Association of ESR1 polymorphism rs2234693 and rs9340799 with postmenopausal osteoporosis in a Chinese population

Postmenopausal osteoporosis (PMO) caused by estrogen deficiency, is the most common type of primary osteoporosis which affects more than 40% of postmenopausal women [1‐3]. As a typical senile disorder with decreasing bone-mineral density (BMD) and microstructural abnormality, PMO may lead to an increased risk for nonstress fractures [4]. Although, PMO is close related to estrogen levels following menopause, many factors, such as genetic elements had play important roles in the risk of osteoporosis [5, 6]. Among these factors, genetics are found to play a pivotal role in the occurrence of osteoporosis and have received highly attention [6]. Twin studies in adult Caucasian woman revealed that the heritability of BMD might be between 50 and 85% [7]. Genome-wide association study also reported that almost 400 single nucleotide polymorphisms (SNPs) distributed in more than 150 different loci, were associated with low BMD and osteoporosis [8].

Estrogen activity is modulated through estrogen receptor α (ER-α) and β (ER-β) which are encoded by ESR1 on chromosome 6q25.1 and ESR2 on chromosome 14q23.2 respectively [9, 10]. Both ER-α and ER-β isoforms are expressed in osteoblasts, osteoclasts, and bone marrow stromal cells [11, 12]. However, ESR1 is the major mediator of estrogen action in bone and has been widely studied as a candidate gene associated with PMO [13]. Two polymorphisms rs2234693 and rs9340799 had been reported to close related with PMO, however, these findings were inconclusive [14‐16]. Mondockova et al. had reported that the rs9340799 was significantly associated with BMD at the femoral neck [17], whereas, another study by tanriover et al. had showed that no relationship of the two genes with PMO [18]. In addition, another study by Tang et al. in a meta-analysis showed that the ESR1 rs2234693 T allele may increase the risk of hip fracture, but the rs9340799 polymorphism was not associated with hip fracture [19]. Thus, to draw a more precise association of ESR1 polymorphism (rs2234693 and rs9340799) with the risk of PMO, we sought to assess the impact of ESR1 polymorphism with PMO and determine a possible association in postmenopausal Chinese women in a case-control study.

A total of 380 unrelated postmenopausal women over 45 years old were recruited from the outpatient of Xi’an Hospital of Traditional Chinese Medicine. All the subjects should menopause at least one year before enrollment. BMD was measured by DAX (GE company) and osteoporosis was diagnosed under World Health Organization criteria. Briefly, a T-score above − 1 standard deviation (SD) was considered normal and below − 2.5 SD as osteoporosis. All participants were divided into healthy group and osteoporosis group according to BMD results. Individuals with serious illness and those who accepted hormone replacement therapy (HRT) or drugs (bisphosphonates, steroids, thyroid hormones or GnRH analogs et al.) which may affect bone mass were excluded. Information about risk factors such as body mass index (BMI), menarche, menopause, family and personal history of fractur, smoking habits and alcohol habits were also collected. This study was approved by the Ethical Committee of Xi’an Hospital of Traditional Chinese Medicine and all the researches were performed in accordance with the Declaration of Helsinki.

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, 22]. The most important adverse health outcome of osteoporosis is bone fractures. Women at postmenopausal stage are faced to extremely high risk of osteoporosis [23‐25]. Several candidate genes, such as ESR1, the major mediator of estrogen action in bone, have been reported to be associated with BMD and osteoporosis [26‐28]. Ioannidis et al. had revealed that ESR1 is a susceptibility gene for fractures [29]. 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 [14]. Nevertheless, Wang et al. had showed that rs2234693 polymorphism but not rs9340799 was associated with PMO [23]. And Kurt et al. showed that both rs9340799 and rs2234693 polymorphism were contribute to the determination of bone mineral density in Turkish postmenopausal women [30]. 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.

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 [21]. 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. In addition, there was significant difference under BMI in the baseline characteristic, this may cause the bias to the results. 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.