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NHLBI-led Team Untangles Gene Networks Involved in Blood Pressure Regulation

NEW YORK (GenomeWeb) – Using network approaches, researchers from the US National Heart, Lung, and Blood Institute and their colleagues combined genome-wide association and mRNA expression data to home in on sets of co-expressed genes that appear to influence blood pressure regulation.

As they reported in Molecular Systems Biology today, the NHLBI-led team drew on data from more than 3,600 people participating in the Framingham Heart Study to identify four potentially causal gene modules and key driver genes contained within them.

"Our work was able to pinpoint several gene networks closely linked to the regulation of blood pressure," first author Tianxiao Huan from NHLBI said in a statement.

In addition, Huan and her colleagues traced the function of one key driver gene — SH2B3 — to response to angiotensin II infusion in a mouse model, indicating that this approach may help identify new treatment targets.

For this study, Huan and her colleagues examined the gene expression profiles of 3,679 Framingham Heart Study participants of European descent who were not taking an antihypertensive drug. They correlated gene expression changes they observed in this cohort with systolic blood pressure, diastolic blood pressure, and hypertension and, after accounting for age, BMI, gender, and other factors, came up with 83 associated genes.

At the same time, the researchers constructed gene co-expression networks from that gene expression data to develop gene co-expression network modules that they then also correlated to blood pressure phenotypes. Of these 27 gene co-expression network modules, seven were significantly associated with either systolic or diastolic blood pressure, the researchers said.

While that set of 83 blood pressure-related genes wasn't significantly enriched for any gene ontology terms, the seven gene co-expression network modules were linked to a variety of functions, including chromatin modification, immune cell-mediated cytotoxicity, inflammatory response, and more. This suggested to the researchers that genes involved in a range of biological processes are tightly co-regulated with respect to blood pressure.

Using a SNP set enrichment analysis approach, the researchers found that four of the gene co-expression network modules appeared to be potentially causal and that more than a dozen genes in those modules appeared to contribute to their association with blood pressure regulation.

For instance, one SNP, dubbed rs3184504, had been linked with blood pressure through a genome-wide association study, and it is linked with the expression of four genes in the set of genetically inferred causal blood pressure genes.

Using blood Bayesian networks and protein-protein interaction networks other groups had developed, Huan and her colleagues further zoomed in on key driver genes by testing whether the surrounding region of each gene in those four gene co-expression network modules was enriched for other potentially causal blood pressure genes.

These top key driver genes, they noted, were involved in subnetworks that appeared to regulate blood pressure-related genes.

For example, a missense SNP in an exon of SH2B3 has been associated with blood pressure and hypertension in a GWAS and is linked to expression changes in 10 other genes the researchers identified. These genes, Huan and her colleagues said, were enriched for activity in the intracellular signaling cascade, T-cell activation, and T-cell differentiation. This SH2B3-subnework was also enriched for genes known to be linked to blood pressure.

Previous work had linked SH2B3 to blood pressure regulation, Huan and her colleagues said, but how it had its effect wasn't clear.

Mice lacking the SH2B3 gene, they noted, had normal baseline blood pressure, though it became elevated in response to a low dose of angiotensin II, an effect not seen in wild-type mice.

In addition, RNA sequencing of the whole-blood transcriptomes from wild-type and Sh2b3-/- mice indicated that more than 2,240 genes were differentially expressed between the two, especially ones involved in immune and inflammatory response. These genes significantly overlapped with the SH2B3 genetic subnetwork, and those overlapping genes were enriched for ones involved in the intracellular signaling cascade and T-cell activation, the researchers reported.

"Moving forward, it should be possible to study additional key driver genes in this way, which should help in our efforts to identify novel targets for the prevention and treatment of hypertension," Huan added.