Plasma Proteomics Linking Primary and Secondary diseases: Insights into Molecular Mediation from UK Biobank Data

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.