This study demonstrated a significant association between rs2046210 and an increased risk of BC in a Han Chinese population. The subsequent meta-analysis based on 36 studies consisting of 53,379 cases and 55,493 controls also confirmed the strong association under all genetic models in an overall population. To the best of our knowledge, this is the first meta-analysis seeking to clarify the association between this polymorphism and BC risk, and the sensitivity and cumulative analyses confirmed that the positive finding was stable and the precision of estimation was progressively boosted as more studies were involved. These results clearly revealed the role of this polymorphism, which is near the ESR1 gene, in BC susceptibility.
In the overall meta-analyses, all genetic models presented significant heterogeneity. However, the heterogeneity had been mostly explained by the ethnicity of study population according to the result of meta-regression analyses. After being stratified by ethnicity, it demonstrated that this polymorphism had a significant association with BC risk in Asians and only a weaker and unstable association in Europeans. Meanwhile it could not be validated in Africans. The strength of the association with rs2046210 varies greatly across ethnic groups. One probable reason is the considerable differences in genetic architecture across ethnic SNPs. Another plausible hypothesis suggests that rs2046210 is only a marker SNP of causative variants and resides in different linkage disequilibrium (LD) patterns among the three ethnic populations.
Intriguingly, in further analysis, we found that this association was more significant in ER negative than in ER positive BC. Two recent interesting studies 
indicated that this polymorphism was associated with an increased risk of BC with BRCA1 mutation carriers, but not associated in BRCA2 mutation patients. Remarkably, accumulating evidence showed that the large majority of BRCA1 mutation carriers presented with ER negative tumors 
, which could partly explain why ER negative cases were accompanied by a stronger association. Additionally, recent studies in mice have revealed that the mammary stem cell compartment could be regulated by estrogen and progesterone through a paracrine signaling mechanism from ER positive cells to ER negative cells 
. Thus, polymorphisms near the ESR1 locus could affect the occurrence and development of ER negative tumors through the paracrine pathway. In the stratified meta-analysis, we also found that rs2046210 was significantly associated with BC risk in both premenopausal and postmenopausal women for allelic model, which was kept in line with the result of our case-control study. However, there was no evidence showing that the association was stronger in post- than pre-menopausal women.
Considering the relative vicinity of rs2046210 to the ESR1 gene, it was speculated that the SNP itself or causal variants in LD with it might alter ESR1 gene expression, thus affecting the susceptibility to BC. However, the functional genomic analyses and in vitro functional experiments conducted by Cai et. al 
provided no support for the potential involvement of this polymorphism in the regulation of ESR1. Although dozens of SNPs have been reported in high LD with this polymorphism, functional evaluations on them and their related genes were still warranted. Herein, we conjectured that this SNP might communicate with the ESR1 gene via a long-range chromatin loop. Nevertheless, it was just a postulation and needed to be confirmed by further longitudinal studies.
In conclusion, our case-control study and the subsequent meta-analysis effectively corroborated the impact of rs2046210 near the ESR1 gene on BC risk, and showed that the polymorphism had a larger effect on Asians than on Europeans or Africans. However, the function of this SNP is still unclear; future fine-mapping of the BC susceptibility loci tagged by rs2046210 is warranted and the underlying biological mechanism of this polymorphism still needs further investigation.