Osteoporosis is a multifactorial disease, characterized by loss of tissue microarchitecture and low BMD. It has been estimated that 30% of women and 12% of men were affected by osteoporosis [8, 20]. The most important adverse health outcome of osteoporosis is bone fractures. Women at postmenopausal stage are faced to extremely high risk of osteoporosis[21–23]. Several candidate genes, such as ESR1, the major mediator of estrogen action in bone, have been reported to be associated with BMD and osteoporosis [24–26]. Ioannidis et al. had revealed that ESR1 is a susceptibility gene for fractures. However, the polymorphism of ESR1 with PMO was still inconclusive.
Studies to elucidate the ESR1 genetic contributions to PMO have continued for several decades. To a much lesser extent, the association between BMD and a polymorphism in the promoter region of ESR1, characterized by a variable number of studies and still not come to a unified conclusion. Mondockova et al. had found that rs9340799 polymorphism may contribute to decreased BMD in postmenopausal women in southern Slovakia. Nevertheless, Wang et al. had showed that rs2234693 polymorphism but not rs9340799 was associated with PMO. And Kurt et al. showed that both rs9340799 and rs2234693 polymorphism were contribute to the determination of bone mineral density in Turkish postmenopausal women. In our study, we had found that the GG genotype and the dominant genetic model of rs9340799 were susceptible to PMO, whereas, no relationship was found in rs2234693. These results were partly in accordance with former studies.
Although our case-control study had got the positive conclusions of rs9340799 polymorphism with PMO, these results should be treated with caution. A meta-analysis was also conducted to further elucidate the relationship of disease and polymorphism. Our meta-analysis of pooled analysis had showed that either homozygote, heterozygote, recessive, allelic models or dominant of rs9340799 and rs2234693 were the risk factor of PMO. These may be attributed to a small sample size, different ethnic background and different examine methods. These data need to be replicated in a larger cohort, and functional studies will be necessary to investigate whether and how ESR1 gene polymorphism involved in the pathogenesis of PMO.
The rs2234693 and rs9340799 polymorphic sites are located in the promoter region of the first intron of ESR1 gene, and so far, their functional consequences are unknown. Although case-control study had partly revealed the relationship of the polymorphism, its mechanism is still not clear. We speculate that introns may contain regulatory elements, and the mutation may cause methylation and finally influence the effect of ESR1.
The results of our study may help in identifying patients with potential PMO risk; however, several limitations should not be ignored. Firstly, as the quantity of the patients were not large enough, thus give rise to failure to achieve statistical significance of rs2234693. Secondly, all participants enrolled were recruited from hospital which might result in potential selection bias. Thirdly, some potential confounding factors which may overestimate or underestimate the effect of gene polymorphism. Eventually, the meta-analysis was only enrolled 4 relative studies, this may give rise to publication bias and finally influence the overall results.