When Robert Roberts, MD, joined the University of Ottawa Heart Institute as President and CEO in 2004, he came with a mandate: establish the Institute as a world leader in cardiovascular genetics research.
“Over the past 50 or so years, the data have been pretty consistent that somewhere around 50 per cent of heart disease is due to genetic predisposition,” said Dr. Roberts in 2010. “If we’re going to really have comprehensive prevention efforts, we need to know both the lifestyle and genetic risk factors. So, for the genetic part of that, we need to find the genes.”
In almost 10 years of concentrated effort since Dr. Roberts’ arrival, the Heart Institute has succeeded both in discovering a host of genes linked to cardiovascular disease risk and in becoming a recognized leader in the field. Upon joining the Heart Institute, Dr. Roberts actively pursued philanthropic support for what would become the Ruddy Canadian Cardiovascular Genetics Centre, establishing the only genetics centre in Canada—and one of only a few worldwide—dedicated to research into the genetics of heart disease.
The Ruddy Centre opened in 2005, founded on a $5 million gift from John and Jennifer Ruddy and an additional $1.7 million from several other Ottawa-area donors. Dr. Roberts later garnered a $10 million grant from the Canada Foundation for Innovation. With matching provincial funds, $4.7 million of this grant was dedicated to acquiring the equipment and personnel needed by the centre to pursue, on a massive scale, a type of cutting-edge genetics research called genome-wide association studies.
Genome-wide association studies, or GWAS, look for common genetic variations that contribute a small but real increase or decrease in the risk of developing a disease. Because the changes in risk these variations contribute are small, very large populations must be studied to tease out their effect—an expensive and time-consuming effort.
The Ruddy Centre had an early big win in 2007 when it helped the laboratory of Ruth McPherson, MD, PhD, confirm that a gene variant called 9p21 increases the risk of heart disease by up to 40 per cent, regardless of other established risk factors, such as cholesterol, blood pressure and diabetes.
The 9p21 discovery was a landmark for several reasons: It was the first common genetic risk factor for heart disease ever discovered and the first common risk factor for heart disease of any type discovered since cholesterol. What’s more, its impact on an individual’s risk for the disease was substantial. This finding launched the Heart Institute into an ongoing worldwide search for other common genes that influence the risk of heart disease.
Alexandre Stewart, PhD, principal investigator of the Ruddy Centre, remembers going to the American Heart Association meeting to present the results of the 9p21 study and being approached by a German group that wanted to form an international consortium to pool GWAS resources. “I came back and proposed this to Dr. Roberts, and without batting an eyelash, he said, ‘We absolutely have to be part of a consortium. There’s no question—at the rate we’re going, it’s just not going to happen soon enough or fast enough, and we need to join forces,’” said Dr. Stewart. “That was really his Texas sort of big-science mentality: that to be able to answer these big questions, we needed to be working together.”
The resulting consortium, named CARDIoGRAM (for Coronary Artery Disease Genome-Wide Replication and Meta-analysis), consists of leading research institutions from across Europe and North America. CARDIoGRAM went on to identify 13 new genetic variations associated with heart disease and confirm the association of 10 previously identified variants. Only six of these turned out to be related to known risk factors.
“This was a landmark study, and the implications are twofold,” said Dr. Roberts. “First, there’s a whole group of undiscovered mechanisms behind the development of coronary artery disease that is a possible target for drug development. Second, we now have a fair number of genes to screen for in terms of determining risk in the setting of primary prevention.”
As far as locating the genes responsible for coronary artery disease risk goes, “we did what we set out to do,” said Dr. Stewart. This in no way means that the Ruddy Centre’s work is done—the arduous process of understanding how these genes work in the body to affect risk has just begun and will remain the focus of the centre going forward.
“Mapping the location of genes is simply a means to an end,” said Dr. Roberts. “The end is finding those genes and determining what they do and then how we can counteract or enhance their effect.” The expanding CARDIoGRAM consortium, now called CARDIoGRAMplusC4D (Coronary Artery Disease, or C4D, Genetics) to acknowledge the partnership with another group of institutions, recently teased out part of this mystery with a study indicating that many of these gene variations may contribute to an excessive inflammatory response to infection or other bodily challenges, potentially leading to damaged blood vessels and plaque development.
Heart Institute researchers will continue their work with the international team and on their own to better understand how the genetic data gathered over the past decade by the Ruddy Centre and others might improve the prevention, detection and treatment of heart disease. “Dr. Roberts put Ottawa on the map in terms of cardiovascular genetics research,” concluded Dr. Stewart. “By establishing the Ruddy Centre, by branding it and by really pushing its efforts over the past eight years, that’s where his legacy will be remembered.”