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Arquivos de Gastroenterologia

versión impresa ISSN 0004-2803versión On-line ISSN 1678-4219

Arq. Gastroenterol. vol.55 no.1 São Paulo enero/mar. 2018

http://dx.doi.org/10.1590/s0004-2803.201800000-18 

ORIGINAL ARTICLE

ASSOCIATION OF INTERLEUKIN-10 -1082 A/G (RS1800896) POLYMORPHISM WITH SUSCEPTIBILITY TO GASTRIC CANCER: META-ANALYSIS OF 6,101 CASES AND 8,557 CONTROLS

Associação de interleucina-10-1082A/polimorfismo G (rs1800896) com suscetibilidade a câncer gástrico: meta-análise de 6.101 casos e 8.557 controles

Abolfazl NAMAZI 1  

Mohammad FORAT-YAZDI 1  

Mohammadali JAFARI 2  

Soudabeh FARAHNAK 3  

Rezvan NASIRI 4  

Elnaz FOROUGHI 5  

Seyed Mojtaba ABOLBAGHAEI 6  

Hossein NEAMATZADEH 7  

1Department of Internal Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

2Department of Emergency Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

3Department of Endodontic, Arak University of Medical Sciences, Arak, Iran.

4Department of Pediatric Dentistry, Arak University of Medical Sciences, Arak, Iran.

5Department of Restorative and Esthetic, Arak University of Medical Sciences, Arak, Iran.

6Department of Forensic Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

7Mother and Newborn Health Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

ABSTRACT

BACKGROUND:

The promoter -1082 A/G (rs1800896) polymorphism of Interleukin-10 (IL-10) gene have been widely reported and considered to have a significant role on gastric cancer risk, but the results are inconsistent.

OBJECTIVE:

To clarify the association, we conducted a meta-analysis to investigate the associations IL-10 -1082 A/G polymorphism with gastric cancer.

METHODS:

Eligible articles were identified by searching databases including PubMed, Web of Science, and Google Scholar up to August 03, 2017. Odds ratios (OR) with corresponding 95% confidence intervals (CIs) were used to assess the association.

RESULTS:

A total of 30 case-control studies with 6,101 cases and 8,557 controls were included in this meta-analysis. Overall, a significant association between IL-10 -1082 A/G polymorphism and gastric cancer risk was observed under the allele model (G vs A: OR=1.305, 95% CI=1.076-1.584; P=0.007), heterozygote model and (GA vs AA: OR=1.252, 95% CI=1.252-1.054; P=0.011) and dominant model (GG+GA vs AA: OR=1.264, 95% CI=1.053-1.516; P=0.012). In the subgroup analysis by ethnicity, increased gastric cancer risk were found in Asians under the allele model (G vs A: OR=1.520, 95% CI=1.172-1.973; P=0.002), homozygote model (GG+GA vs AA: OR=1.571, 95% CI=1.023-2.414; P= 0.039), heterozygote model (GA vs AA: OR=1.465, 95% CI=1.192-1.801; P≤0.001) and dominant model (GG+GA vs AA: OR=1.448, 95% CI=1.152-1.821; P=0.002), but not among Caucasian and Latinos populations.

CONCLUSION:

These results suggested that the IL-10 -1082 A/G (rs1800896) polymorphism might contribute to the gastric cancer susceptibility, especially among Asians.

HEADINGS: Stomach neoplasms; Interleukin-10; Genetic polymorphism; Meta-analysis

RESUMO

CONTEXTO:

O promotor-1082 A/polimorfismo G (rs1800896) do gene da interleucina-10 (IL-10) é amplamente relatado e considerado por ter um papel significativo no risco de câncer gástrico, porém os resultados são inconsistentes.

OBJETIVO:

Para esclarecer melhor esta associação, realizou-se uma meta-análise para investigar as associações de IL-10-1082 A/polimorfismo G com câncer gástrico.

MÉTODOS:

Artigos elegíveis foram identificados através de pesquisa de bases de dados PubMed, Web of Science e Google Scholar até 3 de agosto de 2017. Razões de possibilidades (OR) com intervalo de confiança de 95% correspondente (CIs) foram usados para avaliar a associação.

RESULTADOS:

Um total de 30 estudos de caso-controle, 6.101 casos e com 8.557 controles foram incluídos nesta meta-análise. Em geral, uma associação significativa entre IL-10-1082 A/G polimorfismo e risco de câncer gástrico foi observada sob o modelo de alelo (G vs A: OR=1.305, 95% CI=1.076-1.584; P=0.007), no modelo heterozigoto (GA vs AA: OR=1.252, 95% CI=1.252-1.054; P=0.011) e modelo dominante (GG+GA vs AA: OR=1.264, 95% CI=1.053-1.516; P=0.012). Na análise de subgrupo pela etnia, foi encontrado risco aumentado de câncer gástrico em asiáticos sob o modelo de alelo (G vs A: OR=1.520, 95% CI=1.172-1.973; P=0.002), modelo heterozigoto (GG+GA vs AA: OR=1.571, 95% CI=1.023-2.414; P= 0.039), e modelo dominante (GG+GA vs AA: OR=1.448, 95% CI=1.152-1.821; P=0.002), mas não entre a população caucasiana e latina.

CONCLUSÃO:

Estes resultados sugeriram que a IL-10-1082 A/polimorfismo G (rs1800896) pode contribuir para a suscetibilidade de câncer gástrico, especialmente entre os asiáticos.

DESCRITORES: Neoplasias gástricas; Interleucina-10; Polimorfismo genético; Metanálise

INTRODUCTION

In the recent years, many exciting discoveries regarding the genomics of gastric cancer have been made, but it remains a major health problem as a result of the population growth, ageing, high mortality and poor prognosis for this disease1-3. The incidence of gastric cancer varies considerably according to age, gender, socio-economic conditions and ethnicity, and despite some of the highest risk populations are in Asian countries such as Japan, Korea and China, other Asian countries present relatively low rates4-6.

To date, the etiology of gastric cancer is still not fully understood7. It is well known that environmental factors such as dietary habits, Helicobacter pylori (H. pylori) infection, tobacco smoking, and alcohol consumption are more important than genetics in the development and progression of gastric cancer1-3,8. However, only 1%-5% of individuals with the bacteria actually develop gastric cancer and the pathogenesis is dependent on bacterial strain virulence, host genetic susceptibility and environmental factors9. Among human cancers, gastric carcinogenesis appears to be a complex multistep processes. Diverse array of genetics factors including functional polymorphisms, chromosomal instability, microsatellite instability, promoter methylation, and abnormal microRNA expression play important roles in gastric cancer carcinogenesis10.

Interleukin-10 (IL-10) is an important immunoregulatory cytokine which plays a key role in controlling the balance between cellular and humoral immune responses11. Previous studies have presented evidence that IL-10 may inhibit tumor development and progression12. It has been reported that the -1082 A/G polymorphism at promoter region of the IL-10 gene may influence this cytokine production and to be associated with the risk of different malignancies including cervical cancer13, esophageal cancer, nasopharyngeal cancer, oral cancer14, colon cancer15, and hepatocellular carcinoma16. However, the precise mechanism by which the between IL-10 polymorphisms may modulate cancer progression remains unknown11,12.

Over the past 2 decades, several epidemiological studies have reported the role of IL-10 -1082 A/G (rs1800896) polymorphism in gastric cancer development17. However, the results were inconsistent rather than conclusive, as result of the small sample size in the most of studies. While meta-analysis is considered a powerful tool for combining data from all eligible studies with more statistical power and obtaining precise estimates. Therefore, we conducted a meta-analysis of all available case-control studies to derive a more precise estimation of the association between of IL-10 -1082 A/G (rs1800896) polymorphism and gastric cancer risk. In addition, current meta-analysis analyzed available data to explore any role of ethnicity and studies quality on the association of IL-10 -1082 A/G (rs1800896) polymorphism in gastric cancer risk.

METHODS

Study identification and selection

A systematic literature search was performed for the relevant available studies published in PubMed, Web of Science, Chinese Biomedical Literature database, China National Knowledge Infrastructure database and google scholar up to August 1, 2017. The search strategy identified the eligible studies using the following keywords: ‘‘Interleukin-10’’, ‘‘IL-10’’, ‘’-1082 A/G‘’, ‘’rs1800896’’, ‘‘polymorphism’’, ‘‘genotype’’, ‘‘variant’’, ‘’mutation’’, ‘’gastric cancer’’, and ‘’stomach cancer’’. Additionally, the reference lists of retrieved studies, review articles, clinical trials and previous meta-analyses, were manually searched for collecting more relevant studies that was missed in the electronic search.

Eligibility criteria

The following inclusion criteria were used in selecting literature for meta-analysis: (a) evaluation of the association between IL-10 -1082 A/G (rs1800896) polymorphism and gastric cancer; (b) studies with case-control or cohort design; (c) sufficient published data for calculating odds ratios (ORs) with their 95% confidence intervals (95% CIs); and (d) publications in English and Chinese. If multiple studies from the same data were available, only the most recent, larger sample size or complete study was selected. The studies were excluded (a) only abstracts, review articles, case reports, letter to editors or editorials; (b) not designed as case-control or cohort studies; (c) not offering essential data; (d) control group not including healthy induvial; (e) duplicate of previous published articles.

Data extraction and quality assessment

The following data of eligible studies were collected by two investigators independently if available: first author, year of publication, country origin, ethnicity, total number of cases and controls, the frequencies of genotypes, genotyping technique, minor allele frequencies (MAFs), P-value for Hardy-Weinberg equilibrium (HWE). In case of disagreement, consensus was obtained by discussion, or a third author would assess these articles. The quality of selected studies was tested by the confirmation of HWE in control groups, and studies without the confirmation of HWE in controls were defined as low-quality studies, while studies with the confirmation of HWE in controls were defined as high-quality studies.

Statistical analysis

The strength of the association between the IL-10 -1082 A/G (rs1800896) polymorphism and gastric cancer risk was measured by crude odds ratios (ORs) with 95% confidence intervals (CIs). Pooled estimates of the OR were obtained by calculating a weighted average of OR from each study. The statistical significance of the pooled OR was determined using the Z-test. The meta-analysis examined the IL-10 -1082 A/G (rs1800896) polymorphism association under the allele model (G vs A), the homozygote model (GG vs AA), homozygote model (GA vs AA), heterozygote model and (GA vs AA), dominant model (GG+GA vs AA), and recessive model (GG vs GA+AA). The Q-statistic and the I2-statistic were used to assess the heterogeneity between studies in the meta-analysis. I2 was a value describe the degree of heterogeneity between studies, where 0-25% indicated no observed heterogeneity and larger values showed increasing heterogeneity, with 25%-50% regarded as low, 50%-75% as moderate, and 75%-100% as high18,19. A P-value greater than 0.10 for the Q-statistic indicates a lack of heterogeneity between studies, so the pooled OR estimate of the included studies was calculated by the fixed-effects model (Mantel-Haenszel method)20. Otherwise, the random-effects model (the DerSimonian and Laird method) was used21. The heterogeneity between studies was adjusted by subgroup analysis, HWE status and meta-regression. Departure from Hardy-Weinberg equilibrium (HWE) in controls was tested by the chi-square test, and a P-value <0.05 was considered significant. 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 dataset on the pooled OR. Funnel plots and Egger’s linear regression test were used to provide diagnosis of the potential publication bias22,23. To ensure reliability and accuracy of the results, two investigators entered the data into the software independently and reached a consensus. All statistical analyses were performed by using Comprehensive Meta-Analysis software version 2.20 (Stata Corp., College Station, TX, USA). All the P values were two-sided, and a P value less than 0.05 was considered statistically significant.

RESULTS

Based on the search criteria and manual search of references cited in the published case-control studies and meta-analyses, 67 individual articles were found. After screening the titles and abstracts, 29 articles were excluded because they were not relevant to the association of IL-10 -1082 A/G polymorphism with risk of gastric cancer. After reading the full texts of the remaining 37 articles, we found one article had not sufficient data of genotype for calculating OR and 95% CI, four articles were meta-analyses, and two articles were reviews. Finally, a total of 30 studies4-7,10-14,16-20,24-39 published from 2002 and 2015 with 6,101 cases and 8,557 controls met our inclusion criteria. The main characteristics of these studies were listed in Table 1. Among the 31 case-control studies, there were 21 studies of Asians24-30,33-46, six studies of Caucasians47-52, and three studies of Latinos53,54,32 descendants. The countries of these studies included China, Korea, Japan, Taiwan, India, USA, Italy, Finland, Spain, Romania, Costa Rica, Honduras and Chile. All the genotype distributions of controls were in agreement with HWE for IL-10 -1082 A/G polymorphism except for eleven stu­dies27,29,30,34,38,41,42,45-47,49. Twenty of 31 studies were in accordance with HWE and were therefore defined as high-quality studies (Table 1).

TABLE 1: Main characteristics of studies included in this meta-analysis 

First author Country (Ethnicity) Case Control Cases Controls MAFs HWE
Genotypes Allele Genotypes Allele
-1082A/G (rs1800896) 6101 8557 AA AG GG A G AA AG GG A G
Wu 200237 China (Asian) 150 220 135 14 1 284 16 208 11 1 427 13 0.029 0.057
Wu 200338 China (Asian) 220 230 195 23 2 413 27 217 11 2 445 15 0.032 0.002
El-Omar 200348 USA (Caucasian) 314 210 120 133 61 373 255 59 103 48 221 199 0.473 0.812
Savage 200434 China (Asian) 84 382 4 20 60 28 140 20 81 284 120 644 0.842 ≤0.001
Lee 200528 Korea (Asian) 122 120 104 17 1 225 19 101 18 1 220 20 0.083 0.842
Lu 200530 China (Asian) 250 300 201 43 6 445 55 268 29 3 565 35 0.058 0.037
Guo 200542 China (Asian) 179 443 93 56 3 285 73 267 164 12 698 188 0.212 0.023
Zambon 200552 Italy (Caucasian) 120 644 48 56 25 141 99 232 326 86 790 498 0.386 0.087
Alpízar-Alpízar 200553 Costa Rica (Latinos) 45 44 45 0 0 90 0 43 1 0 87 1 0.011 0.939
Morgan 200632 Honduras (Latinos) 170 162 121 42 7 284 56 101 49 11 253 71 0.220 0.145
Kamangar 200651 Finland (Caucasian) 112 208 38 47 27 123 101 72 96 37 244 172 0.414 0.613
Sugimoto 200736 Japan (Asian) 105 168 78 26 0 184 26 134 34 0 302 34 0.101 0.144
García 200750 Spain (Caucasian) 404 404 123 204 77 450 358 133 189 82 455 353 0.436 0.322
Bai 200840 China (Asian) 111 111 89 22 (AG+GG) - - 104 7 (AG+GG) - - - -
Forte 200849 Italy (Caucasian) 42 185 21 16 5 58 26 83 66 36 235 135 0.364 ≤0.001
Kang 200944 Korea (Asian) 335 335 281 49 4 613 57 289 35 0 634 36 0.054 0.304
Ko 200925 Korea (Asian) 84 336 67 12 1 153 15 276 35 1 632 40 0.059 0.921
Xiao 200939 China (Asian) 220 624 176 41 3 393 47 593 31 0 1208 40 0.032 0.524
Zhou 200846 China (Asian) 150 150 29 62 59 120 180 52 53 45 157 143 0.476 ≤0.001
Shin 201135 Korea (Asian) 632 237 534 91 7 1159 105 199 38 0 436 38 0.080 0.179
Liu 201129 China (Asian) 234 243 189 39 6 417 51 217 23 3 457 29 0.059 0.014
He 201243 China (Asian) 196 248 154 42 0 350 42 194 54 0 442 54 0.108 0.054
Zeng 201245 China (Asian) 151 153 27 60 64 114 188 48 53 52 149 157 0.513 ≤0.001
Kim 201223 Korea (Asian) 495 495 416 72 7 904 86w 435 56 1 932 58 0.058 0.564
Chand‐Bhayal 201241 India (Asian) 100 132 47 35 18 129 71 40 50 42 130 134 0.507 0.005
Pan 201333 China (Asian) 308 308 263 41 4 567 49 264 41 3 596 47 0.076 0.329
Kuo 201427 Taiwan (Asian) 358 358 235 101 22 571 145 281 67 10 629 87 0.121 0.019
Hormazabal 201454 Chile (Latinos) 147 172 79 54 14 212 82 88 71 13 247 97 0.282 0.799
Burada 201047 Romania (Caucasian) 63 78 9 54 0 72 54 12 66 0 90 66 0.423 ≤0.001
Kumar 201526 India (Asian) 200 250 74 96 30 244 156 85 122 43 464 36 0.071 0.945

MAF: minor allele frequencie; HWE: Hardy-Weinberg equilibrium.

Quantitative data synthesis

The main results of this meta-analysis were listed in Table 2 and Figure 1A, 1B. Overall, there was a significant association between IL-10 -1082 A/G polymorphism and gastric cancer in overall under the allele model (G vs A: OR=1.305, 95% CI=1.076-1.584; P=0.007, Figure 1A), the heterozygote model (GA vs AA: OR=1.252, 95% CI=1.252-1.054; P=0.011) and the dominant model (GG+GA vs AA: OR=1.264, 95% CI=1.053-1.516; P=0.012, Figure 1B), but not under the homozygote model (GG vs AA: OR=1.225, 95% CI=0.925-1.622; P=0.157) and the recessive model (GG+GA vs AA: OR=1.150, 95% CI=0.929-1.425; P=0.200).

TABLE 2: The meta-analysis of IL-10 -1082 A/G polymorphism and gastric cancer risk 

Subgroup Study number Genetic model Type of model Heterogeneity Odds ratio Publication Bias
I 2 (%) P H OR 95% CI Z test P OR P Beggs P Eggers
Overall 29 G vs. A Random 85.89 ≤0.001 1.305 1.076-1.584 2.701 0.007 0.398 0.393
25 GG vs. AA Random 52.67 0.001 1.225 0.925-1.622 1.416 0.157 0.107 0.118
29 GA vs. AA Random 67.95 ≤0.001 1.252 1.252-1.054 2.555 0.011 0.338 0.438
30 GG+GA vs. AA Random 74.13 ≤0.001 1.264 1.053-1.516 2.517 0.012 0.253 0.483
25 GG vs. GA+ AA Random 39.20 0.024 1.150 0.929-1.425 1.281 0.200 0.107 0.071
By ethnicity
Caucasian 6 G vs. A Fixed 27.54 0.228 0.975 0.867-1.096 -0.427 0.669 1.000 0.911
5 GG vs. AA Fixed 44.94 0.123 0.975 0.767-1.239 -0.208 0.835 1.000 0.814
6 GA vs. AA Fixed 13.69 0.327 0.915 0.759-1.104 -0.929 0.353 0.425 0.867
6 GG+GA vs. AA Fixed 32.65 0.191 0.975 0.817-1.164 -0.280 0.780 0.452 0.916
5 GG vs. GA+ AA Random 52.81 0.076 1.048 0.847-1.297 0.434 0.664 1.000 0.995
Asian 21 G vs. A Random 87.13 ≤0.001 1.520 1.172-1.973 3.152 0.002 0.770 0.860
18 GG vs. AA Random 53.70 0.004 1.571 1.023-2.414 2.063 0.039 0.225 0.198
20 GA vs. AA Random 67.76 ≤0.001 1.465 1.192-1.801 3.645 ≤0.001 0.314 0.272
21 GG+GA vs. AA Random 76.34 ≤0.001 1.448 1.152-1.821 3.173 0.002 0.349 0.400
18 GG vs. GA+ AA Random 40.62 0.038 1.290 0.934-1.781 1.547 0.122 0.129 0.056
Latinos 3 G vs. A Fixed 0.00 0.375 0.843 0.651-1.091 -1.298 0.194 1.000 0.665
2 GG vs. AA Fixed 36.06 0.211 0.862 0.460-1.613 -0.466 0.641 NA NA
3 GA vs. AA Fixed 0.00 0.766 0.774 0.553-1.083 -1.494 0.135 0.296 0.442
3 GG+GA vs. AA Fixed 0.00 0.609 0.786 0.572-1.078 -1.493 0.135 1.000 0.604
2 GG vs. GA+ AA Fixed 33.01 0.222 0.944 0.512-1.743 -0.183 0.855 NA NA
By studies quality
High quality 18 G vs. A Random 88.61 ≤0.001 1.336 1.016-1.756 2.071 0.038 0.129 0.361
16 GG vs. AA Random 43.12 0.034 1.225 0.892-1.683 1.253 0.210 0.052 0.021
19 GA vs. AA Random 71.94 ≤0.001 1.187 0.962-1.465 1.596 0.110 0.441 0.699
21 GG+GA vs. AA Random 73.11 ≤0.001 1.150 0.929-1.424 1.286 0.198 0.263 0.570
16 GG vs. GA+ AA Fixed 29.33 0.130 1.060 0.890-1.263 0.656 0.512 0.052 0.015
Low quality 10 G vs. A Random 79.54 ≤0.001 1.260 0.968-1.641 1.721 0.085 0.755 0.790
10 GG vs. AA Random 66.60 0.001 1.268 0.754-2.134 0.894 0.371 0.720 0.554
11 GA vs. AA Random 54.98 0.014 1.460 1.121-1.902 2.806 0.005 0.436 0.848
12 GG+GA vs. AA Random 76.86 ≤0.001 1.449 1.033-2.033 2.150 0.032 0.450 0.854
10 GG vs. GA+ AA Random 52.26 0.026 1.109 0.770-1.597 0.555 0.579 0.858 0.932

FIGURE 1A Forest plot of gastric cancer risk associated with the IL-10 -1082 A/G (rs1800896) polymorphism. A. Allele model (G vs A) and B. Dominant model (GG+GA vs. AA). The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the weight (inverse of the variance). The diamond represents the summary OR and 95% CI. 

FIGURE 1B: Forest plot of gastric cancer risk associated with the IL-10 -1082 A/G (rs1800896) polymorphism. A. Allele model (G vs A) and B. Dominant model (GG+GA vs. AA). The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the weight (inverse of the variance). The diamond represents the summary OR and 95% CI. 

Subgroup analysis of Asians showed that there was a significant association between IL-10 -1082 A/G polymorphism and increased risk of gastric cancer under the allele model (G vs A: OR=1.520, 95% CI=1.172-1.973; P=0.002), the homozygote model (GG vs AA: OR=1.571, 95% CI=1.023-2.414; P=0.039), the heterozygote model and (GA vs AA: OR=1.465, 95% CI=1.192-1.801; P≤0.001) and the dominant model (GG+GA vs AA: OR=1.448, 95% CI=1.152-1.821; P=0.002). However, subgroup analysis of Caucasians and Latinos showed that there was no association between IL-10 -1082 A/G polymorphism and increased risk of gastric cancer in the Caucasians and Latinos populations (Table 2).

Subgroup analysis of studies with high quality showed that there was a significant association between IL-10 -1082 A/G polymorphism and increased risk of gastric cancer only under the allele model (OR=1.336, 95% CI=1.016-1.756, P=0.038, Table 2). However, in the subgroup analysis of studies with low quality, there was still a significant association between IL-10 -1082 A/G polymorphism and increased risk of gastric cancer under heterozygote model (GA vs AA: OR=1.460, 95% CI=1.121-1.902; P=0.005) and dominant model (GG+GA vs AA: OR=1.449, 95% CI=1.033-2.033; P=0.032) (Table 2).

Test of heterogeneity and sensitivity analysis

The heterogeneity test showed that there was significant between-study heterogeneity in terms of the IL-10 -1082 A/G polymorphism in all five genetic models (Table 2). Then, we used a meta-regression analysis to explore the source of heterogeneity by Ethnicity and quality of studies. Results showed that ethnicity contribute to substantial heterogeneity. Furthermore, we performed sensitivity analyses to assess the influence of each individual study on the pooled ORs by sequential omission of individual studies, such as the study that did not conform to HWE. However, the corresponding pooled ORs were not materially altered by removing any individual study. Moreover, in all tests the I2 value for heterogeneity did not reduced. Therefore, the sensitivity analysis confirmed that the results of this meta-analysis were statistically reliable and stable.

Publication bias

Begg’s funnel plot and Egger’s test were used to assess the potential publication bias in the literature. However, the shape of funnel plots did not reveal any evidence of funnel plot asymmetry (Figure 2A, 2B). Then, the Egger’s test was used to provide statistical evidence for funnel plot symmetry. The results also provided statistical evidence for the absence of publication bias.

FIGURE 2: Begg’s funnel plot of publication bias test. A. The homozygote model (GG vs AA), B. The recessive model (GG vs Ga+ AA). Each point representes a separete study for the indicated association. Log (OR),natural logarithm of OR. Horizontal line, mean effect size. 

DISCUSSION

To date, several case-control studies have been reported to evaluate the association between IL-10 -1082 A/G polymorphism and gastric cancer. However, the results were inconsistent and most studies in Caucasian and Latinos populations failed to identify an association with gastric cancer. The current study was not the first meta-analysis aimed to evaluate the associations between IL-10 -1082 A/G polymorphism and gastric cancer. However, the current meta-analysis was the most comprehensive assessment of the association between IL-10 -1082 A/G polymorphism and gastric cancer, which extended the previous meta-analyses with a larger sample size and different subgroups. Additionally, we believe the current meta-analysis is most accurate meta-analysis on the association due to the subgroup analysis by studies quality according to the Hardy-Weinberg equilibrium (HWE) status.

A total of 30 studies with a total of 6431 controls and 3631 cases were eligible for the meta-analysis of IL-10 -1082 A/G polymorphism and gastric cancer. In this meta-analysis, a significant association of the of IL-10 -1082 A/G polymorphism with gastric cancer risk was found under the allele model (G vs A: OR=1.305, 95% CI=1.076-1.584; P=0.007), heterozygote model and (GA vs AA: OR=1.252, 95% CI=1.252-1.054; P=0.011), dominant model (GG+GA vs AA: OR=1.264, 95% CI=1.053-1.516; P=0.012), and in Asians. The inconsistent results between Asians and other ethnicity (Caucasians and Latinos) on subgroup analysis partly may be caused by genetic diversity in different ethnicities. Furthermore, as gastric cancer is a multifactorial disease, except genetic factors, environmental factors play important roles in the pathogenesis of gastric cancer.

We found that the results of our meta-analysis are consistent with a meta-analysis of 20 case-control studies with a total of 3631 cases and 6431 controls published in 2012 by Ni et al. to examine the relationship between IL-10 -1082 A/G polymorphism and gastric cancer17. They have found that the IL-10 -1082 A/G polymorphism was associated with susceptibility to gastric cancer infection in Asians. However, their study had some limitations should be mentioned. First, they wrongly not included a study by Bai et al., 2008 because they reported only the number of combined group GG+GA rather than the number of genotype GG and GA. Second, they have excluded all studies that deviated from HWE, which it seems publication bias have been occurred at the start of their meta-analysis. However, meta-analyses should report both the magnitude and the statistical significance of deviation from HWE40. There is currently no consensus for whether to select eligible studies according to HWE status. In the current meta-analysis the results was different by HWE status or studies quality, it is suggested that the analysis with studies departed from HWE may be more reliable. Third, they have performed some subgroup analyses by sample size and publication before or after 2005, which we suggested unnecessary to do these subgroup analyses. Fourth, their results reliability and the number of studies are considerably smaller than that needed to receive the robust conclusions.

Between-study heterogeneity is inevitable in a meta-analysis55. Thus, one of the most important goals of the meta-analysis is to identify the source of heterogeneity56. Basically, between-studies variability and variability due to sampling error are main sources of heterogeneity in a set of studies in a meta-analysis19,31,55,56. The between-study heterogeneity in the current meta-analysis existed in overall under all genetic models and subgroup analyses in Asians. There was no significant heterogeneity after subgroup analyses among Caucasians and Latinos population. Moreover, after removing the study deviating from HWE, the heterogeneity did not disappear. Thus, the results revealed that studies in Asians may be the major source of heterogeneity in overall models.

The current meta-analysis had several strengths. Most importantly, this is the biggest and most recent meta-analysis of the association between IL-10 -1082 A/G polymorphism and gastric cancer. Therefore, this was more powerful than previous meta-analysis. In addition, a subgroup analysis among mixed population and HWE status was conducted and demonstrated that the IL-10 -1082 A/G polymorphism not significantly associated with gastric cancer risk in Caucasian and mixed populations. Third, we did not detect any publication bias indicating that the whole pooled results should be unbiased.

Despite the clear strength of our study including large sample sizes, some limitations of this meta-analysis should be acknowledged. Second, the overall OR was based on individual unadjusted ORs, and some important confounding factors, such as age, gender, dietary, Helicobacter pylori (H. pylori) infection, tobacco smoking, and alcohol consumption, gastric cancer site (cardia and noncardia) and histological type must be adjusted for. Third, although the funnel plots and Egger’s tests showed that publication bias did not affect our results, only published studies published in English or Chinese with sufficient data were included, thus, publication bias may have occurred at the start of current meta-analysis. Finally, lack of original data from origin data in the including studies limited our evaluation of potential gene-gene and gene-environment interactions and even different polymorphic loci of the same gene which may modulate the gastric cancer susceptibility.

In conclusion, this meta-analysis suggests that IL-10 -1082 A/G (rs1800896) polymorphism may be associated with increased gastric cancer risk. Moreover, further studies estimating the effect of gene-gene and gene-environment interactions are necessary to better understanding of the association between the IL-10 -1082 A/G (rs1800896) polymorphism and risk of gastric cancer.

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Disclosure of funding: no funding received

Recibido: 05 de Agosto de 2017; Aprobado: 11 de Septiembre de 2017

Correspondence: Mohammad Forat-Yazdi. Department of Internal Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. E-mail: mohammad.foratyazdi@gmail.com

Declared conflict of interest of all authors: none

Authors’ contributions: Namazi A, Forat-Yazdi M and Abolbaghaei SM conceived and research design. Farahnak S, Nasiri R, and Foroughi E selected the articles. Neamatzadeh H and Jafari M performed data analysis. The manuscript was drafted by Namazi A, Forat-Yazdi M and Neamatzadeh H critically reviewed and discussed with the other co-authors. All the authors read and approved the final manuscript.

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