Isaac Shakson, Ellis Randall J, Gusev Alexander, Murthy Venkatesh L, Udler Miriam S, Patel Chirag J
Department of Biomedical Informatics, Harvard Medical School, Boston, MA. 02215.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
medRxiv. 2025 May 8:2025.05.07.25327178. doi: 10.1101/2025.05.07.25327178.
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.
环境暴露会影响疾病风险，但其潜在的生物学机制仍知之甚少。我们展示了蛋白质组的人类暴露组结构（HEAP），这是一个整合遗传、暴露组和蛋白质组数据的框架和资源，以揭示生活方式如何通过血浆蛋白影响疾病。将HEAP应用于英国生物银行53014名参与者的2686种蛋白质，我们在135种生活方式暴露中识别出超过11000种暴露-蛋白质关联。暴露解释了蛋白质组变异的很大一部分，9%的蛋白质受生活方式的影响大于遗传因素。对270种疾病的中介分析揭示了将暴露与疾病风险联系起来的蛋白质；例如，IGFBP1和IGFBP2介导了运动和饮食对2型糖尿病的影响。这些发现在运动和GLP1激动剂的干预研究中蛋白质组的一致性变化得到了支持，强调了治疗相关性。HEAP通过揭示生活方式塑造人类健康的机制，为推进疾病预防和精准医学提供了一种资源。
