Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Lam, D.
Polycystic Ovary Syndrome ¿ Finding Links between Steroids and Glucose Pathways
[ Dissertation ] Medical University of Graz; 2013. pp. 128
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- Autor*innen der Med Uni Graz:
- Lam Uyen Do Phuong
- Betreuer*innen:
- Gülly Christian
- Obermayer-Pietsch Barbara
- Pieber Thomas
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- Abstract:
- ABSTRACT Introduction: Polycystic ovary syndrome (PCOS) can lead not only to hyperandrogenemia, hirsutism and fertility problems, but also to metabolic disturbances including obesity, cardiovascular events and a disposition to diabetes type 2. Accumulating evidence suggests some degree of inflammation associated with prominent aspects of PCOS. Vitamin D deficiency is also highly prevalent in PCOS women. Vitamin D deficiency per se can lead to problems with insulin metabolism and inflammation and is also associated with a number of other metabolic diseases, such as chronic kidney disease, hypertension, multiple sclerosis and estrogen-sensitive breast cancer. Thus, the identification of a susceptibility gene for PCOS would be a significant step towards understanding and treating this condition. Aims We aimed to discover new candidate genes for genetic studies in PCOS, in order to investigate an association of genetic variants in the inflammation-associated gene MEP1A (rs17468190 (G/T), GeneBank ID: NM_005588.2) with metabolic disturbances in PCOS and healthy control women and to assess MEP1A expression in a diabetes mouse model. Further, we used cell-culture models to evaluate whether the MEP1A gene is more generally associated with glucose and vitamin D metabolism, and how vitamin D metabolites as well as insulin and PTH might affect MEP1A gene expression. Methods: Data of genetic variants in 3,267 patients out of the LUdwigshafen RIsk and Cardiovascular (LURIC) study were visualized and annotated by WGAViewer software. Candidate genes were selected based on HapMap and National Center for Biotechnology Information (NCBI) ¿ single nucleotide polymorphism (SNP) database, Ensembl genome browser 63, and literature. Genetic variants rs17468190 (G/T) of the MEP1A gene were replicated in 576 PCOS women and 206 controls using a Taqman fluorogenic 5¿-exonuclease assay. This polymorphism was tested for an association with anthropometric, metabolic, hormonal, and functional parameters of PCOS. Further, tissue from leptin receptor-deficient (db/db) mice and C57BL/6 control mice was obtained for an analysis of MEP1A gene expression by polymerase chain reaction (PCR) and electrophoresis. In a functional study, human hepatocellular carcinoma (HepG2) cells were treated with insulin, vitamin D metabolites (25-hydroxyvitamin D3 [25(OH)D3], 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]), and parathyroid hormone (PTH). The expression of MEP1A mRNA was measured by quantitative real-time polymerase chain reaction (qPCR).