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

Kristina Allen-Brady,Felice Sorrentino,Rufus Cartwright,Romana Cuffolo,John W F Chua,Marianne Koch

doi:10.1007/s00192-021-04782-2

Abstract

Introduction and hypothesisFamily 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.MethodsUpdating 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pooled associations using interim Venice criteria.ResultsWe screened 504 new abstracts and included 46 published and 7 unpublished studies.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.ConclusionThe 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.

Highlights

Introduction and hypothesisFamily and twin studies demonstrate that pelvic organ prolapse (POP) is heritable, but the genetic etiology is poorly understood
Three large meta-analyses demonstrated a significant impact of family history on the development of or recurrence of POP with odds ratios ranging between 1.84 to 2.64 [2,3,4] with an affected first-degree relative
Given current evidence supporting a genetic predisposition for pelvic organ prolapse, we have identified four variants through meta-analysis of candidate gene studies significantly associated with POP

Summary

Introduction

Introduction and hypothesisFamily and twin studies demonstrate that pelvic organ prolapse (POP) is heritable, but the genetic etiology is poorly understood. Three large meta-analyses demonstrated a significant impact of family history on the development of or recurrence of POP with odds ratios ranging between 1.84 to 2.64 [2,3,4] with an affected first-degree relative (mother or sister). In a Swedish registry including data for 61,323 women with a history of POP surgery, the relative risk of prolapse surgery was found to be 6.58 (95% CI 6.32–6.86) for their sisters and 2.56 (2.41–2.73) for their mothers [5] These results were further clarified in a population-based study in the USA involving 453,522 total women and 4628 women with a history of POP surgery that found that risk increased with increasing numbers of affected relatives, from RR of 2.36 (95% CI 2.15–2.58) for ≥ 1 affected first-degree relative to RR 6.26 with ≥ 3 first-degree relatives (95% CI 1.29–18.20) [6]. Maternal inheritance of POP has been found to be a more significant contributor to the development of POP, but paternal inheritance contributes to risk [6, 7]

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Conclusion