Molecular landscape of pelvic organ prolapse provides insights into disease etiology and clues towards putative novel treatments

Abstract

Background: Pelvic organ prolapse (POP) represents a major health care burden in women but its underlying pathophysiological mechanisms have not been elucidated. Objective: To integrate the results from a large scale exome chip study with published genetic and expression data into a molecular landscape of POP. Design, setting, and participants: The exome chip study was conducted in 526 women with POP and 960 healthy controls. To corroborate the findings, we analysed differential gene expression data from 12 POP patients. Vaginal fibroblasts from 4 women with POP were used to test the effect of the anti-diabetic drug metformin. Outcome measurements and statistical analysis: The exome chip study used a case-control design to identify single nucleotide variants (SNVs) associated with POP after Bonferroni correction. The molecular landscape was built using the UniProt and PubMed databases to identify functional interactions between the POP candidate genes/proteins. We performed enrichment and upstream regulator analyses of the differentially expressed genes. The effect of metformin in fibroblasts was assessed using one-sample t-test. Results and limitations: We found significant association between POP and SNVs in 54 genes. The proteins encoded by 26 of these genes fit into a molecular landscape, together with 37 other POP candidate molecules and two POP-implicated microRNAs. This landscape is located in and around epithelial cells and fibroblasts of the urogenital tract and harbors four interacting biological processes - epithelial-mesenchymal transition, immune response, modulation of the extracellular matrix, and fibroblast function - that are regulated by sex hormones and TGFB1. Based on the landscape, we predicted and showed that metformin alters gene expression in fibroblasts of POP patients in a beneficial direction. The main limitation of our study is that we have no independent replication of the exome chip results. Conclusions: The integrated molecular landscape of POP that we built provides insights into the biological processes underlying the disease and clues towards novel treatments. Patient summary: We reported the first exome chip study of POP and combined the genes identified in this study with other data from the literature to build a 'molecular landscape' of POP. This landscape will advance our understanding of the disease and may lead to novel treatments.

Advancing our understanding of genetic risk factors and potential personalized strategies in pelvic organ prolapse: largest GWAS to date reveals 19 novel associated loci

“…Overall, further functional follow-up is needed to better characterize the regulatory functions of the loci uncovered and experimental work is warranted to confirm and strengthen the role of the candidate genes we propose in the identified loci. Similarly, the role of rare variants into pelvic organ prolapse remains understudied and deserves further attention (85).…”