Estrogen receptor αlpha gene (ESR1) PvuII and XbaI polymorphisms are associated to metabolic and proinflammatory factors in polycystic ovary syndrome
Introduction
Polycystic ovary syndrome (PCOS) is a complex disorder that involves the interaction of environmental and genetic factors. PCOS is the most common endocrine disorder in women, affecting approximately 5–10% of those of reproductive age, and is characterized by metabolic, reproductive, and psychological alterations (Michelmore et al., 1999, Azziz et al., 2006, Farrell and Antoni, 2010). Furthermore, PCOS patients present increased risk for developing metabolic syndrome, dyslipidemia, glucose intolerance, type 2 diabetes mellitus (T2DM), hypertension, and other cardiovascular diseases (Azziz et al., 2006, Cobin, 2013).
The etiology of PCOS is unknown (Azziz et al., 2006, Dunaif, 1995, Franks, 1995), but men and women who are first-degree relatives of women with this syndrome have an increased risk for developing obesity, insulin resistance, and T2DM. However, the mode of inheritance remains unknown, as does the interaction of genetic background with acquired risk factors, such as diet and lifestyle (Legro et al., 2002, Sam et al., 2008).
Estrogens play an important role in the development and functioning of the male and female reproductive systems. They also act on the skeletal system, lipid metabolism, and the maintenance and protection of the cardiovascular and nervous systems (Corbo et al., 2011). The gene-encoding estrogen receptor (ESR) is located on the long arm of chromosome 6 (6q25.1). It contains 8 exons, and its introns have been shown to be highly conserved (Ponglikitmongkol et al., 1988, Molvarec et al., 2007a). Alternative splicing is observed after gene transcription, resulting in different mRNAs, which differ primarily in the 5′ untranslated region (Flouriot et al., 2000, Kos et al., 2001). Two major isoforms of the ESR gene have been described: ESR1 (ERα) and ESR2 (ERβ), which have distinct patterns of tissue expression (Moore et al., 1998).
The ESR1 isoform is expressed in various organs, such as the uterus, liver, kidney, and heart, and particularly in the testis and ovary (Tietz, 1998). This receptor is also coexpressed in tissues, such as the mammary gland, epididymis, thyroid, adrenal, and bone, and in certain regions of the brain (Matthews and Gustafsson, 2003).
ESR1 is a nuclear hormone receptor that functions as an activator of transcription factors and consists of 595 amino acids, with a molecular weight of approximately 66 kDa. The estrogen receptor is activated not only by binding to estrogen, but also by binding to several growth factors (Molvarec et al., 2007b). The absence of ESR1 can be associated with an increase in circulating luteinizing hormone (LH) levels and a loss in the maturation of follicles, resulting in anovulatory follicles and atresia (Schomberg et al., 1999).
The main polymorphisms are located in intron 1 of this gene and consist of the substitution 397T/C, which creates a restriction site for the PvuII (rs2234693) enzyme, and 351A/G, which creates a site for XbaI (rs9340799). These polymorphisms have been associated with male and female infertility, breast cancer, osteoporosis, Alzheimer's disease, cardiovascular diseases, hemostatic abnormalities, preeclampsia, increased abdominal circumference, systemic lupus erythematosus, T2DM, age at menarche, and the onset of menopause (Corbo et al., 2011, Molvarec et al., 2007b, Weel et al., 1999, Schuit et al., 2005, Huang et al., 2006, Stavrou et al., 2006, Lu et al., 2009). A possible functional mechanism attributed to the polymorphisms of the ESR1 gene includes a change in mRNA processing, producing different variants or isoforms of the protein.
Although the etiology of PCOS is unknown, there is an involvement of sex steroid hormones in the pathophysiology of this syndrome. Therefore, polymorphisms in genes involved in the action of estrogen may contribute to a woman's susceptibility to PCOS. Thus, the aims of this study were to evaluate whether the frequency of PvuII and XbaI polymorphisms in the ESR1 gene is altered in women with PCOS, and to investigate the influence of these polymorphisms in metabolic and inflammatory profiles in this population.
Section snippets
Subjects
This case–control study evaluated 99 Brazilian women with PCOS and 104 healthy women without the syndrome; women in both groups were aged 20 to 50 years. Women with PCOS were recruited at the academic hospital of Federal University of Minas Gerais (UFMG) in Belo Horizonte, Brazil, between 2011 and 2013. The control group was recruited from university employees and students in the same period. The study was approved by the Research Ethics Committee of UFMG (CAAE 0379.0.203. 000-11). All
Results
Clinical and biochemical characteristics of the PCOS and control groups are shown in Table 1. No difference was observed regarding age when comparing both groups. As expected, higher testosterone levels were observed in the PCOS group (P < 0.001) than in the control group. Moreover, higher values for BMI, WC, LAP, insulin, and FSH were observed in the PCOS group (P < 0.05). Although the PCOS group had higher CRP levels, this difference was not significant when compared to the control group. Fasting
Discussion
In our study, we evaluated the importance of the ESR1 gene polymorphisms PvuII and XbaI in the development of PCOS. Furthermore, we sought to investigate the relationship between these polymorphisms and the clinical and biochemical variables in patients with the syndrome.
The finding of higher levels of testosterone in women with PCOS compared with the control group was expected because the hyperandrogenic state is frequently observed in PCOS and is a diagnostic criterion of the disease.
Insulin
Conflict of interest statement
The authors disclose no conflict of interest.
Acknowledgments
The authors would like to thank the Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). FMR, MOS and KBG are grateful to CNPq Research Fellowship (PQ). The authors also thank Simone Martins Gonçalves and Dalva Maria de Resende for technical support.
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