Multi-omic insight into the causal networks of arsenic-related genes in the pathogenesis of type 2 diabetes mellitus

The development of type 2 diabetes mellitus (T2DM) is closely associated with environmental arsenic exposure. This study aimed to investigate the genetic link between arsenic-related genes (ARGs) and T2DM through summary-data-based Mendelian randomization (SMR), colocalization testing, and integrated multi-omics functional analysis. Human-derived ARGs were systematically curated from the Comparative Toxicogenomics Database (CTD). We conducted SMR analyses integrating expression quantitative trait loci (eQTL), protein QTL (pQTL), and methylation QTL (mQTL) data with T2DM GWAS summary statistics sourced from the DIAGRAM consortium. Subsequent functional investigations included single‑cell expression profiling to delineate cell‑type‑specific mechanisms and protein‑protein interaction network construction to identify core regulatory modules, and quantitative real‑time PCR (qPCR) validation of the identified genes. Multi-omics analyses revealed that 179 ARGs were functionally enriched in response to oxidative stress and in the cellular response to oxidative stress. SMR revealed 22 expression-level, 7 protein-level, and 45 methylation-level causal associations with T2DM risk. The key drivers included CD14 (expression OR 1.04, 95 % CI 1.02–1.07, P HEIDI = 0.03; protein OR 1.04, 95 % CI 1.01–1.08, P HEIDI = 0.02) and HIF1A (multivariable MR P < 0.01 across three methods). Integrated multi-omics evidence further highlighted CD14 (a mediator of oxidative stress and immune dysfunction in macrophages), AKR1C1 (an oxidative stress and inflammatory modulator), GSR (a central enzyme in glutathione redox homeostasis), PRDX1 (an antioxidant and redox sensor), and UGT1A6 (a factor in β-cell resistance to oxidative damage), which exhibited concordant protein-expression trends. Single-cell profiling revealed ARG dysregulation in expanded T2DM immune populations, with CD14 significantly upregulated in macrophages. PPI networks demonstrated functional interplay among core genes that regulate glutathione metabolism under arsenic exposure in T2DM development. RT-qPCR analysis of MIN6 cells showed that exposure to 5 µM NaAsSO₂ markedly increased Cd14 and Prdx1 expression ( P < 0.05), while Gsr exhibited a slight, non-significant upward trend. Consolidated multi-omics evidence establishes environmental arsenic exposure as a critical etiological factor in T2DM, advances mechanistic insights into disease pathogenesis, and delineates complex genetic causal pathways underlying T2DM development. • Investigating pollutant-disease causality through SMR-based approaches. • Multi-omics evidence establishes arsenic as critical T2DM factor. • Five arsenic-responsive targets implicated in T2DM pathogenesis identified. • Single cell RNA-seq and PPI analysis were used to validate ARGs functionally.