Integrated multi-omics analysis identifies TBC1D10C as an NK- and T cell-associated diagnostic biomarker in childhood...

Childhood obesity is a growing global health crisis associated with an increased risk of metabolic and cardiovascular diseases in adulthood. While accumulating evidence implicates immune dysregulation in obesity pathogenesis, the specific transcriptional alterations of immune cells, particularly NK cells and T cells in the context of childhood obesity, and their potential as non-invasive diagnostic biomarkers, remain largely unexplored. Here, we investigated the transcriptional alterations of NK cells and T cells in childhood obesity and evaluated their potential as non-invasive diagnostic biomarkers. To this end, we integrated bulk RNA-seq datasets (GSE205668 and GSE87493), adipose single-cell RNA-seq data (GSE159960), and blood qPCR validation to identify NK- and T-cell-related diagnostic biomarkers for childhood obesity. Differential expression analysis and WGCNA were applied to the bulk datasets to derive obesity-associated candidates, and single-cell RNA-seq was used to define immune-cell composition, infer NK-cell pseudotemporal dynamics, and quantify cell-cell communication. Genes shared between the bulk and single-cell analyses were prioritized using an ensemble machine-learning workflow comprising 110 model configurations and five feature-selection methods. TBC1D10C expression was validated by qPCR in an independent cohort of 29 children. Transcriptome-based analyses indicated reduced relative representation of NK cells and T cells in childhood obesity, with altered transcriptional programs and inferred impairment of NK-CD4 + T-cell communication. A 13-gene NK- and T-cell-based diagnostic signature was derived, and TBC1D10C was consistently prioritized by all feature-selection methods. The signature showed good discrimination between childhood obesity and controls across datasets (AUC 0.753-0.808), and comparable performance was observed for TBC1D10C alone. Enrichment analyses associated higher TBC1D10C expression with immune pathways, including Th1/Th2 differentiation, IL-17 signaling, and NK cell-mediated cytotoxicity. qPCR confirmed significant upregulation of TBC1D10C in peripheral blood from children with obesity. Across independent cohorts and platforms, TBC1D10C was identified as a reproducible NK- and T-cell-associated biomarker for childhood obesity, and immune dysregulation relevant to obesity pathophysiology may be reflected by its expression. Therefore, we propose TBC1D10C as a promising diagnostic biomarker and highlight its potential role in the immunopathology of childhood obesity.