Integrative network analysis reveals molecular mechanisms of blood pressure regulation

Abstract

Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP-associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3,679 individuals, using network approaches. BP transcriptomic signatures at the single-gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression-related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP-related genes were uncovered. As proof-of-concept, we validated SH2B3, one of the top key drivers, using Sh2b3−/− mice. We found that a significant number of genes predicted to be regulated by SH2B3 in gene networks are perturbed in Sh2b3−/− mice, which demonstrate an exaggerated pressor response to angiotensin II infusion. Our findings may help to identify novel targets for the prevention or treatment of hypertension.

Transcriptome-Wide Analysis Identifies Novel Associations With Blood Pressure

“…14,19,38 A Sh2b3 −/− knockout leads to markedly elevated BP in response to low dose of angiotensin II. 16 …”

Linking inflammation and hypertension via LNK/SH2B3

“…Recognizing that genes, rather than working in isolation, interact with other genes in complex regulatory networks, Levy and colleagues designed a novel systems biology framework to integrate gene expression (transcriptomic) data with blood pressure GWAS and cellular network modeling to determine if perturbations in gene subnetworks are linked to hypertension [*14]. They used genetic and transcriptomic data (>17,000 measured gene transcripts isolated from whole blood) from 3,679 Framingham Heart Study participants who were not receiving antihypertensive drug treatment.…”

“…At a false discovery rate of <0.05, there were 2,240 differentially expressed genes, supporting a large-scale perturbation of the transcriptome in LNK −/− mice. These gene signatures showed significant overlap with the genes identified by the in silico model and were enriched for genes involved in inflammation and T cell activation as predicted by the SH2B3 subnetworks [*14]. …”

Role of Axl in T-Lymphocyte Survival in Salt-Dependent Hypertension

“…A recent human study (3,679 untreated hypertensive individuals; The Framingham Heart Study) showed that apoptosis, T cell activation, and T cell differentiation are enriched in a gene-gene interactions network for a mutation in SH2B adaptor protein 3 (SH2B3) that cause increased blood pressure (BP) 11 . Not surprisingly, one of the sub-networks of the whole blood transcriptome included the Gas6/Axl pathway in relation to high BP genetic susceptibility 11 .…”

“…Not surprisingly, one of the sub-networks of the whole blood transcriptome included the Gas6/Axl pathway in relation to high BP genetic susceptibility 11 . Previous genetic studies in a Sabra rat model of salt-sensitive hypertension identified Axl as a candidate gene 12 .…”