Identification of Circulating Proteins Associated With Blood Pressure Using Mendelian Randomization

Area of Science:

• Cardiovascular Genetics
• Biomarker Discovery
• Hypertension Research

Background:

• Hypertension is a major modifiable risk factor for cardiovascular disease and mortality.
• The underlying pathophysiological mechanisms of hypertension are not fully understood.
• Mendelian randomization (MR) is a valuable tool to assess causal relationships, minimizing bias.

Purpose of the Study:

• To identify novel circulating proteins associated with blood pressure using a comprehensive biomarker screen.
• To leverage Mendelian randomization (MR) for robust causal inference in hypertension research.

Main Methods:

• A large-scale Mendelian randomization (MR) study screened 227 blood biomarkers for associations with blood pressure metrics.
• Genetic data from the ORIGIN and International Consortium for Blood Pressure studies were combined with large replication cohorts (UK Biobank).
• Further MR analyses explored relationships with cardiovascular risk factors and outcomes to elucidate mechanisms.

Main Results:

• Six biomarkers demonstrated significant associations with blood pressure after multiple testing correction.
• Novel associations included urokinase-type plasminogen activator (uPA) with systolic blood pressure, adrenomedullin (ADM) with systolic blood pressure and pulse pressure, interleukin 16 (IL16) with diastolic blood pressure, and cellular fibronectin (cFn) and insulin-like growth factor-binding protein 3 (IGFBP3) with pulse pressure.
• Replication in the UK Biobank confirmed most findings, with further MR analyses linking NT-proBNP to stroke, IGFBP3 to diabetes, and cFn to BMI.

Conclusions:

• Novel circulating protein biomarkers associated with blood pressure were identified using Mendelian randomization.
• These identified biomarkers hold potential for improving cardiovascular risk assessment.
• The identified markers may serve as future therapeutic targets for hypertension management.