Mendelian Randomization Reveals Causal Pathways Between Plasma Protein Quantitative Trait Loci and Graves'Disease Mediated by Immune Cells

Graves disease (GD) is an autoimmune disorder characterized by hyperthyroidism caused by thyroid-stimulating antibodies (TRAb) activating the thyroid-stimulating hormone receptor (TSHR). Current treatments, including antithyroid drugs, radioactive iodine therapy, and surgery, can control hormone secretion but fail to prevent the immune systems persistent attacks on the thyroid gland. This highlights the need for in-depth research into the immune pathogenesis of GD to develop novel therapeutic strategies. The study results showed that several key pQTLs, including ACE, PMM2, FCRL4, and DPEP1, are significantly associated with GD. Further investigation revealed that ACE inhibitors (ACEIs) are potentially relevant for GD treatment. These inhibitors are not only widely used in the treatment of hypertension and cardiovascular diseases but also exhibit immune-regulatory effects. For example, by modulating the activity of T cells and B cells, ACEIs have demonstrated anti-inflammatory effects in models of various immune-related diseases. This study is the first to combine pQTLs with immune cell regulatory mechanisms to explore their impact on the pathogenesis of GD. By integrating genetic variants, immune cell phenotypes, and causal relationship analysis, we not only validated previously reported GD-related pQTLs but also identified new candidate signals and pathways. These findings deepen our understanding of GD pathogenesis and provide a foundation for developing precision therapies and combination treatments targeting GD and related autoimmune diseases.