Causal relationship between IgG N-glycosylation and autoimmune thyroid diseases, and the possible mediating role of immune cells and inflammatory cytokines

Immunoglobulin G N-glycans have been associated with the risk of autoimmune thyroid diseases (AITD). In the present study, we investigated the potential causal relationship between IgG N-glycosylation and AITD risk. Employing 2-sample Mendelian randomization (MR) and mediation analysis, we evaluated the causal associations between IgG N-glycosylation and 4 types of AITD, Graves' disease, autoimmune thyroiditis, autoimmune hyperthyroidism and autoimmune hypothyroidism - using genome-wide association study summary data. Fifteen IgG N-glycan traits were found to have causal relationships with AITD. Moreover, upon considering inflammatory cytokines and immune cell phenotypes as outcomes, 6 inflammatory cytokines and 14 immune cell phenotypes exhibited significant causal relationships with IgG N-glycan traits. Subsequent mediation analyses using 2-step MR revealed that "CD25 on CD24+ CD27+ B cells" mediated the causal association between IGP11 and GD, "HLA DR+ T cell%lymphocyte" mediated the causal association between IGP59 and autoimmune thyroiditis, and "B_NGF" mediated the causal association between IGP59 and autoimmune hyperthyroidism. However, further validation through using multivariable Mendelian randomization (MVMR) indicated that only B_NGF played a mediating role in the causal relationship between IGP59 and autoimmune hyperthyroidism, as other 2 mediators did not yield significant results. This MR study comprehensively assessed the interrelationships among IgG glycosylation, inflammatory cytokines, immune cells, and AITD, identifying potential biomarkers for predicting AITD prognosis and risk.