The probability of POP was higher in women with COL3A1 2209G>A. This polymorphism showed to be a relevant risk factor for POP.

Introduction and hypothesisPelvic organ prolapse (POP) and other disorders, such as varicose veins and joint hypermobility, have been associated with changes in collagen strength and metabolism. We hypothesized that these various disorders were more prevalent in both POP patients and their family members.MethodsIn this study, the prevalence of various collagen-associated disorders, including POP, was compared between POP patients (n = 110) and control patients (n = 100) and their first and second degree family members.ResultsPOP patients reported a higher prevalence of varicose veins, joint hypermobility and rectal prolapse and were more likely to have family members with POP as compared to the control group (p < 0.01). In contrast, the family members of the POP group did not report a higher prevalence of collagen-associated disorders compared to the family members of the control group (p = 0.82).ConclusionsPOP and other collagen-associated disorders may have a common aetiology, originating at the molecular level of the collagens.

Introduction and hypothesis There is growing evidence that pelvic organ prolapse (POP) is at least partly caused by underlying hereditary risk factors. The aim of our study was to provide a systematic literature review and meta-analysis of clinical studies on family history of POP as a risk factor for POP in individual women. Methods The databases PubMed and Embase were searched. Clinical studies reporting on family history of POP in relation to POP in individual women were included. Results Sixteen studies were included, of which eight enabled us to calculate a pooled odds ratio (OR). The pooled OR of POP in case of a positive family history of POP was 2.58 (95 % confidence interval 2.12–3.15). Conclusions Women with POP are substantially more likely to have family members with the same condition compared to women without POP. This strengthens the hypothesis that genetic predisposition plays an important role in the development of POP.

The previously found statistically significant association between the rs1800255, COL3A1 2209 G>A polymorphism as measured with PCR-RFLP and POP could no longer be demonstrated. This raises concerns regarding the results of other association studies using PCR-RFLP.

Proxy SNPs rs4281556 rs79077061 and rs10837192 used in replication cohorts. † Monomorphic across 5 of 6 replication cohorts.

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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.

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—epithelial-mesenchymal transition, immune response, modulation of the extracellular matrix, and fibroblast function—that 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.