Researchers identify rare genetic marker that protects against cardiovascular disease

According to researchers from McMaster University and the Montreal Clinical Research Institute, they have identified a “fountain of youth” in a rare genetic marker that is unique to a few French-Canadian families.

Left: Vascular biologist Richard Austin, medical professor and one of the senior authors of the study. Right: Montreal Clinical Research Institute endocrinologist Michel Chrétien, an emeritus professor at the University of Montreal. Image Credit: Mcmaster University.

Dubbed PCSK9Q152H, the mutation of the PCSK9 gene was originally believed to provide protection from cardiovascular diseases. But new studies have revealed that this mutation may also protect against other human diseases, primarily liver diseases.

According to the investigators, this would enable the few lucky subjects with the PCSK9^Q152H mutant to remain in good health and live longer. The study was recently published in the renowned Journal of Clinical Investigation.

The study was headed by Richard Austin and Paul Lebeau, both vascular biologists from McMaster University, and by Michel Chrétien, an endocrinologist from Montreal Clinical Research Institute and an emeritus professor at the University of Montreal.

These are exciting findings—what we’ve found may represent a kind of fountain of youth. Now we want to see whether we can come up with a gene therapy approach to overexpress this specific mutant gene variant in the liver, and thereby offer an innovative treatment for a number of diseases that normally lead to early death.”

Richard Austin, Study Senior Author and Medical Professor, McMaster University

News of the rare PCSK9^Q152H mutation was initially published in 2011, after the study’s lead clinical investigator, Chrétien, detected it in a French-Canadian family.

The mutated gene is predominantly expressed in the liver and this gene not only lowers an individual’s plasma LDL-cholesterol (“bad”) but also prevents cardiovascular diseases. Chrétien and his IRCM collaborator Hanny Wassef also detected this mutated gene in two other large French-Canadian families.

They observed that individuals carrying this gene mutation are unexpectedly healthy well into their late 80s and mid-90s. Apart from their low risk of cardiovascular diseases and low plasma LDL-cholesterol, their liver function is fully normal when quantified through imaging as well as a comprehensive medical assessment, noted the researchers from the University of Montreal.

But until now, the fundamental mechanism through which the mutation represented a health benefit other than protection from cardiovascular disease continued to be elusive.

In the latest research, the researchers from McMaster University demonstrated that the overexpression of this specific gene variant in the livers of mice that do not carry the PCSK9^Q152H mutation had an unexpected protective effect against dysfunction and injury of their liver.

Overexpression of this gene variant also caused a significant reduction in their circulating PCSK9 concentrations —just as it does in persons, reducing the bad cholesterol of individuals and keeping them in good cardiovascular health.

When we initiated these studies, we had speculated that introducing the mutant PCSK9^Q152H protein into the liver of mice would cause liver injury or dysfunction.”

Richard Austin, Study Senior Author and Medical Professor, McMaster University

But, “to our amazement, overexpression of the mutant gene variant in the livers of mice failed to cause stress in the cellular manufacturing and packaging system called the endoplasmic reticulum, or ER, and actually protected against ER stress-induced liver injury,” added Lebeau.

In laboratory settings, the researchers from McMaster University went on to demonstrate that this mutant gene variant serves as an exclusive co-chaperone protein to stabilize many familiar ER chaperones, such as GRP94 and GRP78, and to boost their protective activity against damage to the liver.

These results from Dr. Austin’s group are particularly gratifying since they experimentally explain that this gene mutation, known to lower cardiovascular accidents, also protects against liver injury and dysfunction, even in individuals who are in their late 80s and mid-90s.”

Michel Chrétien, Emeritus Scientist, Ottawa Hospital Research Institute

“Furthermore, these findings should allow us to determine whether this unique mutation provides additional protection against liver diseases such as cancer, over and above its protective effect against cardiovascular accidents,” Chrétien concluded.