Mendelian Randomization Analysis of Immune Cell Targets in Hashimoto's Thyroiditis Progression to Hypothyroidism.

INTRODUCTION

This study aimed to identify immune cell traits that may contribute to the progression of Hashimoto's Thyroiditis (HT) to autoimmune hypothyroidism (AIH) using Mendelian Randomization (MR) analysis.

METHODS

We integrated publicly available Genome-Wide Association Study (GWAS) datasets and performed two-sample MR to evaluate the causal effects of 731 immune cell phenotypes on HT and AIH. Single-Nucleotide Polymorphisms (SNPs) were selected as Instrumental Variables (IVs). Multiple MR approaches, including Inverse Variance Weighting (IVW), MR-Egger, and weighted median methods, were applied to ensure result robustness.

RESULTS

Thirty-three immune cell traits showed evidence of a causal association with HT, and thirty- nine traits were linked to AIH. Eight immune cell phenotypes were found to have causal relationships with both HT and AIH: CD39+ activated Treg %, activated Treg, CD8dim NKT AC, CD27 on IgD- CD38-, CD3 on CM CD8br, CD3 on secreting Treg, CD3 on CD4 Treg, CD62L on monocyte, and CD45RA on naive CD8br (p<0.05). Reverse MR did not support the causal effects of HT or AIH on these immune traits.

DISCUSSION: The results emphasize the contribution of regulatory T cells (Tregs) and cytotoxic T-- cell-related phenotypes in HT pathogenesis and its progression toward hypothyroidism. Dysregulation of immune tolerance, potentially involving impaired Treg function and heightened cytotoxic activity, may accelerate thyroid follicular damage. These findings highlight possible cellular targets for immunomodulatory interventions and align with current evidence regarding T-cell dysfunction in autoimmune thyroid disease.

CONCLUSION

Eight immune traits with consistent causal associations across both HT and AIH were identified, providing insights into disease mechanisms and potential therapeutic avenues. Future research should validate these findings experimentally and across diverse populations.