Association Between Circulating Cytokines and Endometriosis: A Mendelian Randomization Study

Abstract

Existing evidence shows the importance of circulating cytokines in studying female reproductive system dysfunction. Endometriosis (EM) is thought to be associated with multiple immune cytokines, but its causality has not been proven. Utilising Genome-Wide Association Study (GWAS) data, we performed Mendelian randomisation (MR) to assess causality between 41 cytokines and EM. Positive Single Nucleotide Polymorphisms (SNPs) were annotated via Multi-marker Analysis of GenoMic Annotation (MAGMA) and intersected with EM-associated genes from Weighted Gene Co-expression Network Analysis (WGCNA). Shared genes underwent single-gene Gene Set Enrichment Analysis (GSEA). The association of shared genes with endometriosis was validated by the quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) method. Two-sample MR identified TNF-Related Apoptosis-Inducing Ligand (TRAIL) as causally linked to EM. Inverse variance weighting (IVW) revealed that elevated TRAIL levels reduced EM risk (β = -0.061, p = 2.267e-6). WGCNA identified DSG 2 (a TRAIL-related gene related to EM). Quantitative analysis based on clinical samples confirmed the low expression of DSG 2 in patients with endometriosis. GSEA indicated DSG 2 participation in many signalling pathways. MR analysis revealed that elevated TRAIL levels significantly reduce the risk of EM. MAGMA and WGCNA analyses identified DSG 2 as a key gene associated with TRAIL. Gene expression analysis combined with GSEA suggested that decreased DSG 2 expression may influence the development of EM through various pathways. These results offer new potential diagnostic markers and therapeutic targets for EM.

Keywords: Mendelian randomization; WGCNA; circulating cytokines; endometriosis.