Estrogen receptor 1 gene polymorphisms are associated with metabolic syndrome in postmenopausal women in China

Metabolic syndrome (MetS) constitutes a threat to human health, with estimated prevalence rates of 17–40 and 16.3% in the Middle East and North Africa, respectively [1]. Its prevalence has also increased from 23.8% between 2000 and 2005, to 27% between 2010 and 2015 in China [2]. MetS increases the risk of coronary artery disease, stroke, fatty liver disease, diabetes mellitus (DM), insomnia, and several cancers [3, 4]. Adult Treatment Panel III (ATP III) proposed that MetS encompasses at least three of the following ailments: abdominal obesity, high triglyceride (TG) levels, low high-density lipoprotein cholesterol (HDL-C) amounts, high blood pressure (BP), and high fasting blood glucose (FBG) [5]. All MetS variations increase the risk of cardiovascular disease (CVD). CVD incidence and mortality are significantly reduced in premenopausal women compared with men, but this difference gradually diminishes after menopause [6], with a corresponding increase in MetS incidence [7].

Hormones have critical functions in MetS pathogenesis and progression. Estrogen is associated with many aspects of MetS [8] such as glucose tolerance, fat metabolism, and BP [9]. Estrogen exerts its physiological functions in combination with estrogen receptors (ERs). ERs are nuclear hormone receptors (transcription factors) found in macrophages, adipose cells, vascular smooth muscle cells, and vascular endothelial cells [10, 11]. Estrogen receptor-α (ESR1) and β (ESR2) represent two known estrogen receptors that have been assessed using transgenic ERa (ERa^_/^_) and/or ERb (ERb^_/^_) knockout mice [12, 13].

The subtypes of ER, ESR1, and ESR2 are distinct in structure and function (likely in carbohydrate and lipid metabolism) [14]. ESR1 and ESR2 are found on chromosomes 6q25.1 and 14q23.2, respectively [15]. Single nucleotide polymorphisms (SNPs) in ESR1, such as PvuII (rs2234693) and XbaI (rs9340799), are involved in MetS [16]. As for ESR2, the risk of MetS is determined by the RsaI (1082A > G) (rs1256049) and AluI (1730A > G) (rs4986938) polymorphisms [17]. ESR1 and ESR2 SNPs are associated with metabolic factors in Western populations [18]. Here we assessed associations of four representative ESR1 and ESR2 polymorphisms with MetS and related phenotypes in postmenopausal Han Chinese women.

Changing lifestyles, socioeconomic status, and dietary habits have likely contributed to a rapid increase in the incidence of MetS, which is currently considered a major threat to human health worldwide [21]. High MetS prevalence is found among postmenopausal women [22]. Associations of several polymorphisms in the ESR1 and ESR2 genes with MetS or related components have been described [23]. These associations were also reported in the Study of Women’s Health Across the Nation (SWAN) trial of perimenopausal African-American, Caucasian, Chinese, and Japanese women between 42 and 52 years old [24]. The current study revealed positive associations of ESR1 polymorphisms with MetS in postmenopausal Chinese Han women. Subjects harboring the G allele of XbaI, or the A-T and G-C haplotypes of XbaI–PvuII polymorphisms of ESR1, showed elevated risk of MetS. Similar results were obtained in studies of women of different ages [25, 26]. Two ESR2 subtypes, including RsaI and AluI, were not significantly associated with Mets in this study.

ERb^_/^_ mice show normal or improved glucose tolerance and insulin release compared with wild type counterparts [27]. Meanwhile, ERa^_/^_ animals display glucose intolerance and insulin resistance [12]. ESR1 and ESR2 are widely distributed in various organs and tissues related to sugar metabolism. Associations of ESR1 polymorphisms and (T2DM) were demonstrated [28]. ESR2 polymorphisms are associated with MetS in Chinese and Japanese populations; in addition, SNPs in the ESR1 show associations with insulin sensitivity in Asian women [24]. ER-α can exert co-modulatory functions with insulin receptor substrate 1 (IRS1) to modulate insulin signaling [29]. Previous studies suggested an inhibitory effect of ERb on glucose transporter four (GLUT4) expression, and revealed that unchecked ERb activity could result in diabetes [25, 30]. As shown above, patients harboring the minor alleles of XbaI and PvuII gene polymorphisms, in both homozygous (GG and CC) or heterozygous (AG and TC) forms, had higher FBG, fasting serum insulin and HOMA-IR. Meanwhile, those carrying the RsaI polymorphism of ESR2 (homozygous or heterozygous) had lower fasting serum insulin and HOMA-IR.

Estrogens have critical functions in lipoprotein metabolism. An imbalance between ESR1 and ESR2 in the adipose tissue could therefore affect the development of metabolic diseases. Epidemiological studies showed hyperlipidemia is a significant risk factor for atherosclerosis, stroke, CAD, and MI [31]. In mice, ERb absence inhibit triglyceride accumulation, maintains normal insulin signaling in the liver and skeletal muscle, and ameliorates whole body insulin sensitivity as well as glucose tolerance [32]. ESR1 polymorphisms are associated with LDL particle size, reduced LDL cholesterol, and TC in adolescent female individuals [33]. SNPs in ESR1 show associations with the degree of adiposity, BMI, and waist circumference [34]. The PvuII T allele of ESR1 and associated genotypes and haplotypes are associated with risk of hyperlipidemia in postmenopausal Chinese Han females [35]. In addition, women with the PvuII T allele show elevated amounts of small LDL particles [36]. Furthermore, postmenopausal women with the T allele have reduced HDL-C and elevated TG, and are more vulnerable to lipid metabolism disorders [37]. These findings were corroborated by several other reports showing associations of ESR1 polymorphisms with BMI; however, associations of ESR2 polymorphisms with hyperlipidemia remain unclear. A study showed that homozygotes for the AluI (rs4986938) of ESR2 have higher BMI, serum TG and apolipoprotein B, and reduced HDL-C [38]. In mice, ESR2 deficiency is associated with abnormal vascular function and hypertension [39]. ESR2 polymorphisms are also associated with hypertension in postmenopausal Japanese women [40]. As shown above, positive associations were obtained of the G allele of XbaI polymorphism of the ESR1 gene with elevated TG, TC, LDL-C levels, as well as lower HDL-C, in postmenopausal Chinese women. The RsaI and AluI polymorphisms of ESR2 exhibited associations with TG, TC and LDL-C amounts.

Currently, MetS incidence is higher in postmenopausal women compared with age—matched males. Interventions to halt the rapidly increasing MetS incidence are of great clinical interest. Several studies have assessed associations of ESR1 and ESR2 with MetS or related components in different populations, but have often yielded conflicting findings. Furthermore, very few such studies have evaluated Chinese subjects. We here demonstrated associations of ESR1 and ESR2 polymorphisms with MetS and related components, especially obesity, and lipid and glucose metabolism, in postmenopausal Chinese Han females. Meanwhile, the G allele frequency of the XbaI polymorphism was markedly elevated in MetS patients compared with the control group. The RsaI and AluI polymorphisms of the ESR2 gene were not associated with MetS. In addition, XbaI and PvuII polymorphisms of ESR1 were associated with some MetS components. The current findings could include biases related to sample size, age, and ethnicity. Nevertheless, the present data could provide valuable insights into MetS epidemiology, particularly in Han Chinese individuals, providing a basis for the development of novel therapeutic interventions.