Qian Hanyu, Wu Chao, Li Bo, Rosenzweig Anthony, Wang Meng
Stanley and Judith Frankel Institute for Heart and Brain Health, University of Michigan Medical Center, Ann Arbor, MI, USA.
Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
medRxiv. 2025 Sep 2:2025.08.29.25334726. doi: 10.1101/2025.08.29.25334726.
Diabetes, hypertension, and dyslipidemia are major risk factors for cardiovascular (CVD), cerebral, and renal diseases (RD). However, the underlying molecular mechanisms, particularly the biological paths linking these primary conditions to downstream diseases remain incompletely understood. In this study, we investigated the role of plasma proteins as mediators of secondary disease development using data from ~50,000 UK Biobank participants. Across three primary diseases and 18 subsequent conditions, we identified 1,461 significant mediation pathways involving 395 unique plasma proteins. Notable examples included GDF15 consistently mediating the diabetes-CVD link and ADM mediating the hypertension-pulmonary disease pathway. Protein mediators of secondary disease development were highly enriched in immune, metabolic, and cytokine-related pathways. Mendelian randomization supported causal roles for 84 proteins, highlighting their potential as therapeutic targets. Moreover, the identified mediating proteins improved predictive accuracy for secondary disease risk compared to other proteins and traditional clinical risk factors from machine learning methods. For example, in individuals with hypertension, the inclusion of top mediating proteins improved prediction accuracy for glomerular disease risk by approximately 14% measured by C-index. Stratified analyses based on disease severity revealed additional disease progression pathways and mediating proteins, such as APOE mediating the association between severe diabetes and Alzheimer's disease. Together, these findings implicate plasma proteins as central molecular mediators linking these primary diseases to subsequent development of a secondary condition and nominate promising targets for biomarker development and therapeutic intervention.
糖尿病、高血压和血脂异常是心血管疾病（CVD）、脑血管疾病和肾脏疾病（RD）的主要危险因素。然而，其潜在的分子机制，尤其是将这些原发性疾病与下游疾病联系起来的生物学途径仍未完全明确。在本研究中，我们利用来自约50000名英国生物银行参与者的数据，研究了血浆蛋白作为继发性疾病发展介导因子的作用。在三种原发性疾病和18种后续病症中，我们确定了1461条涉及395种独特血浆蛋白的显著介导途径。值得注意的例子包括GDF15一直介导糖尿病与CVD的联系，以及ADM介导高血压与肺部疾病的途径。继发性疾病发展的蛋白介导因子在免疫、代谢和细胞因子相关途径中高度富集。孟德尔随机化支持了84种蛋白质的因果作用，突出了它们作为治疗靶点的潜力。此外，与机器学习方法中的其他蛋白质和传统临床危险因素相比，所确定的介导蛋白提高了继发性疾病风险的预测准确性。例如，在高血压患者中，纳入顶级介导蛋白可使肾小球疾病风险的预测准确性提高约14%（以C指数衡量）。基于疾病严重程度的分层分析揭示了额外的疾病进展途径和介导蛋白，如APOE介导严重糖尿病与阿尔茨海默病之间的关联。总之，这些发现表明血浆蛋白是将这些原发性疾病与继发性疾病后续发展联系起来的核心分子介导因子，并为生物标志物开发和治疗干预提名了有前景的靶点。
