Unraveling the connection between Hashimoto's Thyroiditis and non-alcoholic fatty liver disease: exploring the role of CD4+central memory T cells through integrated genetic approaches

Abstract

Purpose: Exploring the connection between Hashimoto's thyroiditis (HT) and non-alcoholic fatty liver disease (NAFLD) through integrated genetic approaches.

Methods: We utilized integrated genetic approaches, such as single-cell RNA sequencing (scRNA-seq) data analysis, Mendelian Randomization (MR), colocalization analysis, cell communication, and metabolic analyses, to investigate potential correlations between HT and NAFLD.

Results: Through the integrated analysis of scRNA-seq data from individuals with HT, NAFLD, and healthy controls, we observed an upregulation in the proportion of CD4⁺central memory (CD4⁺CM) T cells among T cells in both diseases. A total of 63 differentially expressed genes (DEGs) were identified in the CD4⁺CM cells after the differential analysis. By using MR, 8 DEGs (MAGI3, CSGALNACT1, CAMK4, GRIP1, TRAT1, IL7R, ERN1, and MB21D2) were identified to have a causal relationship with HT, and 4 DEGs (MAGI3, RCAN3, DOCK10, and SAMD12) had a causal relationship with NAFLD. MAGI3 was found to be causally linked to both HT and NAFLD. Therefore, MAGI3 was designated as the marker gene. Reverse MR and Steiger filtering showed no evidence of reverse causality. Colocalization analyses further indicated close links between MAGI3 and HT as well as NAFLD. Finally, based on the expression levels of MAGI3, we stratified CD4⁺CM cells into two subsets: MAGI3⁺CD4⁺CM cells and MAGI3^-CD4⁺CM cells. Functional analyses revealed significant differences between the two subsets, potentially related to the progression of the two diseases.

Conclusion: This study delves into the potential connections between HT and NAFLD through integrated genetic methods. Our research reveals an elevated proportion of CD4⁺CM cells within T cells in both HT and NAFLD. Through MR and colocalization analysis, we identify specific genes causally linked to HT and NAFLD, such as MAGI3. Ultimately, based on MAGI3 expression levels, we categorize CD4⁺CM cells into MAGI3⁺CD4⁺CM cells and MAGI3^-CD4⁺CM cells, uncovering significant differences between them through functional analyses.

Keywords: Colocalization analysis; Hashimoto’s thyroiditis; Mendelian Randomization; Non-alcoholic fatty liver disease; Single-cell RNA sequencing.