Integrating Proteomics and Mendelian Randomization to Identify New Therapeutic Targets

Hypertension is a major risk factor for cardiovascular disease, stroke, renal failure, and other end-organ damage. It is estimated that over 1.4 billion people worldwide suffer from hypertension, with a significant portion remaining undiagnosed or inadequately treated. The pathophysiology of hypertension is multifaceted, involving complex interactions between genetic, environmental, and physiological factors that influence vascular resistance, cardiac output, and sodium homeostasis.

At the core of hypertension is increased systemic vascular resistance, primarily driven by endothelial dysfunction, arterial stiffness, and vascular remodeling¹. The endothelium plays a key role in maintaining vascular homeostasis by regulating vasodilation, inflammatory responses, and thrombosis. Dysfunction in endothelial signaling pathways—characterized by reduced nitric oxide bioavailability, increased oxidative stress, and chronic low-grade inflammation—contributes to sustained hypertension². The renin-angiotensin-aldosterone system is another fundamental pathway implicated in hypertension. Angiotensin II, the key effector molecule of this system, promotes vasoconstriction, sodium retention, and inflammation, exacerbating blood pressure elevation and vascular damage. Beyond classical mechanisms, emerging evidence highlights the role of immune dysregulation and metabolic disturbances in hypertension^{3, 4}. Chronic low-grade inflammation, driven by immune cell infiltration into vascular tissues and upregulation of pro-inflammatory cytokines, exacerbates vascular dysfunction and increases blood pressure⁵.

Recent proteomic and genomic studies suggest that hypertension is influenced by circulating proteins involved in immune modulation, endothelial integrity, mitochondrial function, and metabolic regulation^{6, 7}. Identifying novel protein biomarkers and therapeutic targets is critical for improving hypertension management, particularly in patients with resistant hypertension^{8, 9}. In this issue of AJH, a study led by Dr. Huizhen Yu¹⁰ provides a significant advancement in hypertension research by integrating large-scale proteomic and genomic data to identify potential therapeutic targets. The authors examined the plasma proteome of 7,213 European American participants from the “Atherosclerosis Risk in Communities” study¹¹ and incorporated genome-wide association study data from FinnGen R10¹², consisting of 102,864 hypertension cases and 289,117 controls. A comprehensive analytical approach, including cis-Mendelian randomization and Bayesian colocalization analysis, was applied to evaluate the causal effects of circulating proteins on hypertension risk. Sensitivity analyses were performed to validate robustness, and independent replication was conducted using cis-protein quantitative trait loci genetic instruments from the deCODE database.

By leveraging large-scale proteomic and genomic datasets, the study offers a robust framework for understanding hypertension’s molecular underpinnings and guiding precision medicine approaches. The study identified 18 plasma proteins with significant associations with hypertension following Bonferroni correction¹⁰. Of these, ERAP1 (Endoplasmic Reticulum Aminopeptidase 1) and ACVRL1 (Activin A Receptor Like Type 1) were consistently validated as potential therapeutic targets. ERAP1 exhibited a strong inverse correlation with hypertension risk, suggesting its role in modulating immune pathways relevant to blood pressure regulation. Similarly, ACVRL1, a protein involved in endothelial function, was found to be protective against hypertension, underscoring the importance of vascular integrity in blood pressure control.

ERAP1 and hypertension

ERAP1 is an aminopeptidase involved in antigen processing and immune system regulation. It is primarily recognized for its role in trimming peptides for major histocompatibility complex class I presentation. However, emerging evidence suggests that ERAP1 also plays a crucial role in cardiovascular physiology¹³. ERAP1 is involved in the regulation of vasoactive peptides, including angiotensin II, a key mediator of hypertension. Dysregulation of ERAP1 activity may contribute to altered angiotensin II degradation, leading to heightened vasoconstriction and sodium retention¹⁴. Additionally, ERAP1 influences inflammation through its effects on antigen presentation and immune cell activation¹⁵. Chronic inflammation is increasingly recognized as a driver of hypertension, with pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 contributing to endothelial dysfunction and vascular remodeling. The inverse correlation between ERAP1 and hypertension risk suggests a protective role, potentially through mechanisms involving immune modulation and vascular homeostasis. This finding aligns with recent research indicating that genetic variants in ERAP1 influence blood pressure regulation and cardiovascular outcomes^{15, 16}. Future studies should explore the therapeutic potential of ERAP1 modulation in hypertension, particularly in patients with inflammatory comorbidities.

ACVRL1 and Endothelial (Dys)Function in Hypertension

ACVRL1 is a key regulator of endothelial cell function and vascular remodeling. It is a member of the transforming growth factor-beta receptor family, which plays a critical role in maintaining vascular integrity¹⁷. Mutations in ACVRL1 are associated with hereditary hemorrhagic telangiectasia, a disorder characterized by abnormal vascular development and susceptibility to hemorrhage¹⁸. Identifying ACVRL1 as a protective factor against hypertension underscores the importance of endothelial homeostasis in blood pressure regulation. Endothelial dysfunction, characterized by impaired nitric oxide production, increased endothelin-1 activity, and reduced angiogenic capacity, is a hallmark of hypertension. ACVRL1 signaling modulates endothelial responses to hemodynamic stress, promoting adaptive vascular remodeling and preventing excessive vasoconstriction¹⁹.

Given its role in vascular health, targeting ACVRL1 may offer a novel therapeutic avenue for hypertension. Enhancing ACVRL1 activity could improve endothelial resilience and reduce vascular stiffness, thereby lowering blood pressure. However, given the complexity of transforming growth factor-beta signaling, potential adverse effects, such as abnormal angiogenesis, must be carefully considered. Future research should investigate the feasibility of ACVRL1-targeted therapies in preclinical hypertension models.

Of note, Huizhen Yu and colleagues¹⁰ employed several advanced analytical techniques that enhance the reliability and validity of their findings. Cis-Mendelian randomization minimizes confounding and reverse causality by leveraging genetic variants associated with circulating protein levels to infer causality¹⁹. Unlike traditional observational studies, which are prone to biases, this approach provides a robust framework for identifying causal relationships. Equally important, colocalization analysis distinguishes true causal associations from spurious findings due to linkage disequilibrium²⁰, strengthening the evidence for ERAP1 and ACVRL1 as hypertension-related proteins. Replication using independent datasets ensures that the associations identified are not due to random chance. The consistency of ERAP1 and ACVRL1 findings across different cohorts reinforces their translational potential as therapeutic targets. Moreover, multiverse sensitivity analysis evaluates the robustness of causal relationships across different analytical models, reducing the likelihood of false-positive results.

Despite its strengths, the study has several limitations that warrant consideration. The population primarily consisted of European Americans, limiting the generalizability of findings to other ethnic groups. Given the genetic diversity in hypertension susceptibility, future studies should include multi-ethnic cohorts to validate these associations. While Mendelian randomization minimizes confounding, it does not account for post-translational modifications or environmental influences that may affect protein function. Integrating proteomic analyses with functional studies is essential for a comprehensive understanding of these targets. Albeit ERAP1 and ACVRL1 emerge as promising therapeutic candidates, their precise mechanisms in blood pressure regulation require further investigation. The findings highlight the importance of immune regulation and endothelial function in blood pressure control, providing new avenues for drug development. Future research should focus on validating these findings in diverse populations, elucidating the mechanistic pathways linking ERAP1 and ACVRL1 to hypertension, and exploring the therapeutic potential of targeting these proteins. Dedicated investigations should assess whether pharmacological modulation of these proteins can achieve meaningful blood pressure reduction in (animal models of) hypertension.