Hiam, Danielle (2018) The Molecular Basis of Polycystic Ovary Syndrome: Genetics, Epigenetics and Insulin Resistance. PhD thesis, Victoria University.

Abstract

Polycystic Ovary Syndrome (PCOS) is a common and complex endocrinopathy. The proposed pathophysiology of PCOS is a synergistic relationship between perturbed gonadotropin pulsatility, hyperandrogenism, insulin resistance and inflammation. However, the nuances of these relationships are yet to be fully elucidated. The biological origins of PCOS are driven by heritability and a polygenic predisposition that is exacerbated by environmental factors (e.g. obesity). Therefore, the aetiology of PCOS is considered multifactorial. While familial clustering of PCOS symptoms is well documented, providing evidence for a genetic contribution to the condition, lifestyle factors also mediate the influence of the underlying mechanism of PCOS. These mechanisms likely involve epigenetics, which are the molecular interactions between genetics and lifestyle. Epigenetic modifications, like DNA methylation alter chromatin structure and gene expression. These DNA modifications are associated with the pathogenesis of obesity-related chronic diseases, yet there is limited evidence in PCOS. Therefore, the overall aim of this thesis was to assess different molecular mechanisms that are postulated to contribute to the aetiology of the syndrome by i) conducting an overview of systematic reviews to synthesise the current evidence and quality of evidence for the relationship between candidate gene polymorphisms and PCOS, ii) investigate the differences in global DNA methylation in specific immune cell populations in women with and without PCOS, iii) identify differences in genome-wide DNA methylation patterns and gene expression in immune cells of women with and without PCOS, iv) to further explore molecular mechanisms of PCOS-specific insulin resistance. My research concluded that there is very little evidence in the literature to ascribe specific genetic variations in PCOS, clearly highlighting a need for standardisation in the design and analysis of genetic association studies in PCOS. I also report that immune cells in women with PCOS display hypo-methylation in T helper cells, T cytotoxic cells, B cells and monocytes. Furthermore, immune cells displayed genome-wide differential gene expression and DNA methylation patterns in T helper cells in women with PCOS. Finally, I show that PCOS-specific insulin resistance may be regulated distal to Akt via interactions with the TGFβ signalling network. In summary, this thesis advances the fundamental understanding of the molecular basis of the aetiology of PCOS and offers a novel hypothesis to drive future research to better understand the syndrome and PCOS-specific insulin resistance.

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