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

Authors

Qi Jiang, Bin Li, Yunfei Ma, Wanying Shi, Liang Ding, Naifan Hu, Yunhao Zhao, Yingli Qu, Zheng Li, Peijie Sun, Yifu Lu, Donghui Zhang, Huibin Jin, Zhi Li, Ying Zhu, Feng Zhao, Beifang Yang, Sheng Wen, Ying Zhu, Yuebin Lv, Jianbo Tian, Xiaoming Shi, Xiaoping Miao

Published in

Journal of hazardous materials. Volume 517. Pages 142905. Jul 07, 2026. Epub Jul 07, 2026.

Abstract

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.

PMID:
42748818
Bibliographic data and abstract were imported from PubMed on 17 Sep 2026.

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