In our meta-analysis, a statistically significant finding could be noted with the overall reduced risk of gastric cancer among Asians but not among Caucasians (TT vs CT-plus-CC); the opposite tendency toward the risk of gastric cancer could also be observed between Caucasians and Asians via cumulative meta-analysis sorted by publication time and total sample size. Thus, IL-10-819 TT genotype may seem to be more protective from overall gastric cancer susceptibility among Asians. To be sure, the different or even conflicting risk associations, if so, among different ethnicities should be further meticulously investigated and confirmed in the future.
Our further subgroup analyses also indicate that a statistically significant reverse association was witnessed in Asians high quality subgroup but not in Asians median-and-low quality subgroup; the reverse association tendency was also observed in Caucasians high quality subgroup, although the statistical significance could not be reached. The consistent reverse association trend between Asians high quality subgroup and Caucasians high quality subgroup could be apparently seen. The strong statistical significant reverse association could be found among the combined high quality subgroup regardless of ethnicities based on the recessive genetic model in our meta-analysis. Furthermore, the recessive genetic model was confirmed through the recalculation of OR1 (p value), OR2 (p value), and OR3 (p value) in the combined high quality subgroup regardless of ethnicities. Therefore, it should be advocated that more rigorous high-quality studies should be designed in the future so as to accurately explore the real associations between IL-10-819 TT genotype and gastric cancer susceptibility among different ethnicities.
] out of 11 eligible studies were dealt with noncardia-subtype gastric cancer and 4 [15
] with cardia-subtype gastric cancer. No statistically significant findings could be noted with either subtype (TT vs CT-plus-CC). 2 studies [18
] in our meta-analysis were dealt with pathologically intestinal-subtype gastric cancer and only 1 [19
] out of 11 studies was dealt with pathologically diffuse-subtype gastric cancer. No statistically significant finding could be noted in intestinal-subtype but in diffuse- subtype cancer (TT vs CT-plus-CC). As is known, cardia-subtype gastric cancer differs from noncardia-subtype gastric cancer in etiology, pathology, carcinogenesis, and/or prognosis [30
], so is intestinal-subtype cancer versus diffuse-subtype cancer. It could be said that the indiscriminate combination of cardia-subtype and noncardia-subtype cases or intestinal-subtype and diffuse-subtype cases in the majority of eligible studies may mask or at least underestimate the strength of the real associations [7
Furthermore, it was reported that gastric cancer develops in those with H. pylori
infection rather than in uninfected ones [33
]. In our meta-analysis, no statistically significant reverse association with gastric cancer was found either among H. pylori
positive cancer patients compared with H. pylori
negative controls or among H. pylori
positive cancer patients compared with H. pylori
positive controls (TT vs CT-plus-CC), but the p value in the former was approximate to 0.05, insinuating that IL-10-819 TT genotype may seem to be more protective from overall gastric cancer susceptibility in persons infected with H. pylori
. Certainly, the real association between H pylori
infection and IL-10-819 TT genotype and gastric cancer susceptibility should be further meticulously investigated in the future.
With the coming of new genotyping technologies like seminested polymerase chain reaction, TaqMan allelic discrimination test, direct sequencing, the allele specific primer-polymerase chain reaction, pyrosequencing, or real-time PCR, we may witness an upsurge of genetic association studies in the future. In our meta-analysis, a statistically significant reverse association with gastric cancer susceptibility was only noted in direct sequencing technique subgroup but not in any other genotyping subgroup. The fact that the most significant result can be witnessed in direct sequencing technology in our meta-analysis is not necessarily a valid reason to demonstrate that other technologies cannot be used. Certainly, for a novel genotyping technique to be employed for the study of a particular genetic polymorphism, this technology should better be confirmed using direct sequencing. In that case, this new technology can be seen as valid as direct sequencing. Or the sensitivity and specificity of those genotyping techniques need to be explored so as to seek out optimal approaches which could minimize the genotyping errors [7
]. Our opinion is that direct sequencing should be more used in future well-designed studies among different ethnicity populations.
And the mechanism of the influence of IL-10-819 SNP on carcinogenesis is still unknown, but it has been reported that IL-10 SNPs may influence immune function through modulating the activities of the NK cell, T cells, and macrophages and thus alter the disease progression [34
]. Additionally, another investigated SNP at position -1082 (A/G) was reported to be significantly increased in prostate cancer patients and its action, together with VEGF and IL-8, was suspected to possibly influence cancer angiogenesis [35
]. Whether IL-10-819 SNP may also influence cancer angiogenesis is worthy of further investigating in the future.
Finally, the strength of our meta-analysis could be summarized as follows. We sought to find as many publications as we could by means of various searching approaches. Any study that appeared to deviate from HWE was not excluded mechanically in our meta-analysis unless there are other convincing grounds for doubting the quality of the study [36
]. We laid more emphasis on assessing biases across studies and pinpointing the potential sources of heterogeneity via subgroup and sensitivity analyses. More importantly, we have made great efforts to stratify ethnicity into Asians subgroup and Caucasian subgroup in accordance with accessible data. In particular, we have conducted overall meta-analysis among different ethnicity populations to carefully choose the most likely appropriate genetic model. We also have stratified the included studies through other subgroup analyses like anatomic classification, pathologically Lauren's classification, H. pylori
infection status, sample size, and quality appraisal scores. We comprehensively assessed the publication biases using several means like Begg's and Egger's tests as well as funnel plot tests. In view of this, we convince that the results of our meta-analysis, in essence, are sound and reliable.
Certainly, there are some unavoidable limitations in our meta-analysis. Firstly, the information about overall gastric cancer susceptibility is predominantly provided, while other information about pathologic subtypes or anatomic subtypes of gastric cancer is less provided. Thus, the specific subtype results should be considered with caution. Secondly, with the merely published studies included in our meta-analysis, publication bias is very likely to occur, though no statistically significant publication bias is found in our meta-analysis. Thirdly, slight to moderate heterogeneity could be witnessed among the included studies. So as to minimize the potential bias, we designed a rigorous protocol before conducting our meta-analysis, and performed a scrupulous search for published studies using explicit methods for study selection, data extraction, statistical analysis, adoption of the most appropriate genetic model with extreme caution and sensitivity analysis.