Proteome‐Wide Mendelian Randomization Identifies Natriuretic Peptide‐B and Novel Proteins as Potential Regulators of Pulse Pressure in Humans

Abstract

Background

Large‐artery stiffness (LAS) significantly contributes to cardiovascular morbidity and death and is characterized by increased pulse pressure (PP). The biology underlying large‐artery stiffness in humans remains incompletely understood.

Methods and Results

We investigated associations between PP and circulating levels of 2941 proteins among 53 016 UK Biobank participants. Analyses were adjusted for age, sex, mean arterial pressure, body mass index and stroke volume. Interaction analyses assessed the effect modification by sex on these relationships. We evaluated causal associations between plasma protein levels and PP, using inverse variance–weighted Mendelian randomization as the main analysis and Bayesian colocalization as a sensitivity analysis. A 5% false discovery rate threshold was used to account for multiple comparisons. Measured levels of 871 proteins were significantly associated with PP when adjusting for age, sex, mean arterial pressure, and body mass index, and 61 remained significantly associated after further adjusting for stroke volume. Top associations included NPPB (natriuretic peptide B), thrombospondin‐2, paraoxonase‐2, and sclerostin. Genetic analyses indicated that genetically predicted levels for 16 proteins were significantly associated with PP after false discovery rate correction, including fibroblast growth factor 5 (β_IVW per SD change in protein levels=0.47 [95% CI, 0.34–0.61]), NPPB (β_IVW=−1.40 [95% CI, −1.85 to −0.95]), insulin‐like growth factor binding 3 (β_IVW=−1.143 [95% CI, −1.57 to −0.71]), and furin (β_IVW, 1.31 [95% CI, 0.88–1.73]).

Conclusions

Using complementary epidemiological approaches to triangulate findings, our study identifies novel proteins with a putative causal effect on PP. Notably, our findings identify NPPB with high statistical confidence. This may have potentially impactful implications given the current availability of Food and Drug Administration–approved medications to boost NPPB effects.

Nonstandard Abbreviations and Acronyms

ARCH – Active‐Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk

FRAME – Fracture Study in Postmenopausal Women With Osteoporosis

LAS – large‐artery stiffness

MR – Mendelian randomization

NPPB – natriuretic peptide B

PP – pulse pressure

pQTLs – protein quantitative trait loci

PWV – pulse wave velocity

SMOC2 – SPARC‐related modular calcium binding 2

SV – stroke volume

Clinical Perspective

What Is New?

Our study identified hundreds of novel proteins associated with pulse pressure that may serve as biomarkers of large‐artery stiffness; our causal inference analyses identified 16 proteins with a putative causal effect on pulse pressure, warranting further investigation for their potential role as therapeutic candidates.

The identification of novel biomarkers of pulse pressure highlights the importance of conducting proteomic screening and triangulating evidence from observational, genetic, and clinical evidence; this approach may guide in identifying novel therapeutic avenues and may facilitate the early diagnosis of large‐artery stiffness and downstream target organ damage.

What Are the Clinical Implications?

Notably, our study identified natriuretic peptide B to be potentially causally associated with pulse pressure with a high level of statistical confidence; this may have important implications given the current availability of FDA‐approved medications to boost natriuretic peptide B effects.

The increasing prevalence of the aging population worldwide is an unprecedented demographic phenomenon expected to drive a growing wave of age‐related health care and economic burden globally.¹^,²^,³ Aging and multiple pathological conditions that are acquired over the lifetime lead to increased risk of large‐artery stiffness (LAS).⁴ A clinical consequence of LAS is an increased systolic blood pressure during left ventricular ejection and a decreased diastolic pressure during diastolic runoff, resulting in a higher pulse pressure (PP).⁵ Increased LAS and PP lead to excess pulsatility in the microvasculature, particularly in low‐resistance target organs such as the kidney and the brain,⁵ and impacts left ventricular afterload and coronary perfusion pressure via its effects on pulsatile load.⁵ As such, a higher PP, which is a direct consequence of increased LAS, has been shown to be associated with target‐organ damage (including worsening of kidney function,⁶^,⁷^,⁸^,⁹ cognitive decline,⁵^,⁸ and new‐onset diabetes¹⁰^,¹¹^,¹²), and is established as an independent risk factor for cardiovascular disease and all‐cause death.¹³ Understanding the molecular basis of PP elevation may provide novel insights underlying LAS in humans, thereby leading to the improved diagnosis and treatment of LAS and its downstream clinical manifestations.

Genome‐wide association of plasma proteomics, applied among large‐population cohorts,¹⁴^,¹⁵^,¹⁶^,¹⁷ has paved the way for enhanced insights into the genetic regulation of the plasma proteome, providing a unique opportunity to evaluate the causal effects of individual proteins on the development and progression of various conditions. Mendelian randomization (MR) is a powerful method that enables the identification of causal effects in humans, overcoming some limitations of traditional observational studies such as residual confounding and reverse causality. MR leverages the naturally randomized allocation of genetic variants among the population as instrumental variables, analogous to treatment allocation in a randomized controlled trial. Under certain assumptions, this approach estimates the causal effects of exposures on outcomes.¹⁸ Pairing plasma proteomics with human genetics for causal inferencing can provide important insights on the putative causal relationship between the human proteome and various traits and conditions. However, studies investigating the proteome in relation to the manifestation of LAS, including PP, have not been conducted.

In this study, we aimed to (1) evaluate the relationship between plasma proteins and PP in middle‐aged adults from the UK Biobank and (2) assess the putative causal associations of specific plasma proteins on PP using MR and Bayesian colocalization analysis.

Methods

The study design is illustrated in Figure 1. This study is reported using the Strengthening the Reporting of Observational Studies in Epidemiology–Mendelian Randomization guidelines¹⁹^,²⁰ (https://www.strobe‐mr.org) (Data S1). The UK Biobank study was approved by the UK Biobank’s North West Multi‐Centre Research Ethics Committee. All participants provided written informed consent.