Pelvic organ prolapse (POP) is a highly disabling condition common for a vast number of women worldwide. To contribute to existing knowledge in POP pathogenesis, we performed a systematic review of expression studies on both specific gene and whole-genome/proteome levels and an in silico analysis of publicly available datasets related to POP development. The most extensively investigated genes in individual studies were related to extracellular matrix (ECM) organization. Three premenopausal and two postmenopausal sets from two Gene Expression Omnibus (GEO) studies (GSE53868 and GSE12852) were analyzed; Gene Ontology (GO) terms related to tissue repair (locomotion, biological adhesion, immune processes and other) were enriched in all five datasets. Co-expression was higher in cases than in controls in three premenopausal sets. The shared between two or more datasets up-regulated genes were enriched with those related to inflammatory bowel disease (IBD) in the NHGRI GWAS Catalog. ECM-related genes were not over-represented among differently expressed genes. Up-regulation of genes related to tissue renewal probably reflects compensatory mechanisms aimed at repair of damaged tissue. Inefficiency of this process may have different origins including age-related deregulation of gene expression.

Oxidative stress may play a role in the recurrent miscarriage (RM) with no known etiology. This study was conducted to investigate the association of polymorphisms in oxidative stress-related genes with idiopathic RM. A total of 331 idiopathic RM patients and 197 controls were genotyped for ABCB1 rs1045642, CYP1A1 rs1048943 and rs4646903, COMT rs4680, CAT rs17880664, GCLC rs17883901, GPX4 rs713041, NRF2 rs6721961, SOD2 rs4880, and OGG1 rs1052133. A protective effect of COMT rs4680-G allele on RM was shown in individual SNP analysis: P = 0.0016, OR = 0.47, 95% CI 0.29-0.75. The multi-factor dimensionality reduction (MDR) approach revealed gene-gene interactions for ABCB1, COMT, GPX4, and OGG1 genes. Cumulative gene risk score analysis demonstrated that more than three risk alleles in the genes ABCB1 (rs1045642-T), COMT (rs4680-A), GPX4 (rs713041-T), and OGG1 (rs1052133-G) were associated with idiopathic RM P = 1.2 × 10(-3), OR = 1.97, 95% CI 1.31-2.97. In silico data interpreting by GeneMANIA analysis revealed genetic, physical, pathway, and coexpression networks for these four genes.

Pelvic floor dysfunction, specifically genital prolapse (GP) and stress urinary inconsistency (SUI) presumably co-occur with other connective tissue disorders such as hernia, hemorrhoids, and varicose veins. Observations on non-random coexistence of these disorders have never been summarized in a meta-analysis. The performed meta-analysis demonstrated that varicose veins and hernia are associated with GP. Disease connections on the molecular level may be partially based on shared genetic susceptibility. A unique opportunity to estimate shared genetic susceptibility to disorders is provided by a PheWAS (phenome-wide association study) designed to utilize GWAS data concurrently to many phenotypes. We searched the PheWAS Catalog, which includes the results of the PheWAS study with P value < 0.05, for genes associated with GP, SUI, abdominal hernia, varicose veins and hemorrhoids. We found pronounced signals for the associations of the SLC2A9 gene with SUI (P = 6.0e-05) and the MYH9 gene with varicose veins of lower extremity (P = 0.0001) and hemorrhoids (P = 0.0007). The comparison of the PheWAS Catalog and the NHGRI Catalog data revealed enrichment of genes associated with bone mineral density in GP and with activated partial thromboplastin time in varicose veins of lower extremity. In cross-phenotype associations, genes responsible for peripheral nerve functions seem to predominate. This study not only established novel biologically plausible associations that may warrant further studies but also exemplified an effective use of the PheWAS Catalog data.

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