Causal Effects of Circulating Inflammatory Proteins on Postmenopausal Atrophic Vaginitis in European Populations: A Mendelian Randomization Study with Transcriptomic Validation.

BACKGROUND

Postmenopausal atrophic vaginitis (PAV) is a prevalent and undertreated condition driven primarily by estrogen deficiency. Whether circulating inflammatory proteins causally contribute to PAV pathogenesis remains unknown.

METHODS

Genetic instruments for 91 inflammatory proteins were derived from large-scale proteogenomic GWAS of European ancestry individuals. PAV outcome data were obtained from the FinnGen Consortium Release 12. Primary causal estimates were obtained using the inverse-variance weighted (IVW) method, complemented by MR-Egger, weighted median, and weighted mode analyses. Candidate proteins were defined by IVW p < 0.05 and directional consistency across all four methods. Sensitivity analyses included the MR-Egger intercept test, Cochran's Q test, leave-one-out analysis, funnel plot assessment, and reverse MR. Transcriptomic validation was performed using the publicly available vaginal tissue dataset GSE26761.

RESULTS

Six inflammatory proteins met the candidate criteria: CCL19 (OR: 1.063, 95% CI: 1.003-1.126) and IL12B (OR: 1.050, 95% CI: 1.002-1.100) were associated with increased PAV risk, while CXCL5 (OR: 0.935, 95% CI: 0.874-0.999), TNFRSF9 (OR: 0.930, 95% CI: 0.869-0.996), IL10RA (OR: 0.906, 95% CI: 0.831-0.988), and TGFA (OR: 0.880, 95% CI: 0.790-0.981) were inversely associated with PAV risk. Sensitivity analyses revealed no significant pleiotropy or heterogeneity. Transcriptomic analysis confirmed significantly lower TGFA expression in atrophic compared to control vaginal tissue (P = 0.039), consistent with its MR-derived protective effect.

CONCLUSION

This study provides genetic evidence that circulating inflammatory proteins causally influence PAV risk through distinct immune pathways. TGFA emerges as the most robustly supported candidate, with convergent MR and transcriptomic evidence suggesting a role in vaginal epithelial maintenance. These findings highlight inflammation as a potential contributor to PAV pathogenesis and nominate candidate targets for future mechanistic and therapeutic investigation. Given that multiple inflammatory proteins were tested, these findings should be interpreted cautiously and warrant further validation in independent cohorts.