Mendelian Randomization and Transcriptomics Analysis Reveal Potential Relationships Between Lipids, Immune Cells and PCOS

Abstract

Background: It has been noted that plasma lipid levels are closely associated with polycystic ovary syndrome (PCOS). Immune cells have also been recognized as critical indicators for evaluating the impact of lipids on disease progression. However, there is still a lack of conclusive causal evidence as to whether immune cells mediate the relationship between lipids and PCOS.

Methods: This study used a two-step two-sample Mendelian randomisation (TSMR) analysis to explore the causal relationship between plasma lipid groups and PCOS, and the mediating role of immune cells in this relationship. Transcriptome analysis was used to further explore the relationship between lipid metabolism, immunity, and PCOS.

Results: The inverse variance weighted (IVW) method and Bayesian weighted Mendelian randomized (BWMR) method identified six plasma lipid groups that exhibited causal effects on PCOS, with no evidence of reverse causality. Eighteen immune cell traits are strongly associated with PCOS. TSMR analysis identified SSC-A on CD4+ as the key factor mediating the causal association of PC (0:18:1_20:4) and PI (18:1_18:2) with PCOS, with mediating effects of -0.003 (95% CI [-0.017, 0.012]) and 0.003 (95% CI [-0.021, 0.026]), respectively. Functional enrichment analysis revealed that PCOS was strongly associated with numerous immune pathways. Immune infiltration evaluation results indicated significant disparities in the distribution of a substantial number of immune cells, especially for all types of CD4+ T cells. Furthermore, Metabolic inference analysis revealed that fatty acid biosynthesis is closely related to PCOS.

Conclusion: Our results provide genetic and transcriptomic evidence substantiating the potential relationship between lipids, immune cells, and PCOS. CD4+ T cells might be key mediators in the causal association between lipids and PCOS. Comprehending this relationship could enhance treatment and prevention strategies for PCOS through the comprehensive management of lipid irregularities. Further experimental studies are required to elucidate the detailed mechanisms involved in this relationship.

Keywords: Mendelian randomization; immune cell; plasma lipid; polycystic ovary syndrome; transcriptomics analysis.

Figure 1

Study design.

Figure 2

MR analyzed six lipids for causal association with PCOS. (A) TSMR and BWMR analysis revealed a causal association between 6 plasma lipid groups and PCOS. (B) Forest plot of the results of the reverse analysis. (C) Scatter plot and “leave-one out” of causal relationship between 6 plasma lipid groups and PCOS.

Figure 3

Continued.

Figure 3

Two-step MR analysis of forest graphs. (A) Forest plot of causal relationship between immune cells and PCOS. (B) Forest plot of causal relationship between plasma lipid groups and immune cells.

Figure 4

Gene Identification and Functional Enrichment Analysis Results. (A) Heat map and volcano map on GSE34526. (B) 10 Bubble plots of GO results and KEGG results for PCOS-expressed genes.

Figure 5

PCOS is associated with immune infiltration. (A) Comparison of levels of infiltration of 28 immune cells. (B) Comparison of levels of infiltration of 16 immune cells. (C) Comparison of levels of infiltration of 13 immune cells function (red for PCOS, blue for control, *p < 0.05). (D) The boxplot showed that the biosynthesis of relevant fatty acids was significant between PCOS and control group.