Abstract
Multiple environmental exposures elevate the risk of cardiometabolic diseases (CMDs), yet the impact of combined co-exposures, and their protein-mediated mechanisms remain underexplored. Among 366,261 UK Biobank participants, this study identified five distinct exposure patterns through clustering analysis: Air and Noise Pollution, Social Deprivation, Blue and Green Space, Health Behaviors and Reference. Notably, the Social Deprivation pattern showed the highest CMDs risk, with hazard ratios ranging from 1.15 to 1.40. Inflammatory and immune proteins were associated with all co-exposure patterns. The Air and Noise Pollution and Social Deprivation patterns demonstrated that the common mediating proteins included CDCP1, CXCL17, FGF21, GDF15 and IGFBP4. CXCL13, CA6, SDC1, and PTN mediated Healthy Behaviors, while MMP12 mediated Blue and Green Space pattern. This study offers etiological insight into the comprehensive human environment, draws attention to the population experiencing health disadvantages as a result of co-exposure to social stressors, and elucidates protein-mediated mechanisms linking environmental exposures to disease.