Multi-omics identifies a T2DM-associated immune-regulatory network modulated by electroacupuncture

Area of Science:

• Immunology
• Genetics
• Metabolic Disorders

Background:

• Emerging evidence links immune system activity to type 2 diabetes (T2DM) pathogenesis.
• Specific genes and molecular mechanisms underlying this association require further elucidation.
• Multi-omics data integration offers a powerful approach to uncover these complex relationships.

Purpose of the Study:

• To investigate the mechanistic link between immune-related genes and T2DM.
• To identify key candidate genes involved in T2DM pathogenesis using genetic and omics data.
• To validate the functional role of identified genes and explore therapeutic interventions.

Main Methods:

• Summary data-based Mendelian Randomization (SMR) and colocalization analyses were performed using immune-related quantitative trait loci (QTL) and genome-wide association study (GWAS) data.
• Key candidate genes were functionally validated in a high-fat diet-induced T2DM mouse model.
• Gene expression levels and the impact of electroacupuncture (EA) treatment were assessed using RT-qPCR.

Main Results:

• SMR and colocalization analyses identified LTBP3 and PLXNB2 as core T2DM-associated genes.
• The T2DM mouse model demonstrated altered expression of Plxnb2 and Ltbp3, alongside coordinated changes in the TGF-β pathway, indicating an immune regulatory network.
• EA intervention significantly modulated the expression of genes within this network, including Plxnb2, Ltbp3, and TGF-β.

Conclusions:

• The study highlights the critical role of immune-related genes, such as LTBP3, PLXNB2, TGF-β, and IgA, in T2DM pathogenesis.
• Findings provide direct evidence for the molecular mechanisms of EA's therapeutic effects in T2DM by demonstrating its modulation of these key genes.
• This research integrates human genetic data with in vivo validation to underscore the importance of immune pathways in T2DM.