Systematic review and meta-analysis of genetic association studies of pelvic organ prolapse

Abstract

Introduction and hypothesis Family and twin studies demonstrate that pelvic organ prolapse (POP) is heritable, but the genetic etiology is poorly understood. This review aimed to identify genetic loci and specific polymorphisms associated with POP, while assessing the strength, consistency, and risk of bias among reported associations. Methods Updating an earlier systematic review, PubMed and HuGE Navigator as well as relevant conference abstracts were searched using genetic and phenotype keywords from 2015 to 2020. Screening and data extraction were performed in duplicate. Fixed and random effects meta-analyses were conducted using co-dominant models of inheritance. We assessed credibility of pooled associations using interim Venice criteria. Results We screened 504 new abstracts and included 46 published and 7 unpublished studies. In pooled analyses we found significant associations for four polymorphisms: rs2228480 at the ESR1 gene (OR 0.67 95% CI 0.46–0.98, I2 = 0.0%, Venice rating BAB), rs12589592 at the FBLN5 gene (OR 1.46 95% CI 1.11–1.82, I2 = 36.3%, Venice rating BBB), rs484389 in the PGR gene (OR 0.61 95% CI 0.39–0.96, I2 = 32.4%, Venice rating CBB), and rs1800012 at the COL1A1 gene (OR 0.80 95% CI 0.66–0.96, I2 = 0.0%, Venice rating BAB). Further credible novel variants have also been recently identified in genome-wide association studies. Conclusion The genetic contributions to POP remain poorly understood. Several biologically plausible variants have been identified, but much work is required to establish the role of these genes in the pathogenesis of POP or to establish a role for genetic testing in clinical practice.

The polymorphisms of extracellular matrix-remodeling genes are associated with pelvic organ prolapse

“…The genetic contributions to POP remain poorly understood. Additional work needs to be done to provide further validation of POP predisposition variants in a variety of different populations to establish the role of these genes in the pathogenesis of prolapse [5].…”

“…Previous genetic analyses have revealed candidate genes associated with POP. These genes included collagen type I alpha (COL1A1) [4,5], collagen type III alpha 1 (COL3A1) [6], laminin gamma-1 (LAMC1) [7], and matrix metalloproteinases (MMPs) [8], which are all enrolled in extracellular matrix (ECM) pathways. The latest review comprehensively summarized and identified genetic polymorphisms associated with POP, including steroid hormone receptor genes and collagen/elastic fiber synthesis genes [5].…”

“…These genes included collagen type I alpha (COL1A1) [4,5], collagen type III alpha 1 (COL3A1) [6], laminin gamma-1 (LAMC1) [7], and matrix metalloproteinases (MMPs) [8], which are all enrolled in extracellular matrix (ECM) pathways. The latest review comprehensively summarized and identified genetic polymorphisms associated with POP, including steroid hormone receptor genes and collagen/elastic fiber synthesis genes [5]. Thus, ECM synthesis and metabolism abnormalities may affect the pelvic supporting system and have been considered the potential causes for POP.…”

Interactions between genetic variants and environmental risk factors are associated with the severity of pelvic organ prolapse

“…This conclusion confirmed both genetic and environmental influences on POP. Previous and recent genome-wide association studies, linkage studies, and candidate gene association studies have identified single nucleotide polymorphisms (SNPs) in genes mainly implicated in extracellular matrix organization and disassembly, and steroid hormone receptor genes, [7][8][9][10][11] suggesting a role of pelvic floor supportive tissue trauma and hormone exposure in the pathogenesis of POP. However, few validated loci exist from these studies.…”

Commentary: systematic review and meta-analysis of genetic association studies of pelvic organ prolapse

“…Large population-, family-and twins-based studies have confirmed a genetic risk factor. This fascinating systematic review and meta-analysis by Allen-Brady et al [1], is aimed at identifying the genetic loci and specific polymorphisms associated with POP, while assessing the strength, consistency and risk of bias amongst reported associations. It is important because the genetic contribution to POP is poorly understood whereas there is string evidence of heritability for POP.…”