PHACTR1

The Institute is leading the way on groundbreaking research that is changing our understanding of some of the most common cardiovascular diseases.

The PHACTR1 gene has been identified by Professor Jason Kovacic and his team in our Vascular Biology laboratory as one of the most critical genes in cardiovascular disease.

Research into this gene could pave the way for new targeted therapies for heart disease, improving survival rates for millions of people around the world.

What is PHACTR1?

Phosphatase and actin regulator 1 (PHACTR1) is a gene that encodes PHACTR1 protein in the cell. That is, the specific part of our DNA that codes for PHACTR1 can produce a molecule that we call PHACTR1 protein that can circulate inside our cells.

PHACTR1 is thought to play a role in cell movement, but it seems that it likely has many additional functions which are very poorly understood at the present time.

How was PHACTR1 identified as a critical gene in cardiovascular disease?

PHACTR1 has been suspected as an important gene in cardiovascular disease for over a decade, but due to its complexity, prior research efforts have struggled to understand the gene.

Professor Kovacic and his team at the Institute began their research into PHACTR1 in 2020, continuing Professor Kovacic’s initial PHACTR1 research at the Kovacic Laboratory at the Icahn School of Medicine at Mount Sinai in New York.

In February 2022, Professor Kovacic led a team from the Institute, the Icahn School of Medicine at New York's Mount Sinai, and other sites in Europe and the USA that published a study identifying the most critical genes that cause coronary heart disease and trigger heart attacks. The study identified PHACTR1 as being among the top two genes for causing coronary heart disease.

This finding prompted Professor Kovacic and his team to double down on their PHACTR1 research.

What do we know about the links between PHACTR1 and cardiovascular disease?

Our genes can control the levels of PHACTR1 inside our cells. That is, specific variants of our DNA can regulate the expression of PHACTR1 leading to either increased or decreased levels of the PHACTR1 protein.

What makes this gene so important is that our bodies need a very precise level of PHACTR1 to function optimally. Both too little and too much PHACTR1 have been linked to different vascular diseases.

What diseases have been linked to the PHACTR1 gene?

So far, the PHACTR1 gene has been linked to a range of vascular diseases including migraine; atherosclerosis, which can lead to coronary artery disease (CAD) and heart attack; fibromuscular dysplasia (FMD); and spontaneous coronary artery dissection (SCAD).

Increased levels of PHACTR1 have been linked to migraine, FMD and SCAD. FMD affects the elasticity of the arteries, causing the artery walls to be too weak or too stiff. This can lead to arteries narrowing, becoming enlarged or in some cases, tearing of the artery wall. SCAD is a condition that results when an inner layer of one of the blood vessels in the heart tears. Blood seeps between the artery layers, forms a blockage and can slow or block blood flow to the heart.

Decreased levels of PHACTR1 has been linked to increased risk of atherosclerosis, which is the hardening and narrowing of the arteries in the heart. Atherosclerosis is the most common cause of heart disease and raises the risk of having a heart attack.

Due to the complexity and mystery surrounding the PHACTR1 gene, it is possible that further research could uncover links between the gene and other diseases.

What PHACTR1 research is currently being conducted at the Institute?

The Institute’s researchers are engaged in a series of state-of-the art studies at the cellular level to understand exactly how the PHACTR1 gene causes cardiovascular disease.

Professor Kovacic and his team are currently in the process of writing up the first of a series of studies that will explain the specific mechanisms behind how this gene causes heart attack - including what's going wrong at the cellular level regarding the gene, its signalling, and its pathways.

Professor Kovacic and his team are also currently undertaking pre-clinical studies that involve the removal of the PHACTR1 gene to understand what effects this has in the body. So far, the team has identified links with diabetes and other issues, such as body weight changes and changes in cell types.

These unexpected outcomes have further emphasised the complexity and surprises associated with the PHACTR1 gene.

What technology is being used for the Institute’s PHACTR1 research?

Professor Kovacic and his team are using a multi-omics approach to their research. Multi-omics refers to the analysis of multiple data sets, rather than a single data set. This allows researchers to study PHACTR1 at several different levels to gain a more comprehensive understanding of how the gene functions.

This work is made possible by the facilities at the Institute’s Innovation Centre, including the Ion Mobility 6560 mass spectrometer from Agilent.

What is the clinical significance of this research?

Professor Kovacic and his team hope that by better understanding the function of the PHACTR1 gene, they may be able to work out how to control and regulate the gene to treat and potentially prevent diseases associated with PHACTR1.