Immune Cell Causality and Glucocorticoid Trade-Off in Frozen Shoulder: Integrative MR-RNA-Seq Analysis

Objectives: Frozen shoulder (FS) is characterized by chronic inflammation and fibrosis of the joint capsule, yet the causal roles of immune cell subtypes remain unclear. This study aimed to identify immune cell traits causally associated with FS and evaluate the potential impact of glucocorticoids (GCs) on these immune signatures. Methods: A two-sample Mendelian randomization (MR) analysis was performed using genome-wide association study data for 731 immune cell traits and FS. RNA sequencing (RNA-seq) of FS and control capsular tissues was performed to validate immune cell-related signatures and immune infiltration patterns. MR analysis was further used to investigate the relationship between GCs, FS, and immune cell traits. Results: MR identified seven immune cell traits as potential risk factors and 17 as potential protective factors in FS. RNA-seq confirmed the up-regulation of five of these traits, which positively correlated with the inflammatory, fibrotic and angiogenic features of FS pathology. Notably, GCs showed no causal association with FS but were negatively associated with a protective immune cell trait. Conclusions: Our findings reveal a complex immune cell landscape underlying FS, characterized by both pathogenic and protective immune traits. The integration of MR and RNA-seq analyses highlights potential therapeutic targets and suggests that the immunological consequences of GC therapy warrant further investigation.