper.
Yao Li searched literature, selected study, analysed data, and drafted the article. Yuejia Deng and Ge Feng participated in the literature search and study selection. Jinglin Song designed this study, interpreted data, and revised the article.
This study was supported by the Program for Innovation Team Building at Institutions of Higher Education in Chongqing in 2016 (Grant no. CXTDG201602006).
e-Table 1: Newcastle-Ottawa quality assessment scores for the studies included in the meta-analysis. e-Table 2: sensitivity analysis