{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T15:41:47Z","timestamp":1791906107040,"version":"4.3.4"},"reference-count":66,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T00:00:00Z","timestamp":1679529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Obstetrics and Gynecology of the Radboudumc (Nijmegen, The Netherlands)","award":["NWO 184.021.007"],"award-info":[{"award-number":["NWO 184.021.007"]}]},{"name":"Department of Obstetrics and Gynecology of the Radboudumc (Nijmegen, The Netherlands)","award":["RO1 HD061821"],"award-info":[{"award-number":["RO1 HD061821"]}]},{"name":"Department of Obstetrics and Gynecology of the Radboudumc (Nijmegen, The Netherlands)","award":["PROJ00787 (DIABIP)"],"award-info":[{"award-number":["PROJ00787 (DIABIP)"]}]},{"name":"BBMRI-NL","award":["NWO 184.021.007"],"award-info":[{"award-number":["NWO 184.021.007"]}]},{"name":"BBMRI-NL","award":["RO1 HD061821"],"award-info":[{"award-number":["RO1 HD061821"]}]},{"name":"BBMRI-NL","award":["PROJ00787 (DIABIP)"],"award-info":[{"award-number":["PROJ00787 (DIABIP)"]}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["NWO 184.021.007"],"award-info":[{"award-number":["NWO 184.021.007"]}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["RO1 HD061821"],"award-info":[{"award-number":["RO1 HD061821"]}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["PROJ00787 (DIABIP)"],"award-info":[{"award-number":["PROJ00787 (DIABIP)"]}]},{"name":"European Regional Development Fund (ERDF)","award":["NWO 184.021.007"],"award-info":[{"award-number":["NWO 184.021.007"]}]},{"name":"European Regional Development Fund (ERDF)","award":["RO1 HD061821"],"award-info":[{"award-number":["RO1 HD061821"]}]},{"name":"European Regional Development Fund (ERDF)","award":["PROJ00787 (DIABIP)"],"award-info":[{"award-number":["PROJ00787 (DIABIP)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pelvic organ prolapse (POP) represents a major health care burden in women, but its underlying pathophysiological mechanisms have not been elucidated. We first used a case-control design to perform an exome chip study in 526 women with POP and 960 control women to identify single nucleotide variants (SNVs) associated with the disease. We then integrated the functional interactions between the POP candidate proteins derived from the exome chip study and other POP candidate molecules into a molecular landscape. We found significant associations between POP and SNVs in 54 genes. The proteins encoded by 26 of these genes fit into the molecular landscape, together with 43 other POP candidate molecules. The POP landscape is located in and around epithelial cells and fibroblasts of the urogenital tract and harbors four interacting biological processes\u2014epithelial-mesenchymal transition, immune response, modulation of the extracellular matrix, and fibroblast function\u2014that are regulated by sex hormones and TGFB1. Our findings were corroborated by enrichment analyses of differential gene expression data from an independent POP cohort. Lastly, based on the landscape and using vaginal fibroblasts from women with POP, we predicted and showed that metformin alters gene expression in these fibroblasts in a beneficial direction. In conclusion, our integrated molecular landscape of POP provides insights into the biological processes underlying the disease and clues towards novel treatments.<\/jats:p>","DOI":"10.3390\/ijms24076087","type":"journal-article","created":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T03:50:21Z","timestamp":1679629821000},"page":"6087","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Molecular Landscape of Pelvic Organ Prolapse Provides Insights into Disease Etiology"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4681-4304","authenticated-orcid":false,"given":"Kirsten B.","family":"Kluivers","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina L.","family":"Lince","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra M.","family":"Ruiz-Zapata","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"},{"name":"Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9126-0072","authenticated-orcid":false,"given":"Wilke M.","family":"Post","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rufus","family":"Cartwright","sequence":"additional","affiliation":[{"name":"Department of Gynaecology, Chelsea and Westminster NHS Foundation Trust, Department of Epidemiology and Biostatistics, Imperial College London, London SW7 2AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9986-763X","authenticated-orcid":false,"given":"Manon H.","family":"Kerkhof","sequence":"additional","affiliation":[{"name":"Department of Gynaecology and Reconstructive Pelvic Surgery, Curilion Women\u2019s Health Clinic, 2015 BJ Haarlem, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Widomska","sequence":"additional","affiliation":[{"name":"Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GD Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ward","family":"De Witte","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6857-6001","authenticated-orcid":false,"given":"Jakub","family":"Pecanka","sequence":"additional","affiliation":[{"name":"Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"},{"name":"Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 EZ Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lambertus A.","family":"Kiemeney","sequence":"additional","affiliation":[{"name":"Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 EZ Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sita H.","family":"Vermeulen","sequence":"additional","affiliation":[{"name":"Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 EZ Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelle J.","family":"Goeman","sequence":"additional","affiliation":[{"name":"Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"},{"name":"Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 EZ Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Allen-Brady","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Genetic Epidemiology, University of Utah, Salt Lake City, UT 84132, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5049-0018","authenticated-orcid":false,"given":"Egbert","family":"Oosterwijk","sequence":"additional","affiliation":[{"name":"Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert","family":"Poelmans","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1007\/s00192-009-0902-1","article-title":"The prevalence of pelvic organ prolapse symptoms and signs and their relation with bladder and bowel disorders in a general female 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