A system view and analysis of essential hypertension

Abstract

Objectives: The goal of this study was to investigate genes associated with essential hypertension from a system perspective, making use of bioinformatic tools to gain insights that are not evident when focusing at a detail-based resolution.

Methods: Using various databases (pathways, Genome Wide Association Studies, knockouts etc.), we compiled a set of about 200 genes that play a major role in hypertension and identified the interactions between them. This enabled us to create a protein-protein interaction network graph, from which we identified key elements, based on graph centrality analysis. Enriched gene regulatory elements (transcription factors and microRNAs) were extracted by motif finding techniques and knowledge-based tools.

Results: We found that the network is composed of modules associated with functions such as water retention, endothelial vasoconstriction, sympathetic activity and others. We identified the transcription factor SP1 and the two microRNAs miR27 (a and b) and miR548c-3p that seem to play a major role in regulating the network as they exert their control over several modules and are not restricted to specific functions. We also noticed that genes involved in metabolic diseases (e.g. insulin) are central to the network.

Conclusion: We view the blood-pressure regulation mechanism as a system-of-systems, composed of several contributing subsystems and pathways rather than a single module. The system is regulated by distributed elements. Understanding this mode of action can lead to a more precise treatment and drug target discovery. Our analysis suggests that insulin plays a primary role in hypertension, highlighting the tight link between essential hypertension and diseases associated with the metabolic syndrome.

FIGURE 1

Flowchart describing the methodology used in this study.

FIGURE 2

Hypertension gene list tree-like map indicating subsystem functional annotations. Shaded areas are regions with a high representation of various pathways and systems affecting blood-pressure regulation (the sympathetic activity components, marked by a yellow border, appear in five regions of the map, the other modules are unique). Annotation was performed manually based on gene ontology annotations and uniprot gene descriptions (see Functional Classification section and Table S2 in Supplemental Digital Content for functional assignments, http://links.lww.com/HJH/A894).

FIGURE 3

Phenotypic abnormalities associated with hypertension gene list. Chart of phenotypic abnormalities generated by Webgestalt. Branches represent relevant major human systems and diseases; enriched annotations are marked in red. Phenotypes are taken from the Human Phenotype Ontology Website (http://human-phenotype-ontology.github.io/).

FIGURE 4

Hypertension network regulation. Tree-like representation of the hypertension protein interaction map, showing genes controlled by specific regulators. Circled genes are regulated by enriched elements: Blue – SP1 transcription factor, Green – microRNA548c, Red – microRNA27 (detailed target list in Supplemental Digital Content Table S6, http://links.lww.com/HJH/A894).