Over the past year, Shoemaker’s blood pressure has finally been brought under control, thanks to Calgary hypertension specialist Norm Campbell. Campbell experimented with giving Shoemaker smaller combined doses of three families of antihypertensive medicines she had already been taking. But despite his success with Shoemaker, Campbell is the first to admit that treating hypertension remains, at best, “an inexact science.”
Cracking the genetic code for hypertension would mean a higher likelihood of developing a targeted treatment. That’s why l’Université de Montréal molecular geneticist Alan Deng aims to make the diagnosis and treatment of hypertension more precise and effective through his genetic research. Working with rats, Deng is attempting to identify genes that can lead to, or exacerbate, hypertension. While it’s been estimated that genes play a role in up to 40 percent of high blood pressure cases, so far very little is known about the root causes and mechanisms behind hypertension.
As Deng explains: “There are several causes of hypertension and, right now, we don’t know which cause is yours. So it becomes something of a shot in the dark, and we may be delivering a treatment that is not suitable for you.”
In the early 1990s, Deng attracted international attention when he discovered the location of chromosomes carrying important hypertension genes in “salt-sensitive” rats. The introduction of salt to these rats’ diets speeds up the onset and increases the severity of their hypertension. This mirrors the fact that many humans are sensitive to salt. For such individuals, a salt-heavy diet may increase the likelihood of developing high blood pressure and can exaggerate symptoms.
Deng continues to succeed in narrowing down the regions where these genes exist and examining how individual genes might influence blood pressure. His laboratory is considered a global flagship of genetic research in hypertension using animal models.
Research using rats allows for the kind of genetic manipulation that would be impossible to do in humans. “We can develop genetically identical strains of rats, one with high blood pressure and one with low blood pressure,” says Deng. “We then introduce a specific gene to these strains and see whether the blood pressure goes up or down.”
The results of such animal studies will have human applications, thanks to collaborations with people like Pavel Hamet, a Canada Research Chair in Predictive Genomics at l’Université de Montréal. An internationally recognized authority on hypertension, Hamet is the lead investigator in a study of 120 French-Canadian families in Quebec’s Saguenay-Lac-St-Jean region. Many of the families are direct descendents of the original settlers who came to New France in the 17th century and their genealogical records from that point onwards have been computerized.
In 2005, Hamet and his collaborators published results showing that they had identified 46 chromosomal areas associated with hypertension, each containing hundreds of genes. Family members were screened for 250 clinical characteristics, and their genome is now being scanned against some 50,000 known genetic markers. While there is no reason to believe that people from the Saguenay have higher rates of hypertension than other Canadians, Hamet says the genes that cause hypertension should be easier to find because the family histories are so well documented.
Together, the research being conducted by Hamet, Deng, and their colleagues promises to shed new light on the enduring mysteries surrounding hypertension. For Shoemaker, and millions of her fellow sufferers, that’s good news.
An estimated five million adult Canadians suffer from high blood pressure, which is a leading risk factor for heart disease, stroke, and renal failure. Current antihypertensive medication works in only about 50 percent of patients, and precious time and confidence is lost as physicians search for the right combinations. Many patients are not getting the full benefits of their medication—something that could be rectified if treatment targeted appropriate genes.
“The more often patients have to change medications, the less likely they are to take the drug,” says Norm Campbell, Canadian Chair in Hypertension Prevention and Control at the University of Calgary, and a spokesman for the Heart and Stroke Foundation of Canada. “In other words, they lose confidence in our abilities as physicians, and start to suspect we don’t know what we’re doing.”
The genetic research taking place in Montreal could help this situation. For example, if a gene for salt-sensitive hypertension is found, it can be used to more readily identify patients who are sensitive to salt. Genetic screening could easily and cheaply be done through a simple blood test. Right now, the only way to determine salt-sensitivity is to hospitalize patients for several days and strictly control their diets.
Identifying responsible genes for hypertension will open up a host of new opportunities for developing more effective drugs tailored to individual causes. It should also help predict and prevent unwanted side effects.
Over the long term, genetic discoveries could lead to tests given early in life to identify individuals with a predisposition to develop high blood pressure. Ultimately, such research could lead to a vaccine to prevent hypertension altogether.
Alan Deng works with hypertension researchers in Canada and abroad. His Canadian collaborators are located at the Montreal Heart Institute, the Ottawa Heart Institute, Ottawa Hospital, and the Centre hospitalier de l'Université de Montréal. His international collaborators are at the University of Louisville, Japan’s University of Osaka, and Yunnan University of China.
Pavel Hamet’s Saguenay project involved partnerships with the Hôpital de Chicoutimi (also part of l'Université de Montréal), and researchers from five universities: École Polytechnique de Montréal, l’Université du Québec à Chicoutimi, McGill University, University of Ottawa, and Massachusetts Institute of Technology (MIT). He also has a longstanding collaboration with researchers of the Medical College of Wisconsin.