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Environmental exposures influence disease risk, yet their underlying biological mechanisms remain poorly understood. We present the Human Exposomic Architecture of the Proteome (HEAP), a framework and resource integrating genetic, exposomic, and proteomic data to uncover how lifestyle influences disease through plasma proteins. Applying HEAP to 2,686 proteins in 53,014 UK Biobank participants, we identified over 11,000 exposure-protein associations across 135 lifestyle exposures. Exposures explained a substantial portion of proteomic variation, with 9% of proteins more influenced by lifestyle than genetics. Mediation analyses across 270 diseases revealed proteins linking exposures to disease risk; for instance, IGFBP1 and IGFBP2 mediated the effects of exercise and diet on type 2 diabetes. These findings were supported by concordant proteomic shifts in interventional studies of exercise and GLP1 agonists, underscoring therapeutic relevance. HEAP provides a resource for advancing disease prevention and precision medicine by revealing mechanisms through which lifestyle shapes human health.