Inflammatory cytokines, metabolites, and pre-eclampsia: a two-sample Mendelian randomization study.

OBJECTIVES: Pre-eclampsia (PE) is a leading cause of maternal and fetal mortality, with inflammatory dysregulation implicated in its pathogenesis. This Mendelian randomization (MR) study aimed to investigate the causal effects of 91 inflammatory cytokines on PE and to identify potential mediating metabolites. METHODS: We conducted a two-sample MR analysis using genome-wide association study data from European-ancestry populations: including 91 inflammatory cytokines (14,824 participants), 1,400 plasma metabolites (8,299 participants), and PE (2,355 cases; 264,887 controls). Instrumental variables were selected at P < 1 × 10-5. Causal estimates were assessed using inverse-variance weighted regression, with additional sensitivity analyses to evaluate MR assumptions. Mediation analysis was subsequently performed to identify relevant metabolite pathways. RESULTS: We identified two novel risk factors and two protective factors for PE: genetically proxied elevations in fibroblast growth factor 5 (FGF-5) and Matrix metalloproteinase-1 (MMP-1) increased PE risk, whereas interleukin-10 (IL-10) and interleukin-20 (IL-20) were protective. Importantly, this is the first MR study to identify N-acetyl-L-alanine (ALA) as a significant mediator of cytokine effects in PE. ALA mediated 5.56% of the effect of FGF-5, revealing a pathway whereby elevated FGF-5 reduces ALA levels and consequently increases PE risk. CONCLUSIONS: This study establishes FGF-5 and MMP-1 as novel causal risk factors for PE, while IL-10 and IL-20 exert protective effects. The identification of ALA as a partial mediator of FGF-5 uncovers a new metabolic-inflammatory pathway in the pathogenesis of PE. These findings highlight potential biomarkers and therapeutic targets for the prevention and treatment of PE.