Genetic Association and Drug Target Exploration Between Inflammation-Related Proteins and the Risk of Primary Ovarian Insufficiency.

PURPOSE: Primary ovarian insufficiency (POI) exhibits ovarian dysfunction characteristics, which develops from diminished ovarian reserve (DOR). However, the pathogenesis remains unclear. In this study, we aimed to analyze the causal relationship between inflammation-related proteins and the occurrence of POI at the genetic level, and to identify potential druggable gene targets from inflammation-related genes. PATIENTS AND METHODS: We conducted a Mendelian randomization (MR) analysis to explore causal association for inflammation-related proteins and POI. Genetic instruments for 91 inflammation-related proteins were derived from the Olink(®) Target Inflammation panel with totally 14,824 European participants. Summary statistics for 424 POI cases and 118,796 controls were acquired from the FinnGen. Furthermore, by combining the Olink results from DOR patients with MR results, we highlighted five inflammation-related moleculars in ovarian aging. All were validated by Western-blot and RT-PCR in the POI model. Bioinformatics analysis was performed to reveal potential pathways, and potential drug screening was performed by the DGIdb database. RESULTS: Via inverse-variance weighted (IVW) method, our study identified two proteins, CXCL10 and CX3CL1 might exert protective effects against POI; whereas IL-18R1, IL-18, MCP-1, and CCL28 might increase the risk of POI. Moreover, Wald ratio analyses highlighted additional protective proteins, such as IL-17C, TRANCE, uPA, LAP TGF-β1, and CXCL9; along with risk proteins, including TNFSF14, CD40, IL-24, ARTN, LIF-R, and IL-2RB. Meanwhile, MCP-1/CCL2, TGFB1, ARTN, and LIFR were significantly changed in the POI model, which converged in the oncostatin M signaling pathway. Notably, gene-drug analysis identified CCL2 and TGFB1 as potential therapeutic targets, whereas genistein and melatonin were prioritized as potential drugs for POI treatment. CONCLUSION: Our study highlights the causal role of specific inflammation-related proteins in POI, advancing our understanding of its etiology, and further extends the therapeutic options for improving ovarian function and delaying POI onset.