Treg cells as a protective factor for Hashimoto`s thyroiditis: a Mendelian randomization study

Background and objectives Hashimoto's thyroiditis (HT), a chronic autoimmune disorder impacting thyroid function, is a growing public health concern. The relationship between Treg cells and HT has been extensively studied, with Treg cells considered crucial in suppressing HT progression. However, these studies have mainly been observational, limiting our understanding of Treg cells' impact on HT risk. Leveraging large datasets, we utilized Mendelian randomization (MR) analysis to examine the causal association between Treg cell biomarkers and HT, providing additional validation for these relationships. Methods Comprehensive two-sample Mendelian randomization analysis was performed to determine the causal association between Treg cells signatures and HT in this study. Based on publicly available genetic data, we explored causal associations between 165 Treg cells signatures and HT risk. Results The European cohort study has identified five Treg cell phenotypes that causally protect against HT risk. Resting Treg %CD4 (OR = 0.975, 95% CI = 0.954 similar to 0.998, P = 0.030); CD4 on resting Treg (OR = 0.938, 95% CI = 0.882 similar to 0.997, P = 0.041; CD28- CD8dim %CD8dim (OR = 0.983, 95% CI = 0.969 similar to 0.998, P = 0.030); CD25 on CD39+ resting Treg (OR = 0.926, 95% CI = 0.864 similar to 0.991, P = 0.026); 5) CD28 on activated & secreting Treg (OR = 0.969, 95% CI = 0.942 similar to 0.996, P = 0.025). The Asian cohort study has identified four Treg cell phenotypes negatively correlated with the risk of HT. CD25hi %T cell (OR = 0.635, 95% CI = 0.473 similar to 852, P = 0.002); CD4 Treg %CD4 (OR = 0.829, 95% CI = 0.687 similar to 1.000, P = 0.050); CD127-CD8br %T cell (OR = 0.463, 95% CI =0.311 similar to 0.687, P< 0.001); CD3 on resting Treg (OR = 0.786, 95% CI = 0.621 similar to 0.994, P = 0.044). Conclusion Our study has demonstrated the close connection between Treg cells and HT by genetic means, thus providing foundational basis for future research.