Function Found for Mysterious Heart Disease Gene

June 2014

Oxidative stress in mitochondria (shown in red)
A genetic variant of the gene SPG7 is associated with increased risk of heart disease. University of Ottawa Heart Institute researchers have shown that this variant increases cardiovascular risk by initiating oxidative stress in mitochondria (shown in red) that leads to chronic inflammation and long-term damage of blood vessels. The mitochondria in an unstressed cell would show primarily as green.

Finding a gene associated with disease is one thing. Understanding how it increases the likelihood of contracting that disease can be quite another, especially a complex condition like heart disease. After five years, Heart Institute researchers now know how one genetic variant works and suspect that it contributes to the development of heart disease through processes that promote chronic inflammation and cell division.

So-called pleiotropic genes—genes that affect more than one aspect of human health at the same time—complicate the search for the genetic factors that contribute to complex conditions like diabetes and coronary artery disease. A new study from researchers at the University of Ottawa Heart Institute, published in April in Cell Reports, sheds light on one such pleiotropic gene that likely influences cardiovascular health.

Researchers at the Ruddy Canadian Cardiovascular Genetics Centre first identified a variant in a gene called SPG7 as a potential contributor to coronary artery disease several years ago, but it didn’t pass the stringent statistical tests to definitively label it as a risk factor. This is common with pleiotropic genes, because their effect on multiple physiological traits makes their contribution to any one trait hard to tease out, explained Alexandre Stewart, PhD, the study’s senior author.

Five years ago, Naif Almontashiri, a doctoral student at the Ruddy Centre, made understanding how this gene works the focus of his time at the Heart Institute. His project expanded into an international effort that included researchers across Canada and in Europe who supplied additional expertise in protein function and structure analyses, as well as statistical methods.

It turned out that the gene in question holds instructions for making a protein called SPG7. This protein resides in mitochondria—the tiny power plants of cells that produce the energy cells need to function. SPG7’s job is to help break down and recycle other damaged proteins within the mitochondria.

Normally, SPG7 requires a partner protein to “turn it on” and start this breakdown process. But, in people who carry the genetic variant in question, SPG7 can turn itself on in certain circumstances, leading to increased production of free radicals and more rapid cell division. These factors contribute to inflammation and atherosclerosis.

“We think this variant would definitely heighten the state of inflammation, and we know that inflammation affects diabetes and heart disease,” said Dr. Stewart. Interestingly, the variant also makes people more resistant to the toxic side effects of some chemotherapy drugs.

From an evolutionary perspective, this resistance could help such a genetic variant gain a stable place in the human genome, he added. And indeed, between 13 and 15 per cent of people of European descent possess this variant. “The way the cell detoxifies nasty chemicals is by oxidizing them and degrading them. And if your cells are better at oxidizing foreign things, that could protect you against infection or exposure to toxins. But such an increased inflammatory response may also cause collateral damage that could be detrimental over a lifetime.” For example, it could cause scarring of blood vessels walls, leading to coronary artery disease.

Studies like this one that look to explain the function of genes will be an ongoing priority for research at the Ruddy Centre. Many genes have been shown to contribute to heart disease and the Heart Institute had a hand in many of those discoveries. Now, much work lies ahead in understanding the pathways and mechanisms that tie these genes to heart health.

“The idea of mitochondria contributing to inflammation isn’t new,” concluded Dr. Stewart. “But what is new is that we’ve found one of the switches that regulate this process. We’re excited, because once you know where the switches are, you can start looking for ways to turn them on and off.”