IL-10, originally known as cytokine synthesis inhibitory factor (CSIF), is a powerful anti-inflammatory cytokine. IL-10 can stimulate the expression of carboxypeptidase B2 (CPB2) in inflammatory BC cells, thus increasing the aggressiveness of the cancer cells . IL-10 is involved in the abnormal proliferation of breast ducts and lobules and stimulates mitotic activity, leading to an increased risk of cancer [24, 39]. Studies on the mechanism have shown that the production of IL-10 may represent a new escape mechanism for breast cancer cells to escape the destruction of the immune system. IL-10 gene silencing down-regulated the expression of PI3K/AKT and Bcl2 genes, and increased the cleavage expression levels of BBC3, Bax, caspase3, and caspase3. IL-10 can also induce tumor progression by inhibiting a large number of cytokines such as IL-1a, IL-1b, TNF-DNA, IL-6, IL-8, IL-12, and IL-18. This shows that IL-10 plays an important role in promoting cancer immune escape. This may be closely related to the fact that IL-10 gene polymorphism can change its transcriptional activity or protein structure. These variants may affect the biological function of IL-10, leading to immune dysfunction, affect the anti-tumor immune response, and ultimately increase susceptibility to BC [24, 41, 42].
Studies have shown that the three most common single nucleotide polymorphisms (SNPs) play an important role in regulating IL-10 activity. They were located at the transcriptional starting point of rs1800896 (-1082A/G), rs1800871 (-819T/C) and rs1800872 (-592A/C) and encoded high (GCC), medium (ACC) or low (ATA) expression of IL-10 respectively[43–45]. Several other polymorphic loci of IL10 (rs1800890, rs6703630, and rs6693899) are also controversial, but there are few relevant studies at present. In recent years, race has been involved in many studies on the relationship between IL-10 gene polymorphism and the risk of BC. For example, the IL-10 gene rs1800872 polymorphism was associated with BC susceptibility in this sample from the Mexican population. Also, there was significant association of mutant allele and genotypes of IL-10 rs1800896 with Indian postmenopausal BC. Since the IL-10 gene polymorphism were associated with the risk of BC, we hypothesized that race is the key to the association between IL-10 polymorphism and BC. This meta-analysis conducted the most comprehensive analysis of the relationship between three IL-10 polymorphisms (rs1800896, rs1800871, and rs1800872) and the BC risk of different races. In a subgroup analysis by ethnicity (Asian and Caucasian/mixed race), the three IL-10 polymorphisms (rs1800896, rs1800871, and rs1800872) were significantly associated with BC. It showed that rs1800896 (allele G vs. A: OR = 0.78, 95% CI = 0.65–0.95, P = 0.01; homozygous GG vs. AA: OR = 0.51, 95% CI = 0.31–0.84, P = 0.007; heterozygous GA vs. AA: OR = 0.6, 95% CI = 0.44–0.81, P = 0.0009; dominant GG + GA vs. AA: OR = 0.6, 95% CI = 0.45–0.81, P = 0.0007) were significantly correlated with BC risk in Asia. The rs1800871 heterozygote model (CT vs. TT: OR = 1.8, 95%CI = 1.03–3.13, P = 0.04) was associated with BC risk in the Caucasians. The rs1800872 homozygous model (AA vs CC: OR = 0.74, 95% CI = 0.55–0.99, P = 0.04) was associated with BC risk in Asians, and the allelic model (A vs. C: OR = 0.85, 95% CI = 0.74–0.98, P = 0.03) was associated with BC risk in Asians and Caucasians (A vs C: OR = 0.65, 95%=CI 0.43–0.98, P = 0.04). It is suggested that the ethnic subgroup of IL-10 gene polymorphism is the key factor affecting the susceptibility to BC.
Previously, Dai et al., Abedinzadeh et al and Moghimi et al.  have analyzed the correlation between IL10 polymorphism and breast cancer risk, but their analysis is not comprehensive enough. There are few studies included and the ethnic division is not accurate enough. The quality, quantity and new studies included in the meta-analysis will directly affect the credibility and stability of the results. We used a broad search strategy to capture all relevant information. This meta-analysis conducted a more comprehensive analysis of the relationship between three IL-10 polymorphisms (rs1800896, rs1800871, and rs1800872) and BC risk. 23 studies included in the review span decades (publish between 2004 and 2019). It included the researches both missing and published recently, and ruled out the low quality. So our results more accurately estimate the association between IL-10 polymorphism and BC risk than all previous meta-analysis. In this meta-analysis, the latest, most studies and the quality assessment were good were included. There was no significant publication bias, heterogeneity was small in the subgroups, and the sensitivity analysis results did not change. Therefore, the conclusion of the association between the three IL-10 polymorphisms (rs1800896, rs1800871, and rs1800872) and BC in this meta-analysis is reliable and has certain clinical guidance values. The current meta-analysis is the most comprehensive and has sufficient statistical power to assess the association between IL-10 polymorphism and BC risk.
However, it has several limitations that should be acknowledged. First, due to the limited research on the interaction between these three polymorphic sites and their interaction with the environment, it is impossible to estimate the impact of gene-gene and gene-environment interaction on the results of the study. Secondly, we found that heterogeneity existed in the meta-analysis as indicated by the I2 values. Despite the usage of a random-effects model in some studies, the heterogeneity remained. It is predictable because other factors that affect BC should be considered, such as staging and grading of tumors, age, genetic background, environment, and lifestyle. However, due to the lack of some qualified original data, we are unable to calculate the impact of these factors on BC. Besides, the variation range of the minimum allele frequency is large due to the differences in the regional environment, living habits, ethnic customs, and age (especially in China), which may have a certain impact on the research results, but these are inestimable. In general, the meta-analysis was performed on 23 articles that addressed the specific research question. Moreover, the influence and sensitivity analyses confirmed the robustness of the main results.