Genome-wide interactions with cadmium exposure in dysglycemia: Populational effects and molecular insights.

Dysglycemia is a complex metabolic disorder governed by the interplay between environmental exposures and genetic factors, yet the precise molecular mechanisms driving these gene-environment (G×E) interactions remains poorly understood. Here, we characterized the population-level landscape and molecular causality underlying the interactions between cadmium (Cd), a widespread environmental toxicant, and genetic susceptibility loci in dysglycemia. By conducting a Genome-wide Environmental Interaction (GWEI) study within a sub-cohort of the China National Human Biomonitoring (CNHBM) cohort (N = 1298), we identified 29 genetic risk loci that significantly interact with Cd burden to exacerbate elevated fasting plasma glucose levels. Functional enrichment integrated with metabolomic profiling unmasked a profound multi-omics convergence, positioning epigenetic modifications (e.g. H3K27me3) and zinc-finger transcription factors (e.g. OVOL2, KLFs) as central regulatory hubs that disrupt metabolic homeostasis. To establish causality, we demonstrated that the rs11743277 A>T variant at the lead G×E locus functions as a Cd-responsive enhancer element, facilitating recruitment of TEAD3 and upregulating TICAM2 expression in CRISPR/Cas9-edited HepG2 cells, especially upon Cd exposure. This initiates a TICAM2-mediated inflammatory response, with elevated pro-inflammatory cytokines (IFN-β, TNF-α, IL-6) impairing downstream insulin signaling and glucose utilization. Collectively, these findings establish a robust paradigm for G×E interactions in complex metabolic disorders, revealing how environmental stressors reprogram genetic susceptibilities through molecular checkpoints and paving the way for tailored, precision-prevention strategies in environmental health.