Epidemiological studies have demonstrated that interleukin-10 (IL-10) polymorphisms may be associated with the development of Behcet’s disease (BD). However, the published results were inconsistent. Therefore, this meta-analysis was conducted to derive a more precise relationship between IL-10 polymorphisms and BD susceptibility. Online databases (PubMed, Embase, Science Citation Index (SCI), CNKI, and WanFang) were searched to identify eligible studies. Odds ratio (OR) and a 95% confidence interval (CI) were applied to assess the relationship strength between IL-10 -1082A>G (rs1800896), -819T>C (rs1800871), and -592A>C (rs1800872) polymorphisms and BD susceptibility. Publication bias, sensitivity, and cumulative analyses were conducted to measure the robustness of our findings. Finally, fifteen articles (36 independent case-control studies) involving 5,971 patients and 8,913 controls were included. Overall, significant associations between -819T>C polymorphisms and BD risk were observed in the total population (C vs. T:
Behcet’s disease (BD) is a chronic polygenic autoinflammatory disorder, characterized by multiple affected body parts, with common symptoms including recurrent oral ulcers, ocular inflammation, genital ulcers, and skin lesions [
Interleukin-10 has been proven to be an important cytokine-suppressing, autoimmune and inflammatory response factor. IL-10 may inhibit the antigen-presenting process by downregulating the expression of HLA molecules on the surface of a cell and suppressing the expression of multiple proinflammatory cytokines, such as TNF-
A number of studies have indicated that the aberrant expression of IL-10 might lead to an inflammatory state that is more susceptible to BD [
In 2013, Liang et al. conducted the first meta-analysis based on four case-control studies, exploring the potential association between the three IL-10 polymorphisms mentioned and BD risk [
This meta-analysis was conducted according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [
Three English databases (PubMed, Embase, and Science Citation Index (SCI)) and two Chinese databases (CNKI and WanFang) were searched with the following terms from their inception up to May 1, 2019: “Interleukin 10,” “IL-10,” “rs1800896,” “rs1800871,” “rs1800872,” “polymorphism,” “variant,” “mutation,” “Behcet’s disease,” and “BD.” Some relevant papers cited within retrieved articles were also reviewed through manual searches. The following search strategy was used (PubMed for example):
Interleukin 10 IL-10 rs1800896 rs1800871 rs1800872 #1 OR #2 OR #3 OR #4 OR #5 Polymorphism Variant Mutation #7 OR #8 OR #9 Behcet’s disease BD #11 OR #12 #6 AND #10 AND #13.
All selected studies met the following criteria: (1) case-control design was employed; (2) some polymorphisms of the IL-10 gene was reported; (3) sufficient data on genotypes of each polymorphism locus were provided to calculate the odds ratios (ORs) and 95% confidence intervals (CIs); (4) the most recent or largest sample sizes were selected when multiple publications were repeatedly reported with the same theme; and (5) the articles were written only in English and Chinese. The studies were excluded if they were (1) letters, reviews, or conference reports; (2) duplicate reports with the same theme and samples; (3) animal models or cell line studies; or (4) studies without sufficient data.
Two independent investigators (LXF and HZZ) reviewed the articles and extracted the following information: name of first author in each study, year of publication, study country or region where the study was conducted, ethnicity of research population, design of the control, sample sizes of patients with BD and controls, frequency genotype of distribution data, and genotyping method used. Disagreements were settled through discussion.
Each study included was evaluated via risk assessment of bias by two authors, LXF and HZZ, according to the modified Newcastle-Ottawa Quality Assessment Scale [
Scale for quality evaluation.
Criteria | Score |
---|---|
Representativeness of cases | |
Consecutive/randomly selected cases with clearly defined sampling frame with time, race, quantity, and defined criteria | 2 |
Not consecutive/randomly selected case or without clearly defined sampling frame with time, race, quantity, and defined criteria | 1 |
Not described | 0 |
Source of controls | |
Population-based | 2 |
Hospital based or healthy based | 1 |
Not described | 0 |
Hardy-Weinberg equilibrium in controls | |
Hardy-Weinberg equilibrium | 2 |
Hardy-Weinberg disequilibrium | 1 |
Not available | 0 |
Genotyping examination | |
Genotyping done under “blinded” condition and repeated again | 2 |
Genotyping done under “blinded” condition or repeated again | 1 |
Unblinded done or not mentioned and unrepeated | 0 |
Subjects | |
| 1 |
| 0 |
Association assessment | |
Assess association between genotypes and BD risk with appropriate statistics and adjustment for confounders | 2 |
Assess association between genotypes and BD risk with appropriate statistics and without adjustment for confounders | 1 |
Inappropriate statistics used | 0 |
The pooled ORs with 95% CIs were used to assess the strength of the associations between the IL-10 gene polymorphisms and BD risk. For example, the genetic models of the -1082A>G (rs1800896) polymorphisms were examined: allele contrast (G vs. A), codominant models (heterozygote model: AG vs. AA; homozygote model: GG vs. AA), dominant model (AG+GG vs. AA), and recessive model (GG vs. AA+AG). Similar genetic models were also examined with the other polymorphic loci (-819T>C (rs1800871) and -592A>C (rs1800872)). Heterogeneity was investigated by Cochran’s
A total of 224 potential articles were retrieved from the databases at the first step. During the subsequent screening and selection steps of duplicate checks, title and abstract checks, and text reviews, 209 articles were excluded according to the eligibility criteria. Finally, fifteen articles (36 independent case-control studies) involving 5,971 patients and 8,913 controls were included in this meta-analysis (Figure
Flow diagram of the study selection process.
Characteristics of included studies on IL-10 gene polymorphisms and Behcet’s disease risk.
First author | Year | Country/region | Racial | Source of controls | Case | Control | Genotype distribution | Genotyping methods | NOS | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Case | Control | ||||||||||||||
-1082A>G (rs1800896) | |||||||||||||||
AA | AG | GG | AA | AG | GG | ||||||||||
Wallace-1 | 2007 | UK | Europe | HB | 63 | 182 | 27 | 23 | 13 | 59 | 75 | 48 | PCR-SSP | 0.02 | 5 |
Wallace-2 | 2007 | Jordan and Palestinian | ME | HB | 115 | 113 | 50 | 50 | 15 | 46 | 40 | 27 | PCR-SSP | <0.01 | 5 |
Dilek | 2009 | Turkey | ME | PB | 96 | 124 | 26 | 66 | 4 | 56 | 58 | 10 | PCR-SSP | 0.35 | 8 |
Ates | 2010 | Turkey | ME | PB | 102 | 102 | 39 | 50 | 13 | 44 | 50 | 8 | ARMS-PCR | 0.23 | 7 |
Shahram | 2011 | ME | HB | 147 | 140 | 58 | 81 | 8 | 53 | 75 | 12 | PCR-SSP | 0.04 | 5 | |
Talaat | 2014 | Egypt | ME | HB | 87 | 97 | 32 | 34 | 21 | 32 | 53 | 12 | MS-PCR | 0.16 | 6 |
Hu-1 | 2015 | China | EA | PB | 300 | 350 | 271 | 29 | 0 | 293 | 56 | 1 | PCR-RFLP | 0.32 | 10 |
Al-Okaily | 2015 | Saudi Arabia | ME | PB | 61 | 211 | 14 | 37 | 10 | 36 | 159 | 16 | ARMS-PCR | <0.01 | 7 |
Barış | 2016 | Turkey | ME | HB | 71 | 70 | 98a | 44b | 99a | 41b | PCR-RFLP | NA | 4 | ||
-819T>C (rs1800871) | |||||||||||||||
TT | TC | CC | TT | TC | CC | ||||||||||
Wallace-1 | 2007 | UK | Europe | HB | 63 | 182 | 7 | 28 | 44 | 13 | 67 | 102 | PCR-SSP | 0.66 | 6 |
Wallace-2 | 2007 | Jordan and Palestinian | ME | HB | 115 | 113 | 11 | 61 | 43 | 10 | 43 | 60 | PCR-SSP | 0.57 | 6 |
Dilek | 2009 | Turkey | ME | PB | 96 | 124 | 7 | 50 | 39 | 13 | 47 | 64 | PCR-SSP | 0.33 | 8 |
Ates | 2010 | Turkey | ME | PB | 102 | 102 | 10 | 45 | 47 | 11 | 44 | 47 | ARMS-PCR | 0.88 | 7 |
Mizuki-1 | 2010 | Japan | EA | HB | 611 | 737 | 935c | 287d | 979c | 495d | GeneChip | NA | 5 | ||
Mizuki-2 | 2010 | Korea | EA | HB | 119 | 140 | 184c | 54d | 194c | 86d | GeneChip | NA | 4 | ||
Mizuki-3 | 2010 | Turkey | ME | HB | 1215 | 1279 | 931c | 1499d | 801c | 1757d | GeneChip | NA | 5 | ||
Shahram | 2011 | Iran | ME | HB | 147 | 140 | 12 | 64 | 71 | 12 | 57 | 71 | PCR-SSP | 0.91 | 6 |
Khaib | 2013 | Algeria | Europe | PB | 51 | 96 | 11 | 23 | 17 | 5 | 41 | 50 | Direct sequencing | 0.35 | 7 |
Wu | 2014 | China | EA | PB | 407 | 679 | 209 | 167 | 31 | 302 | 295 | 82 | Sequenom MassArray | 0.45 | 9 |
Talaat | 2014 | Egypt | ME | HB | 87 | 97 | 10 | 35 | 42 | 6 | 41 | 50 | MS-PCR | 0.53 | 6 |
Carapito | 2015 | Iran | ME | HB | 552 | 341 | 376c | 728d | 255c | 579d | Taqman | NA | 5 | ||
Hu-1 | 2015 | China | EA | PB | 300 | 350 | 168 | 126 | 6 | 146 | 160 | 44 | PCR-RFLP | 0.99 | 10 |
Hu-2 | 2015 | China | EA | PB | 418 | 1403 | 216 | 175 | 27 | 558 | 679 | 166 | PCR-RFLP | 0.06 | 10 |
Al-Okaily | 2015 | Saudi Arabia | ME | PB | 61 | 211 | 12 | 22 | 27 | 21 | 102 | 88 | ARMS-PCR | 0.27 | 8 |
Yu | 2017 | China | EA | PB | 1206 | 2475 | 661 | 459 | 86 | 1121 | 1078 | 276 | Real-time PCR | 0.49 | 9 |
-592A>C (rs1800872) | |||||||||||||||
AA | AC | CC | AA | AC | CC | ||||||||||
Dilek | 2009 | Turkey | ME | PB | 96 | 124 | 7 | 50 | 39 | 13 | 47 | 64 | PCR-SSP | 0.33 | 8 |
Ates | 2010 | Turkey | ME | PB | 102 | 102 | 10 | 45 | 47 | 11 | 44 | 47 | ARMS-PCR | 0.88 | 7 |
Mizuki-1 | 2010 | Japan | EA | HB | 611 | 737 | 935e | 287f | 979e | 495f | GeneChip | NA | 5 | ||
Mizuki-2 | 2010 | Korea | EA | HB | 119 | 140 | 184e | 54f | 194e | 86f | GeneChip | NA | 4 | ||
Mizuki-3 | 2010 | Turkey | ME | HB | 1215 | 1279 | 931e | 1499f | 801e | 1757f | GeneChip | NA | 5 | ||
Shahram | 2011 | ME | HB | 147 | 140 | 12 | 66 | 69 | 12 | 57 | 71 | PCR-SSP | 0.91 | 6 | |
Khaib | 2013 | Algeria | Europe | PB | 51 | 96 | 11 | 23 | 17 | 5 | 41 | 50 | Direct sequencing | 0.35 | 7 |
Montes-Cano | 2013 | Spain | Europe | PB | 304 | 313 | 172e | 408f | 157e | 463f | PCR-SSOP | NA | 6 | ||
Hu-1 | 2015 | China | EA | PB | 300 | 350 | 170 | 120 | 10 | 140 | 174 | 36 | PCR-RFLP | 0.09 | 10 |
Al-Okaily | 2015 | Saudi Arabia | ME | PB | 61 | 211 | 12 | 22 | 27 | 21 | 102 | 88 | ARMS-PCR | 0.27 | 8 |
Afkari | 2018 | Iran | ME | HB | 46 | 61 | 24 | 20 | 2 | 16 | 41 | 4 | PCR-RFLP | <0.01 | 5 |
HWE in control. PB: hospital-based control; HB: healthy-based control/normal control; a: A allele; b: G allele; c: T allele; d: C allele; e: A allele; f: C allele; EA: East Asian; ME: Middle East.
Nine case-control studies, involving 1,042 patients and 1,389 controls, were identified on the association between the -1082A>G polymorphism and BD risk in this meta-analysis, and these are shown in Table
Summary ORs and 95% CI of IL-10 gene polymorphisms and Behcet’s disease risk.
Locus | N | OR | 95% CI | OR | 95% CI | OR | 95% CI | OR | 95% CI | OR | 95% CI | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
-1082A>G (rs1800870) | G vs. A | AG vs. AA | GG vs. AA | AG+GG vs. AA | GG vs. AA+AG | ||||||||||||||||
Total | 9 | 0.95 | 0.79-1.15 | 0.60 | 46.1 | 0.91 | 0.65-1.29 | 0.60 | 64.2 | 0.89 | 0.64-1.24 | 0.50 | 29.2 | 0.91 | 0.67-1.23 | 0.53 | 58.1 | 0.99 | 0.59-1.66 | 0.50 | 59.9 |
HWE—yes | 4 | 1.04 | 0.72-1.54 | 0.83 | 69.1 | 0.87 | 0.65-1.17 | 0.99 | 81.9 | 1.45 | 0.83-2.51 | 0.19 | 0 | 1.05 | 0.58-1.92 | 0.87 | 79.0 | 1.30 | 0.61-2.77 | 0.59 | 41.6 |
HWE—no | 4 | 0.85 | 0.70-1.03 | 0.09 | 0 | 0.99 | 0.51-1.94 | 0.36 | 0 | 0.68 | 0.44-1.03 | 0.07 | 15.8 | 0.81 | 0.61-1.07 | 0.13 | 0 | 0.83 | 0.42-1.63 | 0.95 | 66.4 |
Ethnicity | |||||||||||||||||||||
Europe | 1 | 0.72 | 0.48-1.09 | 0.12 | NA | 0.67 | 0.35-1.29 | 0.23 | NA | 0.59 | 0.28-1.27 | 0.18 | NA | 0.64 | 0.36-1.15 | 0.14 | NA | 0.73 | 0.36-1.45 | 0.37 | NA |
ME | 7 | 1.05 | 0.90-1.22 | 0.55 | 7.5 | 1.05 | 0.71-1.55 | 0.79 | 61.1 | 1.00 | 0.69-1.45 | 1.00 | 38.3 | 1.06 | 0.77-1.45 | 0.72 | 46.3 | 1.07 | 0.57-2.04 | 0.83 | 69.0 |
EA | 1 | 0.56 | 0.35-0.89 | 0.01 | NA | 0.56 | 0.35-0.90 | 0.02 | NA | 0.36 | 0.01-8.88 | 0.53 | NA | 0.55 | 0.34-0.89 | 0.01 | NA | 0.39 | 0.02-9.55 | 0.56 | NA |
Design | |||||||||||||||||||||
HB | 5 | 0.89 | 0.74-1.07 | 0.21 | 4.0 | 0.87 | 0.65-1.17 | 0.36 | 0 | 0.74 | 0.43-1.28 | 0.28 | 42.9 | 0.84 | 0.64-1.09 | 0.19 | 0 | 0.83 | 0.42-1.63 | 0.59 | 67.7 |
PB | 4 | 1.02 | 0.70-1.47 | 0.93 | 68.3 | 0.98 | 0.49-1.95 | 0.96 | 82.1 | 1.37 | 0.76-2.46 | 0.30 | 0 | 1.01 | 0.53-1.90 | 0.98 | 80 | 1.30 | 0.59-2.86 | 0.52 | 43.2 |
-819T>C (rs1800871) | C vs. T | TC vs. TT | CC vs. TT | TC+CC vs. TT | CC vs. TT+TC | ||||||||||||||||
Total | 16 | 0.72 | 0.68-0.76 | <0.01 | 38.6 | 0.73 | 0.66-0.80 | <0.01 | 23.0 | 0.52 | 0.39-0.70 | <0.01 | 53.7 | 0.67 | 0.61-0.71 | <0.01 | 22.1 | 0.66 | 0.53-0.82 | <0.01 | 57.8 |
Ethnicity | |||||||||||||||||||||
Europe | 2 | 0.67 | 0.33-1.36 | 0.27 | 78.6 | 0.46 | 0.16-1.37 | 0.17 | 49.3 | 0.36 | 0.07-1.83 | 0.22 | 77.0 | 0.41 | 0.11-1.58 | 0.20 | 70.1 | 0.70 | 0.33-1.47 | 0.35 | 65.0 |
ME | 8 | 0.79 | 0.72-0.86 | <0.01 | 0 | 0.92 | 0.55-1.52 | 0.74 | 40.8 | 0.78 | 0.53-1.14 | 0.20 | 0 | 0.84 | 0.59-1.21 | 0.36 | 7.4 | 0.81 | 0.65-1.01 | 0.06 | 5.2 |
EA | 6 | 0.68 | 0.63-0.73 | <0.01 | 34.1 | 0.72 | 0.65-0.80 | <0.01 | 0 | 0.40 | 0.26-0.62 | <0.01 | 72.6 | 0.67 | 0.60-.74 | <0.01 | 0 | 0.47 | 0.32-0.71 | <0.01 | 71.1 |
Design | |||||||||||||||||||||
HB | 8 | 0.74 | 0.68-0.79 | <0.01 | 36.7 | 0.92 | 0.56-1.49 | 0.73 | 0 | 0.74 | 0.46-1.20 | 0.23 | 0 | 0.83 | 0.52-1.21 | 0.42 | 0 | 0.81 | 0.62-1.04 | 0.10 | 10.7 |
PB | 8 | 0.71 | 0.63-0.80 | <0.01 | 45.7 | 0.72 | 0.65-0.80 | <0.01 | 39.0 | 0.46 | 0.32-0.67 | <0.01 | 65.4 | 0.66 | 0.56-0.78 | <0.01 | 42.3 | 0.59 | 0.44-0.80 | <0.01 | 64.1 |
Genotyping | |||||||||||||||||||||
PCR | 9 | 0.76 | 0.66-0.89 | <0.01 | 42.3 | 0.72 | 0.61-0.84 | <0.01 | 22.8 | 0.57 | 0.37-0.89 | 0.01 | 59.8 | 0.64 | 0.55-0.75 | <0.01 | 3.8 | 0.69 | 0.50-0.94 | 0.02 | 66.6 |
Other | 7 | 0.71 | 0.65-0.78 | <0.01 | 43.2 | 0.73 | 0.57-0.92 | 0.01 | 47.9 | 0.47 | 0.32-0.71 | <0.01 | 50.2 | 0.67 | 0.50-0.88 | <0.01 | 62.2 | 0.59 | 0.48-0.73 | <0.01 | 0 |
-592A>C (rs1800872) | C vs. A | AC vs. AA | CC vs. AA | AC+CC vs. AA | CC vs. AA+AC | ||||||||||||||||
Total | 11 | 0.71 | 0.63-0.80 | <0.01 | 45.4 | 0.64 | 0.40-1.02 | 0.06 | 59.2 | 0.52 | 0.28-0.95 | 0.03 | 61.9 | 0.59 | 0.38-0.92 | 0.02 | 57.1 | 0.70 | 0.50-0.97 | 0.04 | 48.0 |
HWE—yes | 6 | 0.75 | 0.58-0.96 | 0.02 | 60.9 | 0.71 | 0.43-1.19 | 0.20 | 59.6 | 0.54 | 0.28-1.04 | 0.07 | 67.8 | 0.65 | 0.40-1.06 | 0.08 | 59.0 | 0.69 | 0.48-1.00 | 0.05 | 56.6 |
HWE—no | 1 | 0.53 | 0.29-0.95 | 0.03 | NA | 0.33 | 0.14-0.74 | 0.01 | NA | 0.33 | 0.05-2.04 | 0.24 | NA | 0.33 | 0.14-0.73 | 0.01 | NA | 0.65 | 0.11-3.70 | 0.63 | NA |
Ethnicity | |||||||||||||||||||||
Europe | 2 | 0.63 | 0.37-1.09 | 0.10 | 73.7 | 0.25 | 0.08-0.82 | 0.02 | NA | 0.15 | 0.05-0.51 | <0.01 | NA | 0.20 | 0.07-0.61 | 0.01 | NA | 0.46 | 0.23-0.93 | 0.03 | NA |
ME | 6 | 0.77 | 0.69-0.85 | <0.01 | 7.6 | 0.77 | 0.39-1.53 | 0.45 | 65.7 | 0.82 | 0.53-1.27 | 0.37 | 0 | 0.74 | 0.42-1.30 | 0.30 | 55.3 | 0.87 | 0.64-1.13 | 0.29 | 0 |
EA | 3 | 0.60 | 0.53-0.68 | <0.01 | 0 | 0.57 | 0.41-0.78 | <0.01 | NA | 0.23 | 0.11-0.48 | <0.01 | NA | 0.51 | 0.37-0.70 | <0.01 | NA | 0.30 | 0.15-0.62 | <0.01 | NA |
Design | |||||||||||||||||||||
HB | 5 | 0.70 | 0.64-0.76 | <0.01 | 39.1 | 0.61 | 0.18-2.11 | 0.43 | 76.6 | 0.79 | 0.36-1.71 | 0.55 | 8.4 | 0.58 | 0.18-1.85 | 0.36 | 74.4 | 0.84 | 0.54-1.32 | 0.45 | 0 |
PB | 6 | 0.73 | 0.59-0.91 | 0.01 | 57.2 | 0.65 | 0.37-1.16 | 0.14 | 61.6 | 0.48 | 0.23-1.01 | 0.05 | 69.7 | 0.60 | 0.35-1.02 | 0.06 | 60.3 | 0.65 | 0.42-1.02 | 0.06 | 63.2 |
Genotyping | |||||||||||||||||||||
PCR | 7 | 0.77 | 0.64-0.93 | 0.01 | 46.1 | 0.70 | 0.43-1.14 | 0.16 | 60.2 | 0.62 | 0.34-1.11 | 0.11 | 56.2 | 0.66 | 0.43-1.01 | 0.05 | 53.1 | 0.74 | 0.52-1.06 | 0.10 | 48.6 |
Other | 4 | 0.65 | 0.56-0.76 | <0.01 | 47.4 | 0.25 | 0.08-0.82 | 0.02 | NA | 0.15 | 0.05-0.51 | <0.01 | NA | 0.20 | 0.07-0.61 | 0.01 | NA | 0.46 | 0.23-0.93 | 0.03 | NA |
Statistical analysis of the association between IL-10 -1082A>G polymorphism and BD risk in the G vs. A model. (a) ORs and 95% CIs; (b) cumulative analysis; (c) sensitivity analysis; (d) publication bias.
Sixteen case-control studies, involving 5,550 cases and 8,469 controls, were identified on the association between the -819T>C polymorphism and BD risk in this meta-analysis, and these are shown in Table
Statistical analysis of the association between IL-10 -819T>C polymorphism and BD risk in the C vs. T model. (a) ORs and 95% CIs; (b) cumulative analysis; (c) sensitivity analysis; (d) publication bias.
Eleven case-control studies, involving 3,052 cases and 3,553 controls, were identified on the association between the -592A>C polymorphism and BD risk in this meta-analysis, and these are shown in Table
Statistical analysis of the association between IL-10 -592A>C polymorphism and BD risk in the C vs. A model. (a) ORs and 95% CIs; (b) cumulative analysis; (c) sensitivity analysis; (d) publication bias.
Among the selected studies, only three studies provided enough data on the association between the IL-10 -1082A>G, -819T>C, and -592A>C haplotypes and BD risk. Three well-known haplotypes of ATA, ACC, and GCC were found and included in this meta-analysis. The haplotype frequency data were examined, and the quantitative synthesis did not demonstrate any significant associations when the ACC and GCC haplotypes were compared with the ATA haplotype (ACC vs. ATA:
Meta-analysis of the IL-10 -1082A>G, -819T>C and -592A>C haplotype and BD risk.
Contrast | OR | 95% CI | ||||
---|---|---|---|---|---|---|
ACC vs. ATA | Total | 1.04 | 0.80-1.35 | 0.78 | 0 | 0.11 |
Turkey | 1.12 | 0.81-1.57 | 0.45 | 0 | ||
Iran | 0.92 | 0.60-1.39 | 0.68 | NA | ||
GCC vs. ATA | Total | 0.80 | 0.52-1.22 | 0.30 | 60.9 | 0.41 |
Turkey | 0.67 | 0.40-1.13 | 0.14 | 55.9 | ||
Iran | 1.07 | 0.71-1.61 | 0.74 | NA |
NA: not available.
To date, the pathogenesis and etiology of BD have not been elucidated. It is speculated that BD has characteristics of both inflammatory and autoimmune diseases and has a certain genetic susceptibility. Patients with BD have always suffered from serious complications, such as recurrent oral ulcers, genital ulcers, and uveitis. In addition, these microvascular inflammatory injuries are frequently involved in the gastrointestinal tract, central nervous system, large blood vessels, and limb joints in BD patients [
The IL-10 gene is located on chromosome 1 at 1q31-32, occupies more than 4.7 kb of genomic DNA, and consists of five exons and four introns. These are the three most studied genetic variants: -1082A>G (rs1800896), -819T>C (rs1800871), and -592A>C (rs1800872). These polymorphisms and their haplotypes are associated with abnormal circulating levels of IL-10 and contribute to the pathophysiology of various autoimmune and inflammatory diseases. During the triggering and development of BD, many inflammatory markers have been proposed to be involved in the development of BD. IL-10 is one of the most important immunoregulatory cytokines and is mainly secreted by macrophage cells and other T helper 1 (Th1) and Th2 cells [
In 2007, Wallace et al. published the first case-control study of the UK population and suggested that subjects with the -1082AA genotype were weakly associated with BD risk in the general population (
Today, we comprehensively summarized the current evidence and conduct this meta-analysis to explore the precise relationships between IL-10 polymorphisms and BD susceptibility with more stratified analysis. Overall, the pooled results demonstrated a significant association between the -819T>C polymorphism and BD susceptibility in all five genetic models, suggesting that the -819T>C polymorphism may decrease the risk of BD from 48% to 28%. Similarly, decreased BD risk was also observed in the subgroup analysis of the ethnic differences, control design, and genotyping method groups. In the -592A>C polymorphism, the pooled analysis of all five genetic models demonstrated that the mutation of -592A>C lowered the risk of developing BD from 48 to 29%. Moreover, similar results were also observed in many genetic models in the subgroup analysis of HWE status, ethnic differences, control design, and genotyping method groups. Regarding the -1082A>G polymorphism, no significant association was observed for BD risk, except for a few scattered cases of decreased BD risk in the G allele and the AG genotype in the EA population.
Previous studies had demonstrated that these three polymorphisms were proposed to affect the transcription efficiency and expression of the IL-10 gene [
To the best of our knowledge, this report describes the most comprehensive meta-analysis on the issue to date. Some advances were demonstrated in this meta-analysis. First, most case-control studies published on the main three polymorphisms were considered, which would increase the statistical power and help to increase understanding of the association between IL-10 gene polymorphisms and BD risk. Second, a stratified analysis based on HWE status, ethnic differences, control design, and genotyping methods was conducted to explore their potential relationships. Third, a more scientific retrieval strategy and statistical methodology were used, including cumulative analyses, sensitivity analyses, and haplotype analyses.
Of course, there were still some inherent limitations that should be addressed in this meta-analysis. First, there were only 7, 12, and 7 case-control studies on IL-10 -1082A>G, -819T>C, and -592A>C loci, respectively, with complete information on the wild homozygotes, heterozygotes, and mutant homozygotes; the others only had the allele data in this meta-analysis. Therefore, the synthetic results and subgroup analysis could not reveal the real association between IL-10 gene polymorphisms and BD susceptibility with limited sample size. Second, most subjects came from the ME, EA, and Europe; therefore, the results of this systematic review and meta-analysis cannot represent all ethnic populations, and the conclusions are only applicable to these ethnicities. Third, other potential factors, such as living habits, mental stress, age, and immunological disarrangement, were not assessed, as sufficient data were not available. Fourth, this meta-analysis is based on published studies; therefore, potential publication bias may be present, even if the tests utilized in this meta-analysis did not find it. Fifth, moderate or high heterogeneity could be observed in these polymorphism sites. To the best of our knowledge, clinical heterogeneity (sometimes called clinical diversity), methodological heterogeneity (sometimes called methodological diversity), and statistical heterogeneity were the three most common sources. In this meta-analysis, the severity of disease, control design, personal habits, and ethnic differences may be the potential factors that contribute to the existing heterogeneity. These above factors would lead to a deviation in the authenticity and reliability of our results. Fortunately, the heterogeneity was partly alleviated in the stratified analysis based on ethnic differences and control design. In terms of the former, the heterogeneity has obviously been relieved in the subgroup analysis of the Middle East populations in -819T>C and -592A>C polymorphism loci. Given the control design, the degree of heterogeneity has decreased in these studies with healthy-based controls in some genetic models of the -1082A>G and -819T>C polymorphisms.
The current evidence indicates that there is a potential association between IL-10 gene polymorphisms and BD susceptibility, especially the -819T>C and -592A>C polymorphisms. In future studies, more case-control studies with larger sample sizes and different ethnicities are needed to verify these conclusions.
The raw data supporting this meta-analysis are from previously reported studies and datasets. All included data are also available from the corresponding author upon request.
The funders had no roles in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors declare that they have no competing interests.
NYM and LXF designed and wrote the manuscript. NYM and HYY searched the databases and extracted the data. HZZ and CJW analyzed the data. LXF edited and prepared the manuscript for submission. All authors read and approved the final manuscript. Xue-Feng Li and Zhi-Zheng Huang contributed equally to this work.
This study was supported by the Foundations of Hubei Province Health and Family Planning Scientific Research Project (No. WJ2019F135) and Taihe Hospital (2016JZ13).
Search strategies for the online databases.