scholarly journals Advancing our understanding of genetic risk factors and potential personalized strategies in pelvic organ prolapse: largest GWAS to date reveals 19 novel associated loci

2021 ◽  
Author(s):  
Natàlia Pujol-Gualdo ◽  
Kristi Läll ◽  
Maarja Lepamets ◽  
Henna-Riikka Rossi ◽  
Riikka K Arffman ◽  
...  
Keyword(s):  
Risk Factors ◽  
Pelvic Organ Prolapse ◽  
Genetic Risk ◽  
Meta Analysis ◽  
Predictive Ability ◽  
Pelvic Organ ◽  
European Ancestry ◽  
Risk Scores ◽  
C Statistic ◽  
Tissue Abnormalities

Objectives: To identify the genetic determinants of pelvic organ prolapse (POP) and assess the predictive ability of polygenic risk scores (PRS) alone or in combination with clinical risk factors. Design: Meta-analysis of genome-wide association studies (GWAS) and PRS construction and validation. Setting: GWAS summary statistics from three European datasets and individual-level data from Estonian Biobank, including phenotype questionnaire and measurement panel, together with follow-up data from linkage with national health-related registries. Participants: A total of 28,086 women with POP and 546,321 controls of European ancestry. Genetic risk scores were derived from a dataset of 20,118 cases and 427,426 controls of European ancestry and validated in a target dataset of 7,896 cases and 118,895 controls. Cases were defined using ICD codes and classical risk factors were derived from questionnaire data and ICD10 codes. Results: The identified novel loci reinforce the role of connective tissue abnormalities, urogenital tract development and point towards association with a range of cardiometabolic traits. A novel PRS combining 3,242,959 variants demonstrated that women in the top 5 % have 1.63 (95% CI: 1.37 to 1.93) times the hazard of developing POP compared to the rest of the women. When analyzing PRS in incident disease, it showed similar predictive ability (Harrell C-statistic 0.583, sd=0.007) than five established clinical risk factors (number of children, body mass index (BMI), ever smoked, constipation and asthma) combined (Harrell C-statistic 0.588, sd=0.007) and demonstrated its incremental value in combination with these (Harrell C-statistic 0.630, sd=0.007). Conclusions: The largest GWAS meta-analysis in POP to date identified 26 genetic loci which establish links between POP and connective tissue abnormalities, urogenital development and cardiometabolic health. We present a PRS for POP which provides the first potential tool for preventive strategies and early detection of higher risk susceptibility to POP including genetic risk factors.

Age and/or postmenopausal status as risk factors for pelvic organ prolapse development: systematic review with meta-analysis

2021 ◽  
Author(s):  
Luiz Gustavo Oliveira Brito ◽  
Glaucia Miranda Varella Pereira ◽  
Pamela Moalli ◽  
Oksana Shynlova ◽  
Jittima Manonai ◽  
...  
Keyword(s):  
Risk Factors ◽  
Systematic Review ◽  
Pelvic Organ Prolapse ◽  
Meta Analysis ◽  
Pelvic Organ ◽  
Postmenopausal Status

scholarly journals Animal models for pelvic organ prolapse: systematic review

2021 ◽  
Author(s):  
Marina Gabriela M. C. Mori da Cunha ◽  
Katerina Mackova ◽  
Lucie Hajkova Hympanova ◽  
Maria Augusta T. Bortolini ◽  
Jan Deprest
Keyword(s):  
Pelvic Organ Prolapse ◽  
Animal Models ◽  
Vaginal Delivery ◽  
Structural Changes ◽  
Meta Analysis ◽  
Levator Ani ◽  
Complete Recovery ◽  
Pelvic Organ ◽  
Squirrel Monkeys ◽  
Levator Ani Muscle

Abstract Introduction and hypothesis We aimed to summarize the knowledge on the pathogenesis of pelvic organ prolapse (POP) generated in animal models. Methods We searched MEDLINE, Embase, Cochrane and the Web of Science to establish what animal models are used in the study of suggested risk factors for the development of POP, including pregnancy, labor, delivery, parity, aging and menopause. Lack of methodologic uniformity precluded meta-analysis; hence, results are presented as a narrative review. Results A total of 7426 studies were identified, of which 51 were included in the analysis. Pregnancy has a measurable and consistent effect across species. In rats, simulated vaginal delivery induces structural changes in the pelvic floor, without complete recovery of the vaginal muscular layer and its microvasculature, though it does not induce POP. In sheep, first vaginal delivery has a measurable effect on vaginal compliance; measured effects of additional deliveries are inconsistent. Squirrel monkeys can develop POP. Denervation of their levator ani muscle facilitates this process in animals that delivered vaginally. The models used do not develop spontaneous menopause, so it is induced by ovariectomy. Effects of menopause depend on the age at ovariectomy and the interval to measurement. In several species menopause is associated with an increase in collagen content in the longer term. In rodents there were no measurable effects of age apart of elastin changes. We found no usable data for other species. Conclusion In several species there are measurable effects of pregnancy, delivery and iatrogenic menopause. Squirrel monkeys can develop spontaneous prolapse.

Has the time come to integrate genetic risk scores into clinical practice?

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F.V Moniz Mendonca ◽  
M.I Mendonca ◽  
A Pereira ◽  
J Monteiro ◽  
J Sousa ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Practice ◽  
Genetic Variants ◽  
Genetic Risk ◽  
Odds Ratio ◽  
Risk Scores ◽  
Cumulative Number ◽  
Genetic Risk Scores ◽  
Risk Alleles ◽  
Cad Risk

Abstract Background The risk for Coronary Artery Disease (CAD) is determined by both genetic and environmental factors, as well as by the interaction between them. It is estimated that genetic factors could account for 40% to 55% of the existing variability among the population (inheritability). Therefore, some authors have advised that it is time we integrated genetic risk scores into clinical practice. Aim The aim of this study was to evaluate the magnitude of the association between an additive genetic risk score (aGRS) and CAD based on the cumulative number of risk alleles in these variants, and to estimate whether their use is valuable in clinical practice. Methods A case-control study was performed in a Portuguese population. We enrolled 3120 participants, of whom 1687 were CAD patients and 1433 were normal controls. Controls were paired to cases with respect to gender and age. 33 genetic variants known to be associated with CAD were selected, and an aGRS was calculated for each individual. The aGRS was further subdivided into deciles groups, in order to estimate the CAD risk in each decile, defined by the number of risk alleles. The magnitude of the risk (odds ratio) was calculated for each group by multiple logistic regression using the 5th decile as the reference group (median). In order to evaluate the ability of the aGRS to discriminate susceptibility to CAD, two genetic models were performed, the first with traditional risk factors (TRF) and second with TRF plus aGRS. The AUC of the two ROC curves was calculated. Results A higher prevalence of cases over controls became apparent from the 6th decile of the aGRS, reflecting the higher number of risk alleles present (see figure). The difference in CAD risk was only significant from the 6th decile, increasing gradually until the 10th decile. The odds ratio (OR) for the last decile related to 5th decile (median) was 1.87 (95% CI:1.36–2.56; p<0.0001). The first model yielded an AUC=0.738 (95% CI:0.720–0.755) and the second model was slightly more discriminative for CAD risk (AUC=0.748; 95% CI:0.730–0.765). The DeLong test was significant (p=0.0002). Conclusion Adding an aGRS to the non-genetic risk factors resulted in a modest improvement in the ability to discriminate the risk of CAD. Such improvement, even if statistically significant, does not appear to be of real value in clinical practice yet. We anticipate that with the development of further knowledge about different SNPs and their complex interactions, and with the inclusion of rare genetic variants, genetic risk scores will be better suited for use in a clinical setting. Funding Acknowledgement Type of funding source: None

scholarly journals Incidence and risk factors for reoperation of surgically treated pelvic organ prolapse

2011 ◽  
Vol 23 (1) ◽  
pp. 35-41 ◽  
Author(s):  
Patrick Dällenbach ◽  
Carol Jungo Nancoz ◽  
Isabelle Eperon ◽  
Jean-Bernard Dubuisson ◽  
Michel Boulvain
Keyword(s):  
Risk Factors ◽  
Pelvic Organ Prolapse ◽  
Pelvic Organ
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