Abstract
PURPOSE: Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder, with dysregulated lipid metabolism and immune dysfunction. However, it remains unclear whether immune phenotypes mediate the relationship between lipidomes and PCOS. METHODS: A two-step Mendelian Randomization analysis was employed to explore the causal relationship between plasma lipidomes and PCOS and to investigate the mediating role of immune cells. A total of 179 plasma lipidomes and 731 immune phenotypes were analyzed. We used single nucleotide polymorphisms (SNPs) associated with plasma lipidome levels as instrumental variables and applied statistical methods, including the inverse-variance weighted approach, to assess potential causal relationships.The function of immune phenotypes in regulating the relationship between lipids and PCOS was evaluated through mediation analysis. RESULTS: Ten lipid-immune pathways mediating the association between plasma lipidomes and PCOS were identified. Elevated levels of phosphatidylcholines and triacylglycerols increased the risk of PCOS by modulating immune markers such as HLA DR on B cells and CD28 on regulatory T cells. Conversely, phosphatidylinositol (18:1_18:2) demonstrated a protective effect against PCOS through CD33 on myeloid-derived suppressor cells. Six specific plasma lipidomes were causally linked to PCOS risk, including phosphatidylcholine (18:1_20:4) and triacylglycerol (50:4), which increased risk, and phosphatidylinositol (18:1_18:2), which lowered risk. Additionally, 31 immune phenotypes were identified as causally associated with PCOS, with 27 increasing risk and 4 offering protective effects. CONCLUSION: This study provides evidence that immune phenotypes mediate the relationship between plasma lipidomes and PCOS. These findings highlight the potential of targeting both lipid metabolic processes and immune pathways as novel therapeutic strategies for managing PCOS.