Blood pressure, plasma proteins and cardiovascular diseases: a network Mendelian randomisation and observational study
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Background and Aims
The biological pathways leading to elevated blood pressure (BP) and subsequent cardiovascular diseases (CVDs) remain incompletely understood. Investigating the proteomic landscape of BP and its overlap with CVD could provide critical insights into the molecular determinants and pathways involved in BP regulation and its subsequent effect on CVD.
Methods
A proteome-wide Mendelian randomization (MR) study was conducted by leveraging genetic instruments from 2007 plasma proteins to assess their causal effects on BP (systolic and diastolic BP). Proteins showing strong associations with BP were further analyzed for potential causal effects on coronary artery disease (CAD) and stroke subtypes. Network MR was performed to estimate the proportion of CVD risk mediated through BP. Bayesian colocalization was applied to determine whether identified associations share common causal variants. Observational associations were examined in UK Biobank participants to assess associations between proteins, BP, and incident CVD events using linear regression and Cox proportional hazard models.
Results
Proteome-wide MR identified 242 proteins associated with BP, of which 48 were also linked to CAD or stroke, with four (ACOX1, FGF5, FURIN, MST1) also supported by genetic colocalization analyses (FDR 5% and PP ≥70%). Genetically predicted FURIN and FGF5 were strongly associated with BP and stroke risk, while ACOX1, FGF5, and MST1 exhibited potential causal effects on CAD. Network MR suggested that a substantial proportion of their effect on CAD and stroke (30.5%–77.2%) was mediated through BP regulation. Observational analyses further supported these findings.
Conclusions
This study identifies key plasma proteins with potential causal roles in BP regulation and CVD risk, highlighting BP as a major mediator of their effects on CAD and stroke. These findings provide novel insights into the molecular mechanisms underlying hypertension-related CVD and identify promising protein targets for further investigation.
The biological pathways leading to elevated blood pressure (BP) and subsequent cardiovascular diseases (CVDs) remain incompletely understood. Investigating the proteomic landscape of BP and its overlap with CVD could provide critical insights into the molecular determinants and pathways involved in BP regulation and its subsequent effect on CVD.
Methods
A proteome-wide Mendelian randomization (MR) study was conducted by leveraging genetic instruments from 2007 plasma proteins to assess their causal effects on BP (systolic and diastolic BP). Proteins showing strong associations with BP were further analyzed for potential causal effects on coronary artery disease (CAD) and stroke subtypes. Network MR was performed to estimate the proportion of CVD risk mediated through BP. Bayesian colocalization was applied to determine whether identified associations share common causal variants. Observational associations were examined in UK Biobank participants to assess associations between proteins, BP, and incident CVD events using linear regression and Cox proportional hazard models.
Results
Proteome-wide MR identified 242 proteins associated with BP, of which 48 were also linked to CAD or stroke, with four (ACOX1, FGF5, FURIN, MST1) also supported by genetic colocalization analyses (FDR 5% and PP ≥70%). Genetically predicted FURIN and FGF5 were strongly associated with BP and stroke risk, while ACOX1, FGF5, and MST1 exhibited potential causal effects on CAD. Network MR suggested that a substantial proportion of their effect on CAD and stroke (30.5%–77.2%) was mediated through BP regulation. Observational analyses further supported these findings.
Conclusions
This study identifies key plasma proteins with potential causal roles in BP regulation and CVD risk, highlighting BP as a major mediator of their effects on CAD and stroke. These findings provide novel insights into the molecular mechanisms underlying hypertension-related CVD and identify promising protein targets for further investigation.
Date Issued
2026-01-14
Date Acceptance
2025-09-03
Citation
European Heart Journal, 2026, 47 (14), pp.331-342
ISSN
0195-668X
Publisher
Oxford University Press
Start Page
331
End Page
342
Journal / Book Title
European Heart Journal
Volume
47
Issue
14
Copyright Statement
© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
10.1093/eurheartj/ehaf725
Subjects
Proteomics
Blood pressure
Mendelian randomization
Cardiovascular disease
Publication Status
Published
Date Publish Online
2025-10-09