Association of oestrogen receptor alpha gene polymorphisms with systemic lupus erythematosus risk: An updated meta-analysis
Introduction
Systemic lupus erythematosus (SLE) is an idiopathic, complex and multifactorial autoimmune disease, primarily affects women in reproductive years [1]. Although the exact pathogenesis of SLE is not well elucidated, current research evidence showed that genomic, hormonal, and environmental factors and their complex interaction all play a role underlying the pathogenesis of the disease [2,3]. The observation that the risk of the SLE among women exacerbates during pregnancy and decreases during pre-menarche or post-menopause [4], has implicated female hormone estrogen as probable risk factors for SLE. Studies in humans and mouse models of SLE also observed that disease manifestations of SLE are exacerbated after estrogen administration and improved with androgen therapy [5]. In general female SLE patients exhibit higher levels of immune reactivity than males, as estrogen enhances the generation of antibody, supports B cell's survival and blocks tolerance induction of naive B cells in PBMCs of patients with SLE [6,7]. Further, it can stimulate interleukin (IL-1, IL-4, IL-6, IL-10) and interferon IFN-γ secretion [8]. However, no difference was observed between healthy women and women with SLE in the measurement of plasma estradiol levels [8]. Thus, the mechanism is still needed to be further investigated.
Oestrogens are not only produced by the ovary, but it can also generate in peripheral tissues or adrenal glands, and exert their effects through two specific intracellular receptors—estrogen receptor-α (ERα) and estrogen receptor-β (ERβ), which are mapped on different chromosomes [9]. In general, ERα and ERβ are expressed in most immune or immune related cells, but the ERα is shown to be the predominantly expressed, including lymphocytes, plasmacytoid DCs, bone marrow and hematopoietic stem cell [[10], [11], [12]]. Some studies observed that the deficiency of ERα could significantly prolong survival, reduce proteinuria and renal pathology score in lupus-prone murine strains, while others suggested that the lack of ERα could lead to the development of autoantibodies and lupus like immune complex glomerulonephritis [13,14]. This may be caused by the genetic predisposition or the alterations in the genetic structure of ERα. Two single nucleotide polymorphisms of the ERα gene—PvuII polymorphism and XbaI polymorphism, have been studied extensively for their possible association with various complex diseases [[15], [16], [17], [18]], including SLE. However, to date, studies of the impact of variations in ERα gene in relation to SLE susceptibility are inconsistent. In 2014, Cai et al. [19] conducted a meta-analysis comprising of 7 case–control studies and identified that the PvuII polymorphism was significantly associated with SLE susceptibility under a dominant model (P = 0.01). However, it still had some limitations: First, a comparatively small number of SLE patients and controls. Second, the allele of PvuII was not correctly extracted from a case–control association study [20]. Moreover, several more studies that assessed the roles of ERα gene polymorphisms in the occurrence of SLE were published since previous meta-analyses was carried out [[21], [22], [23], [24], [25]]. Therefore, we collected all the available articles using updated meta-analysis to achieve a more properly estimation of the association between ERα gene polymorphisms and the susceptibility of SLE.
Section snippets
Search strategy
To evaluate whether ERα gene polymorphisms are correlated with the susceptibility of SLE, a computerized literature search was performed on Cochrane Library, PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), VIP database and Wanfang (Chinese) up to March 7, 2018 without language limitations. All related investigations using the following keywords and subject terms: “ERα OR Estrogen receptor alpha OR Estrogen”, “SLE OR systemic lupus erythematosus”, and “polymorphism OR
Study characteristics
A total of 99 English-language and 51 Chinese-language studies abstract was primarily identified from the database, of which 110 were potentially relevant studies after duplicates were eliminated. Ninety-eight studies were excluded after thoroughly scrutinizing the title, abstract or full-text. Finally, 12 studies [[20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31]] were included (Fig. 1). The characteristics along with HWE values for healthy controls of these included
Discussion
SLE is a chronic autoimmune disease and most common in female of child-bearing age [32]. It has been shown that estrogen may be a major cause of the gender difference in the incidence of SLE and that the administration of estrogen can not only aggravate the disease manifestations of SLE patients but also cause the disease to flare [33,34]. The action of estrogen on target tissue is mediated via their binding to ER, thus, polymorphisms of ER genes involved in estrogen biosynthesis and metabolism
Conclusion
In conclusion, although existed some limitations, the results of our present meta-analysis strongly showed that the ERα PvuII polymorphism had a significant association with SLE risk in overall (CC+CT vs TT, CC vs TT, CT vs TT and C vs T models) and Asians (CC+CT vs TT, CT vs TT and C vs T models) population, while ERα XbaI polymorphism had a increased risk of SLE susceptibility in Asians under GA vs AA model. This study provided a new sight for people to better understand the mechanism of SLE,
Conflicts of interest
The authors declare that they have no competing interests with respect to the authorship and/or publication of this article.
Author contributions
Conceived and designed the experiments: Qiaomei Xie, Yanfeng Zou, Fang Wang.
Methodology: Yanfeng Zou, Faming Pan, Hong Su, Qiaomei Xie.
Analyzed the data: Qiaomei Xie, Susu Li, Man Zhang.
Writing – original draft: Qiaomei Xie.
Writing – review & editing: Yanfeng Zou, Fang Wang, Huaqing Hu, Shanqun Jiang.
Acknowledgment
We thank all the the people who offer help for this study.
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Qiao-Mei Xie, Hua-Qing Hu contributed equally to this work and is considered co-first authors.