Evaluating the causal role of circulating inflammatory cytokines and plasma metabolites on aplastic anemia

Aplastic anemia (AA) is a rare, potentially life-threatening bone marrow failure syndrome characterized by immune-mediated destruction of hematopoietic stem/progenitor cells. Inflammatory cytokines and plasma metabolites are key regulators of T cell activity, but their causal roles in AA pathogenesis remain to be clarified. Two-sample Mendelian randomization (MR) was used to assess causal relationships between 91 circulating inflammatory cytokines, 1400 blood metabolites, and AA risk, and further mediation Mendelian randomization was applied to explore potential mediating pathways, with inverse-variance weighted method as the primary statistical method. Interleukin-13 (IL-13) is causally associated with reduced AA risk (odds ratio = 0.8731, 95% CI = 0.7720-0.9876, P = .0308), while leukemia inhibitory factor receptor (LIFR) links to increased risk (odds ratio = 1.1677, 95% CI = 1.0463-1.3031, P = .0056). Forty six plasma metabolites showed casual associated with AA, among which perfluorooctane sulfonate, andro steroid monosulfate, hydroxy-cmpf, spermidine to N-acetylputrescine ratio, cysteine to 5-oxoproline ratio, pyruvate to 3-methyl-2-oxobutyrate ratio, X-25520, epiandrosterone sulfate, epiandrosterone sulfate, N-acetyl-beta-alanine, cholate to adenosine 5'-monophosphate (AMP), spermidine to histidine ratio, cysteine s-sulfate have the most significant effects (P < .01). No causal effect of AA on IL-13 or LIFR, though AA may lower levels of 4 metabolites. IL-13 and LIFR affect the blood concentrations of 6 metabolites, and 3 metabolites influence IL-13 or LIFR levels, no evidence supports these metabolites acting as intermediaries in regulating AA risk. This study identifies inflammatory cytokines and blood metabolites as potential pathogenic factors in AA.