Polymorphism and pelvic organ prolapse: combining strict inclusion criteria and environmental risk factors as a good standard for further studies

Pelvic organ prolapse (POP) is a frequent, distressing clinical entity that impacts quality of life and social activities. The estimated prevalence is 3–6% in the general female population but increases with age (1). Many studies have confirmed the presence of familial aggregation and inherited risk factors in POP (2), and large meta-analyses have demonstrated that a woman’s family medical history has a significant impact on the development or recurrence of POP (3). Hence, researchers have tried to identify genetic variants that predispose to POP. Two strategies have been used: (I) multiple candidate gene studies that focus on a small number of single nucleotide variants (SNP), typically in a small number of patients; and (II) genome-wide association studies (GWAS) of large cohorts. However, the results of observational studies have shown that certain socioeconomic, demographic and/or medical variables like age, body mass index, vaginal delivery, and birth weight, may be independent risk factors for POP (4,5). Many confounding factors might therefore bias the estimated genetic associations with POP. In studies of associations with SNPs, the ethnic origin of the study population origin must also be taken into account (SNP frequencies vary greatly with the ethnic origin), and studies must be replicated in different countries.

The limited quantity of literature data prompted da Silva et al. (6) to evaluate the association between POP and the rs1036819 polymorphism in the ZFAT gene in a population of 826 postmenopausal Brazilian women with vs. without POP. DNA was extracted from peripheral blood cells and genotyped for the rs1036819 polymorphism. As in previous studies, various exclusion criteria were applied: a history of urogenital cancer, cancer onset during the study, previous radiotherapy, and previous pelvic surgery. Although POP was not associated with rs1036819 in da Silva et al.’s study population, it was associated with some of the previously mentioned demographic and medical variables, such as age, the number of pregnancies, vaginal delivery and a family history of POP.

Da Silva et al. (6) concluded their report by describing the study’s limitations and strengths; one of the strengths was the use of strict inclusion criteria. This point is of particular importance when seeking to exclude sources of bias in an association study. Da Silva et al. included postmenopausal women who had been graded with Haylen et al.’s POP Quantification System (7); this was also the case in the study by Bizjak et al. (8), which did not find an association between rs1036819 and POP. The use of strict inclusion criteria has been highlighted in many meta-analyses, including our group’s meta-analysis of endometriosis (9). For example, it was not taken into consideration by the first GWAS which has found significant associations between POP and six SNPs in high-risk familial cases (10) because the control participants had not been phenotyped.

Abulaizi et al.’s study (11) also found an association with rs1036819, albeit in a smaller (n=196) study population (88 women with POP and 108 controls). The allele frequency was 36.5%; this can be compared with the value of 19.3% in the Da Silva et al.’s study and 38.5% in East Asian populations in the gnomAD database (https://gnamad.broadinstitute.org). These differences in allele frequency highlight the presence of population variability and the need to reproduce an initial identification of a positive or negative association. Lastly, the disparities between the results of studies of ZFAT polymorphisms (in Chinese from Chinese mainland, Taiwan residents, American, Korean, Dutch, and Brazilian populations) might be due to ethnic factors and thus different background risks of POP.

Lastly, da Silva et al. concluded that POP is not associated with rs1036819. This is not so surprising given that (I) ZFAT RNA is notably found in skeletal muscle and kidney; (II) ZFAT polymorphisms might be associated with many human diseases; (III) POP probably results from an imbalance problem between the synthesis and degradation of components of muscle and extracellular matrix (12,13); and (IV) the GWAS study, that first reported the rs1036819 SNP in ZFAT, did not provide solid evidence, and the authors were unable to conclusively validate their findings. Furthermore, the Protein Atlas database (https://www.proteinatlas.org/) shows that although ZFAT protein is mainly expressed in testis and placenta.

In conclusion, the results of several recent studies appear to show that genetic variants and environmental factors cannot alone explain the severity of POP; the interaction between polymorphisms and environmental risk factors might be more important. Li et al.’s study (14) highlighted significant interactions between SNPs, maximum birth weight, age, and POP severity. Interestingly, Zhang et al.’s study (15) showed that socioeconomic traits (such as lower educational attainment) were associated with the risk of POP. Hence, all the putative environmental, sociodemographic and socioeconomic risk factors for POP must be taken into account in polymorphism studies. The da Silva et al. study provides preliminary evidence that epidemiological exposure data should be combined with genotyping for risk assessment and patient stratification.

Acknowledgments

The authors thank IRSF (Institut de recherche en santé de la femme: www.irsf.fr) for English proofreading.

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine. The article has undergone external peer review.

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-23-43/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-23-43/coif). The authors have no conflicts of interest to declare.

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