Dissecting Causal Relationships Between Immune Cells, Plasma Metabolites, and PCOS: Evidence From Mediating Mendelian Randomization Analysis

Xia-li Wang,1,2,&ast; Yi-fang He,2,&ast; Shi-kun Chen,3 Jing Cheng,4 Xiu-ming Wu5 1Department of Clinical Medicine, Quanzhou Medical College, Quanzhou, 362000, People’s Republic of China; 2Department of Ultrasound, Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People’s Republic of China; 3Department of Clinical Laboratory, Quanzhou Taiwan Investment Zone Disease Prevention and Control Center, Quanzhou, 362000, People’s Republic of China; 4Quanzhou Science and Technology Center, Quanzhou Medical College, Quanzhou, 362000, People’s Republic of China; 5Department of Ultrasound, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiu-ming Wu, Department of Ultrasound, Quanzhou First Hospital Affiliated to Fujian Medical University, No. 1028 Anji South Road, Quanzhou, Fujian Province, People’s Republic of China, Tel +86 13615916725, Email [email protected]: The relationship between Polycystic ovary syndrome (PCOS) and immune dysregulation, along with metabolic disturbances, remains unclear. This study used Mendelian Randomization (MR) to investigate causal relationships between immune cells, PCOS, and possible metabolite mediators.Methods: We explored the genetic-level relationship between immune cells and PCOS, focusing on metabolites as potential mediators. Data from genome-wide association studies (GWAS) included 731 immune cell types (n=3757), 1400 plasma metabolites (n=8299), and PCOS cases (n=797) versus controls (n=140,558). Bidirectional MR analysis examined immune-PCOS relationships, while two-step MR and mediation analysis identified metabolites as potential mediators. The inverse variance-weighted (IVW) method was used for primary causal assessment, with sensitivity analysis validating results.Results: We identified a total of 33 immune cells that were associated with increased or decreased risk of PCOS (P < 0.05), and these immune cells were also associated with alterations in certain metabolite levels (P < 0.05). Among them, 12 immune cells were found to influence the occurrence of PCOS through the mediation of 17 metabolites. Notably, the effects of Myeloid DC %DC, NKT AC, CD20 on CD20- CD38-, CD25 on memory B cell, and HLA DR on CD33dim HLA DR+ CD11b+ were mediated by multiple metabolites on PCOS development. Similarly, histidine betaine (hercynine) levels and alpha-ketoglutarate to ornithine ratio mediated the association of more than one immune cell with PCOS.Conclusion: This study highlights 12 immune cells impacting PCOS through 17 metabolites, advancing the understanding of immune mechanisms in PCOS risk and suggesting potential therapeutic approaches targeting immune modulation.Keywords: PCOS, immunity, metabolites, mediating role, MR analysis