The Inflammatory-Immune Axis in Thyroid Disease: A Mendelian Randomization Study

Background: An increasing body of research has highlighted a close association between circulating inflammatory proteins and thyroid diseases. However, whether this relationship is causal or if immune cells act as intermediaries remains uncertain. Methods: In this study, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis using data from genome-wide association studies (GWAS) to investigate the potential causal relationships between circulating inflammatory cytokines/proteins, immune cells, and three thyroid diseases: Graves' disease (GD), Hashimoto's thyroiditis (HT), and thyroid cancer (TC). We conducted MR analysis using five methods, with the inverse variance-weighted (IVW) approach as the primary method. Sensitivity analyses were performed to assess horizontal pleiotropy and heterogeneity. To enhance result reliability, we applied a False Discovery Rate (FDR) correction to control for multiple testing biases. Lastly, we utilized a two-step MR design to explore the potential mediating role of immune cells in these causal relationships. Results: Our findings demonstrated a negative association between CCL19 and GD, suggesting that higher levels of CCL19 may be associated with a lower risk of developing GD. Additionally, CCL19 showed a positive correlation with FSC-A on CD4+ T cells, indicating that elevated CCL19 levels are linked to larger cell sizes (FSC-A) in CD4+ T cells. Moreover, FSC-A on CD4+ T cells was inversely associated with GD, suggesting that larger CD4+ T cells (with higher FSC-A) may be linked to a reduced risk of GD. These results indicate that immune cells may act as intermediaries in the pathway involving circulating inflammatory proteins and GD. Conclusion: The study establishes a causal relationship between circulating inflammatory proteins and immune cells in relation to GD, with immune cells serving as intermediaries in the pathway between inflammatory proteins and GD risk.