Sphingomyelins and Their Metabolites Influence the Occurrence of Polycystic Ovary Syndrome Through Proinflammatory Cytokines: A Mendelian Randomization Insight

Abstract

Sphingomyelins and their metabolites can influence levels of proinflammatory cytokines, which in turn can impact the progression of polycystic ovary syndrome (PCOS). However, no research has clearly elucidated the mediating role of proinflammatory cytokines in this process. To delineate the causal relationship of sphingomyelins and their metabolites with PCOS and the mediating role of proinflammatory cytokines. Two-sample Mendelian randomization (MR) analysis was conducted to investigate causation between sphingomyelins and their metabolites with PCOS. A two-step MR analysis was used to examine the mediating role of proinflammatory cytokines. Random-effects inverse variance weighting was primarily used, and the reliability of results was assessed via sensitivity analysis. Four types of sphingomyelins and their metabolites showed potential association with PCOS. Glycosyl-N-stearoyl-sphingosine (d18:1/18:0) levels were positively correlated with PCOS, while sphingomyelin (d18:1/24:1, d18:2/24:0), sphingomyelin (d38:1), and ceramide (d42:2) levels were negatively correlated with PCOS. Proinflammatory cytokines, such as eotaxin, interleukin-20 receptor subunit alpha, and TNF-related apoptosis-inducing ligand (TRAIL) levels, showed a positive correlation with PCOS. TRAIL played a 6.58% potential mediating role in causation between sphingomyelin (d38:1) levels and PCOS. This study provided new evidence of a causal relationship of sphingomyelins and their metabolites with PCOS and elucidated that the proinflammatory cytokine TRAIL may play a certain mediating role in this process. These findings contributed to a better understanding of PCOS pathogenesis.