17| Volume 211, P207, April 2017

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Exome chip study provides novel insights into the genetics of pelvic organ prolapse

      Introduction and aim of the study: Pelvic organ prolapse (POP) is caused by a complex interplay of genetic and environmental factors. The aim of the study was to provide insights into the pathophysiological molecular pathways underlying the disease, by integrating the results from a large scale exome chip study with published genetic and expression data.
      Materials and methods: Blood samples of 526 women with POP and 1911 control individuals were genotyped using an exome chip containing more than 240,000 exonic markers. We then conducted elaborate literature analyses of the top-ranked genes from the exome chip and genes implicated in POP through other evidence, including genetic association studies and expression studies in POP patients.
      Results: The exome chip study yielded significant association between POP and mutations in 44 unique genes. The proteins encoded by 20 of these, together with 28 other POP candidate proteins and two POP-implicated microRNAs, fit into four molecular pathways: i.e. epithelial-mesenchymal transition, immune response activation, modulation of the extracellular matrix, and fibroblast survival and apoptosis. These four pathways were located in epithelial cells and fibroblasts of the urogenital tract, interact with each other and are regulated through signalling involving female sex hormones and the cytokine TGFB1.
      Interpretation of results: The molecular pathways identified yield leads for existing drugs that could be repurposed or new disease-modifying treatments of POP.
      Conclusions: Our findings provide detailed and novel insights into the genetically determined mechanisms that are involved in the pathogenesis of POP. This research has recently been submitted for publication.