A total of 60 article titles were garnered by a search using the PubMed database by using various combinations with above keywords. 31 articles were removed because of unrelated information. Next, 29 articles with full texts were evaluated, and 14 other articles were excluded because meta-analysis (3), review (5), not related to IL-10 polymorphisms (6) (Figure 1). Finally, 15 different articles about 3 SNPs in IL-10 and HIV-1 susceptibility were included (10 articles for rs1800896, 11 for rs1800872 and 3 for rs1800871 SNP) (Table 1). Overall, 24 case-control studies with 3957 cases of HIV-1 as well as 4845 controls were included[19-33]. The controls were mainly healthy individuals. The average NOS of including studies is 7.8, which means our results is credible and representational. Finally, we checked the Minor Allele Frequency (MAF) reported for the five main worldwide populations in the 1000 Genomes Browser (https://www.ncbi.nlm.nih.gov/snp): because the frequency is the same for rs1800871 and rs1800872, so we combined these two sites into a set of bar graph for presentation (Figure 2)
Results of the 3 SNPs in IL-10 and HIV-1 risk are presented in Table 2 and Figure 3-7. For rs1800896 polymorphism (1503 cases and 2089 controls), no association was found in the total and each subgroup, such as the allelic contrast (OR: 1.00, 95% CI: 0.84-1.18, P(heterogeneity): 0.009, P: 0.985 (Figure 3).
For the rs1800872 polymorphism (1883 cases and 2036 controls), individuals carrying the A-allele had an increased association with HIV-1 risk in the total sample population (the allelic contrast: OR: 1.22, 95% CI: 1.02-1.41, P = 0.007 for heterogeneity, P: 0.033, Figure 4A; AA vs. CC: OR: 1.51, 95% CI: 1.10-2.06, P = 0.084 for heterogeneity, P: 0.011; AA vs. AC+CC: OR: 1.49, 95% CI: 1.21-1.83, P = 0.120 for heterogeneity, P: 0.000). In the stratified analysis by ethnicity subgroup, a similar significant association was detected for the Asian population (allelic contrast: OR: 1.17, 95% CI: 1.02-1.34, P: 0.141 for heterogeneity, P: 0.021, Figure 4B; AA vs. CC: OR: 1.42, 95% CI: 1.07-1.88, P = 0.203 for heterogeneity, P: 0.014; AA vs. AC+CC: OR: 1.35, 95% CI: 1.04-1.75, P = 0.334 for heterogeneity, P: 0.024). In addition, in the subgroup analysis by source of control, a significant risk effect was observed in PB (AA vs. CC: OR: 1.69, 95% CI: 1.25-2.27, P = 0.191 for heterogeneity, P: 0.001, Figure 5; AA vs. AC+CC: OR: 1.69, 95% CI: 1.28-2.23, P = 0.291 for heterogeneity, P: 0.000). Finally, different genotype methods were applied, so we tried to analyze the associations, increased trends were found in both PCR-RFLP (AA vs. CC: OR: 1.60, 95% CI: 1.15-2.22, P = 0.125 for heterogeneity, P: 0.005; AA vs. AC+CC: OR: 1.46, 95% CI: 1.07-1.98, P = 0.367 for heterogeneity, P: 0.016, Figure 6A) and sequence methods (AA+AC vs. CC: OR: 1.70, 95% CI: 1.08-2.68, P = 0.520 for heterogeneity, P: 0.022, Figure 6B).
For the rs1800871 polymorphism (571 cases and 720 controls), increased associations were observed in total in two models (TT vs. CC: OR: 1.46, 95% CI: 1.04-2.04, P = 0.337 for heterogeneity, P: 0.028; TT vs. TC+CC: OR: 1.47, 95% CI: 1.08-2.00, P = 0.720 for heterogeneity, P: 0.015, Figure 7).
Bias diagnosis and sensitivity analysis for rs1800896 and rs1800872
Begg’s funnel diagram and Egger’s test were used to evaluate the publication bias of the literature. The shape of the funnel diagram did not show obvious asymmetry, and the Egger’s test did not show publication bias (the allelic contrast, t = 1.5, P = 0.172 for Egger’s test; z = 1.43, P = 0.152 for Begg’s test for rs1800896, Figure 8A,B, and the allelic contrast, t = 1.43, P = 0.189 for Egger’s test; z = 1.43, P = 0.152 for Begg’s test for rs1800872, Figure 8C,D, Table 3). We use sensitivity analysis to determine whether changes in a single study will affect final outcomes. To delete studies which may influence the power and stability of whole study, we applied the sensitive analysis, finally, no sensitive case-control studies were found (rs1800896, Figure 8E; rs1800872, Figure 8F).
Gene-gene network diagram and interaction of online website
String online server indicated that IL-10 gene interacts with numerous genes. The network of gene-gene interaction has been illustrated in Figure 9.