Graves'disease (GD) is a prevalent autoimmune disorder characterized by hyperthyroidism and thyroid dysfunction, driven by thyroid receptor antibodies (TRAb) that activate the thyroid-stimulating hormone receptor (TSHR). Current treatments manage hormone levels but do not address the underlying immune-mediated pathology, highlighting the need for novel therapeutic strategies. This study employs Mendelian randomization (MR) to investigate the causal relationships between plasma protein quantitative trait loci (pQTL) and GD, with a focus on the mediating role of immune cells. Utilizing data from the deCODE Genetics study, FinnGen, and the GWAS Catalog, we identified 24 pQTLs associated with GD, including 10 protective and 14 risk factors. Further mediation MR analysis revealed 34 immune phenotypes linked to GD, of which 10 pQTLs mediated the effects through 14 specific immune phenotypes. Notably, angiotensin-converting enzyme (ACE) emerged as a significant mediator, influencing IgD−CD27− B cells and CD39+ CD4+ T cells. Additionally, potential drug associations were identified, including ACE inhibitors and cilastatin, suggesting new avenues for therapeutic intervention. This study is the first to integrate pQTLs with immune cell-mediated mechanisms using MR, providing novel insights into the pathogenesis of GD and identifying potential targets for future drug development.

The authors have declared that no competing interests exist.

The author(s) received no specific funding for this work.

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