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Heart Failure Regulatory Gene Revealed in Tissue Transcriptome Study

NEW YORK (GenomeWeb) – A team led by researchers at Stanford University has identified a regulatory gene, PPP1R3A, that appears to fall at the center of a genetic network associated with heart failure.

For a study published online today in Nature Communications, the investigators reached into transplant center operating rooms to collect nearly 1,400 heart samples originating from individuals with or without heart failure. Based on gene expression and genotyping profiles for these cases and controls — combined with cardiac expression quantitative trait locus (eQTL) analyses — they put together regulatory gene networks representing healthy hearts and heart failure.

"Regardless of how the heart deteriorates, we believe there's one final, common pathway that ultimately leads to heart failure," senior author Euan Ashley, a professor of medicine, genetics, and  biomedical data science at Stanford, said in a statement.

The PPP1R3A gene appeared to play a central regulatory role in both the healthy and the disease networks, though it showed distinct connections in each. In neonatal rat ventricular myocyte cells and in a mouse model designed to mimic blood pressure overload, meanwhile, the team saw protection from heart failure when the gene was missing.

Based on these results, Ashley speculated that "[i]f we were able to inhibit this gene somehow in humans, we could potentially have a therapeutic drug that could protect patients from heart failure."

"We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure," he and his colleagues wrote.

For their study, the researchers collected 1,352 human heart samples, focusing in on 177 failing and 136 healthy donor heart samples for their array-based genotyping and left ventricle gene expression analyses. In the failing hearts, for example, they saw enhanced expression of 793 genes, including NPPA and NPPB, and lower-than-usual expression of SERCA2A and more than 800 other genes.

From there, the team conducted network analyses based on nearly 8,000 genes with the most variable expression between samples with or without heart failure, coming up with gene co-expression and regulatory networks that highlighted heart failure-related genes in pathways of metabolism, cardiac remodeling, excitation-contraction coupling, and sarcomeres and contraction.

By incorporating case and control genotypes, meanwhile, the researchers narrowed in on more than 1,500 cardiac eQTLs in the heart failure cohort and 936 cardiac eQTLs in the healthy heart controls — eQTL collections that were compared with one another and to regulatory or genome-wide association findings reported in the past.

At the network connectivity level, the team noted, the most pronounced differences between the healthy and failing hearts involved the PPP1R3A gene, prompting follow-up studies to dial down or remove the gene in rat cell line models of cardiac function and in mice models with transaortic constriction to model blood pressure overload. Results from those and other analyses pointed to the possibility of protecting against heart failure in some at-risk individuals by interfering with PPP1R3A.

In the in vitro rat cell experiments, for example, the authors found that "reduction of PPP1R3A expression slows cellular [heart failure] pathology and its associated signaling in vitro by acting as a central regulator in the network of hypertrophy- and [heart failure]-relevant pathways."

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