Review of UK Biobank data identifies plasma protein mediators in cardiometabolic disease progression.

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medRxiv Published April 19, 2026 Medically reviewed April 25, 2026 Study authors: qian, h.; Wu, C.; Li, B.; Rosenzweig, A.; Wang, M. DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Consider plasma proteins as potential biomarkers, noting Mendelian randomization supports causal roles for 84 proteins.

This observational review examines data from the UK Biobank cohort involving 53,030 participants. The scope covers mediating roles of plasma proteins in secondary disease development across conditions including diabetes, hypertension, dyslipidemia, cardiovascular disease, neurological disease, renal disease, pulmonary disease, glomerular disease, and Alzheimer's disease. The study compares models using other plasma proteins or traditional clinical risk factors.

The analysis identified 1,461 significant mediation pathways involving 395 unique plasma proteins across three primary diseases and 18 subsequent conditions. For prediction accuracy regarding glomerular disease risk in hypertension, inclusion of top mediating proteins improved accuracy by approximately 14% measured by C index. Additionally, Mendelian randomization supported causal roles for 84 proteins highlighted as having potential causal roles.

The authors note that molecular mediators linking primary cardiometabolic diseases to downstream disease development, particularly clinically accessible biomarkers, remain incompletely understood. While the study nominates promising targets for biomarker development and therapeutic intervention, causality is not inferred for proteins not supported by Mendelian randomization. The follow-up duration was not reported, and safety data such as adverse events or tolerability were not reported. Practice relevance is limited to identifying potential targets rather than immediate clinical application.

Study Details

EvidenceLevel 5

PublishedApr 2026

View Original Abstract ↓

Diabetes, hypertension, and dyslipidemia are major risk factors for cardiovascular, neurological, renal, and pulmonary diseases. However, the molecular mediators linking these primary cardiometabolic diseases to downstream disease development, particularly clinically accessible biomarkers, remain incompletely understood. Here, we investigated the mediating roles of plasma proteins in secondary disease development using data from 53,030 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 include GDF15 consistently mediating the diabetes cardiovascular disease link and ADM mediating the hypertension pulmonary disease pathway. Identified mediating proteins are highly enriched in receptor mediated signaling and molecular interaction pathways. Mendelian randomization supports causal roles for 84 proteins, highlighting their potential as therapeutic targets. Moreover, these protein mediators improved predictive accuracy for secondary disease risk compared with models using other plasma proteins or traditional clinical risk factors from machine learning methods. For example, among individuals with hypertension, the inclusion of top mediating proteins improved prediction accuracy for glomerular disease risk by approximately 14% measured by C index. Stratification by biomarker defined levels of primary disease control and severity further reveals additional disease pathways and protein mediators, including APOE linking poorly controlled diabetes to increased risk of Alzheimers disease. These findings implicate plasma proteins as key molecular mediators connecting cardiometabolic diseases to their downstream complications and nominate promising targets for biomarker development and therapeutic intervention.