Circulating Inflammatory Biomarkers mediates the causal effect of Aging on Female Pelvic Organ Prolapse: Mendelian Randomization Analysis

Abstract Aims Female pelvic organ prolapse (POP) is a disease associated with aging and inflammation, though it is not determined that aging and inflammation are causative factors. The purpose of this study was to evaluate the causal effects of aging and inflammatory factors on female pelvic organ prolapse (POP). Methods Significant genetic variables were evaluated by assessing genome-wide association study (GWAS) data for POP and 5 age biomarkers (GrimAge, HorvathAge, HannumAge, PhenoAge, and leukocyte telomere length). Initially, a bidirectional MR analysis was conducted utilizing a random-effects inverse variance-weighted IVW method to elucidate the causal association. Other MR methods and sensitivity analyses were also used. Then, we also used a two-step MR analysis to analyze the mediating effect of six circulating inflammatory biomarkers in the causal relationship between age and POP. Finally, two-sample MR analysis was also used to investigate the effects of 190 inflammatory cytokines on POP risk. Results Shorter leukocyte telomere length (LTL), rather than epigenetic clocks is genetically predicted to increase the risk of POP. MR analysis showed that shorter LTL is associated with higher leukocyte count, which can lead to POP. A significant causal association was found between 44 circulating inflammatory cytokines and POP risk. After adjusting for multiple tests, CXCL14, IL17A, IL18, IL6, TNFRSF10B, and TNFSF9 remained statistically significant. Conclusions Our findings provide that leukocyte count mediates the potential genetic causal impact of shorter LTL on the development of POP. Inflammatory cytokines might to be considered as potential targets for intervention in POP.