A gene that plays a vital role in determining people’s susceptibility to a range of potentially fatal vascular conditions, such as heart attacks, has been pinpointed.
The discovery advances understanding of the underlying causes of a wide range of serious health conditions, including hardening of the arteries, and, say researchers from the University of Virginia’s School of Medicine, moves the medical profession a step closer to new treatments and preventative measures that could help people live longer, healthier lives.
Principal investigator, Clint L Miller, PhD, of UVA’s Center for Public Health Genomics and Departments of Biochemistry and Molecular Genetics and Public Health Sciences, said: “The first step towards translating the knowledge of population risk for vascular disease is disentangling the fundamental cellular processes that could be affected.
“Ideally, this can be done systematically in disease-relevant models. By gaining insight into the gene regulatory networks that underlie specific vascular disease pathways, we can develop more tailored interventions or risk metrics for patients.”
Lifestyle choices such as smoking, sedentary behaviour, and a diet heavy in red meat play major roles in the development of vascular conditions such as coronary artery disease, which is a leading cause of death worldwide.
But inherited genetic material also shapes a person’s risk. Understanding precisely how, however, has been a major challenge for scientists.
This is because the subtle changes that take place in blood vessels over time are extremely complex. In coronary artery disease, for example, scientists have determined that genes that affect risk can be found at more than 300 locations on a person’s chromosomes.
That’s a vast area for scientists to explore.
The new discovery from Clint Miller and his collaborators published in the scientific journal Circulation Research, identifies a gene – known as FHL5 – that directs an entire network of units of heredity and processes.
The research team describe FHL5 as akin to a general deploying troops on the battlefield.
That makes it an extremely attractive molecule for scientists seeking to unravel the targetable pathways for new treatments or prognostic tools as they work to prevent the harmful changes that contribute to vascular diseases.
Clint Miller. Credit: Dan Addison | UVA Communications
Clint Miller said: “We hope this work serves as a template for future studes to investigate the functional consequences of perturbing key regulators in the vessel wall. Translating this knowledge to the clinic will require ongoing interdisciplinary collaborations, and we look forward to ultimately seeing the impact of these genetic studies.”
To understand how the FHL5 encoded protein functions, Clint Miller and his team evaluated its effect on smooth muscle cells, which form the structure of arteries.
They found that when FHL5 was too active, the cells began to accumulate too much calcium – known as calcification.
This is a key step in atherosclerosis, the build-up of harmful plaque in the arteries that can lead to heart attacks, strokes and other serious health problems.
Further, the excess gene activity contributed to other critical cellular activities related to vascular disease.
But FHL5’s role doesn’t stop there. Instead, the scientists found, it has a far-reaching effect on other genes and cellular processes that shape the ‘remodelling’ that occurs in the arteries over time.
“By mapping the downstream effectors of vascular remodelling, we hope to shed light on preventative mechanisms,” Clint Miller explained. “Unbiased genetic studies led us to this specific cofactor.
“However, studying its regulatory network could explain its link to several vascular diseases.”
