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Blood pressure, plasma proteins, and cardiovascular diseases: a network Mendelian randomization and observational
Devendra Meena1, Jingxian Huang1, Alexander Smith1
1Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, White City Campus, 90 Wood Lane, London W12 0BZ, UK.
Insights
This study reveals key plasma proteins causally linked to blood pressure (BP) and cardiovascular diseases (CVDs). BP significantly mediates the effects of these proteins on heart attack and stroke risk.
Area of Science:
- Cardiovascular Genetics
- Proteomics
- Systems Biology
Background:
- Understanding the biological pathways of elevated blood pressure (BP) and cardiovascular diseases (CVDs) is crucial.
- The proteomic landscape offers insights into molecular determinants of BP regulation and its impact on CVD.
Purpose of the Study:
- To investigate the causal relationships between plasma proteins, BP, and CVD using a proteome-wide Mendelian randomization approach.
- To identify specific proteins involved in BP regulation and their potential roles in coronary artery disease (CAD) and stroke.
Main Methods:
- A proteome-wide Mendelian randomization (MR) study analyzed 2007 plasma proteins for causal effects on BP (systolic and diastolic).
- Proteins associated with BP were further assessed for causal links to CAD and stroke, employing network MR and Bayesian colocalization.
- Observational analyses in UK Biobank examined protein associations with BP and incident CVD events.
Main Results:
- 242 proteins were associated with BP, with 48 linked to CAD or stroke. Four proteins (ACOX1, FGF5, FURIN, MST1) showed robust genetic support.
- FURIN and FGF5 were linked to BP and stroke; ACOX1, FGF5, and MST1 showed potential causal effects on CAD.
- Network MR indicated BP mediation for 30.5%-77.2% of the protein effects on CAD and stroke.
Conclusions:
- Key plasma proteins with causal roles in BP regulation and CVD risk were identified.
- Blood pressure was confirmed as a significant mediator of protein effects on CAD and stroke.
- These findings offer insights into hypertension-related CVD mechanisms and potential therapeutic targets.
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.
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