The causal association between systemic inflammatory regulators and primary ovarian insufficiency: a bidirectional mendelian randomization study

Abstract

Background: Recent studies have suggested a potential link between systemic inflammatory regulators and primary ovarian insufficiency (POI); however, a causal relationship between them remains unclear. In this study, we explored the causal link between systemic inflammatory regulators and POI risk using a bidirectional, two-sample Mendelian randomization (MR) strategy.

Results: This approach utilized the most extensive genome-wide association study involving 41 systemic inflammatory regulators in a sample of 8,293 Finnish individuals and POI data from the FinnGen consortium (254 cases vs. 118,228 controls). The inverse variance weighting approach served as a primary MR method, and four additional MR techniques (Maximum Likelihood, MR-Egger, Weighted Median, and constrained maximum likelihood and model averaging Bayesian information criterion ) were applied to support and validate results. Cochran's Q statistics were used to assess the heterogeneity of instrumental variables, whereas the MR-Egger and MR Pleiotropy Residual Sum and Outlier tests detected horizontal pleiotropy. The MR Steiger test evaluated the strength of a causal association. Our findings suggest that lower levels of vascular endothelial growth factor (odds ratio [OR] = 0.73, 95% confidence interval [CI]: 0.54-0.99, P = 0.046) and interleukin-10 (OR = 0.54, 95% CI: 0.33-0.85, P = 0.021) are associated with an increased risk of POI. Reverse MR analysis revealed no significant effect of POI on the expression of these 41 systemic inflammatory regulators. No notable heterogeneity or horizontal pleiotropy was observed in the instrumental variables.

Conclusions: This study revealed a causal association between 41 systemic inflammatory regulators and POI, demonstrating that decreased levels of VEGF and IL-10 are linked to an elevated risk of POI. Further investigations are necessary to assess the potential of these biomarkers as early predictors, preventive strategies, and therapeutic targets for POI.

Keywords: Causal inference; Mendelian randomization study; Primary ovarian insufficiency; Systemic inflammatory regulators.

Fig. 1

Scatter plots of significant causality of the Systemic inflammatory regulators and POI. Scatter plot of the effect size and 95% CI of each SNP on Systemic inflammatory regulators and POI risk. The horizontal axis reflects genetic effect of each SNP on Systemic inflammatory regulators. The vertical axis represents the genetic effect of each SNP on POI risk

Fig. 2

Leave-one-out analysis for the impact of individual SNPs on the association between Systemic inflammatory regulators and POI risk. By leaving out exactly one SNP, it shows how each individual SNP influences the overall estimate