The Genetic and Molecular Epidemiology Program of PHRI, conducts the most cutting-edge genetic techniques to assess whether the promise of personalized medicine can be realized. The team explores the genetic risk of stroke, diabetes, obesity and the response to some of the most widely prescribed drugs for these diseases.
The program developed from the large, international INTERHEART study from which DNA sample analysis led to novel insights into genetic determinants of myocardial infarction. The program continued to grow with genetic data analysis from the Arrhythmia team’s ACTIVE and Acute Coronary Syndrome’s CURE studies which indicated that pharmacogenetic testing had limited utility in identifying who would not benefit from clopidogrel therapy, one of the most widely prescribed antiplatelet drugsâa discovery that offers reassurance to the hundreds of thousands of patients taking this medication that they are likely to benefit irrespective of their genes. Results from the Genetic component of the RE-LY trial showed that 30% of Europeans carry a genetic variant protecting them from bleeding when taking the novel anticoagulant dabigatran. Such findings raise the possibility that genetic information may assist in how we treat patients with specific drugs.
The Genetics Program continues to expand through peer-reviewed genetics and biomarker studies for both discovery research and hypothesis-testing research. An integral part of PHRI’s multidisciplinary approach, the Genetics team collaborates on an increasing number of studies.
Select the studies listed below for more information on the Genetics component.
Stroke is the third leading cause of death in Canada (Statistics Canada, 2012) and a major source of long-term disability. Risk factors such as high blood pressure, diabetes, smoking and abnormal heart rhythm are known to increase chances of having a stroke. However, in many individuals who develop stroke, particularly young people, we do not find the reason. Stroke is therefore believed to develop through a combination of known risk factors (e.g. high blood pressure) and genetic factors that make it more likely that a person will have a stroke. It is known that genes contribute to the risk of stroke, since stroke occurs commonly in some families. However, very few ‘genes’ that cause stroke have been identified. With funding from the Heart and Stroke Foundation of Ontario and the Canadian Stroke Network , research done at PHRI aims to identify such genes through a combination of cutting-edge genomics techniques. For instance, based on the hypothesis that rare protein-coding mutations are responsible for stroke in young patients with no classical risk factors, the genetic team at PHRI is performing exome sequencing (i.e. sequencing of all protein coding sequences) in 200 young stroke patients and 200 matching controls. Suffering from a stroke at a young age is a particularly distressing event for patients and their families given the current lack of information on both etiology and prognosis. This project squarely aims to further our understanding of the genetic causes of early strokes. Such investigation is expected to provide insights into genes and biological pathways relevant to stroke. Furthermore, the discovery of rare mutations associated with markedly increased stroke risk has profound public health implications and could lead to novel genetic screening strategies.
Broadly categorized as antiplatelet and anticoagulation agents, antithrombotic drugs are commonly used for prevention and treatment of venous thromboembolism (VTE), acute coronary syndromes and stroke. Nevertheless, it is increasingly recognized that not all patients benefit equally from drug treatment, with some individuals showing evidence of aspirin “resistance” while others carry genetic variants that modify the platelet inhibitory effect of clopidogrel. Likewise, wide variations in the level of active drugs have been noted with the anticoagulation agents dabigatran and apixaban. Such variations result in underdosing some patients (i.e. thrombotic events) and overdosing others (i.e. bleeding events). This project aims to identify the pharmacogenetic determinants of key antithrombotic drugs and evaluate their clinical relevance. The ultimate goal is to optimize antithrombotic therapy based on each individual’s genetic makeup, so as to minimize side effects and improve efficacy. Studying acute coronary syndrome and atrial fibrillation patients, Dr. ParÃ© has shown that effects of loss-of-function alleles do not apply to all patient populations. Furthermore, he has demonstrated that the CYP2C19 gain-of-function allele might be as, or even more, important as the loss-of-function alleles in certain patients. This work was published in the New England Journal of Medicine (ParÃ© et al. N Engl J Med. 363(18):1704-14, 2010) and has led to follow-up publications (ParÃ© et al. Circ Gen. 5(2): 250-6, 2012 and ParÃ© et al. Circ Interv. 4(5): 514-21, 2011). Finally, Dr. ParÃ© has recently described a novel pharmacogenetic association between CES1 and risk of bleed with dabigatran, a novel anticoagulant (ParÃ© et al. Circ 127(13): 1404-12, 2013).
Heart disease is a leading cause of death in Canada. In addition to risk factors such as smoking and diabetes, increased blood cholesterol can lead to atherosclerosis and coronary artery disease. Increased amounts of atherogenic lipoprotein(a) [Lp(a)] is associated with increased risk of heart and blood vessel disease. However, the real importance of Lp(a) is not yet clear because people of differing genetic ancestry have varying amount and sizes of Lp(a). The size of Lp(a) is genetically determined while blood concentrations of Lp(a) are assumed to be also highly (~70%) heritable. The different sizes of Lp(a) make it difficult to measure in the blood, a problem compounded by the observation that smaller size Lp(a) are associated with higher blood Lp(a) concentrations. At the moment, there is uncertainty whether there is one ‘best’ test to use in all ethnic groups or if it is better to use a combination of tests. This project is analyzing Lp(a) in a large number of people from many different ethnic groups using an assay that is insensitive to Lp(a) size and combining with genetic and Lp(a) size information. The goal is to determine how to best measure Lp(a) in populations of diverse ancestry to better determine individual risk of cardiovascular diseases.
Biological samples from the Steroids In caRdiac Surgery (SIRS) randomized clinical trial of intravenous steroids in cardiac surgery patients have been collected to identify biomarkers of adverse cardiovascular outcomes. This CIHR-funded study aims to investigate the combined role of leukocyte gene expression, plasma biomarkers and genetic variants in individual response to surgery and steroid therapy. Annually, more than 2,000,000 patients undergo cardiac surgery, including 30,000 patients in Canada. Cardiac surgery is associated with a high morbidity and mortality, with approximately 5% of patients (100,000 patients globally) not surviving their hospital stay after surgery. Cardiopulmonary bypass (CPB) is a common procedure that is required in a majority of patients undergoing cardiac surgery. CPB initiates a systemic inflammatory response syndrome characterized by an activation of neutrophils, monocytes, macrophages, platelets, coagulation, fibrinolytic, and kallikrein cascades. The systemic inflammatory response syndrome associated with CPB is widely assumed to be responsible for the significant morbidity and mortality associated with cardiac surgery; for example, several investigators have highlighted the central role of inflammatory processes in inducing myocardial injury. In an attempt to minimize the deleterious effects of CPB, the CIHR-funded SIRS trial evaluated the benefits of steroids on major clinical outcomes in cardiac surgery. This project strives to develop novel clinical algorithms based on leukocyte gene expression profiles before and after CPB to identify patients at risk of poor outcomes, defined as a composite of death, nonfatal myocardial infarction, nonfatal cardiac arrest, or nonfatal stroke. This project is expected to improve the health of cardiac surgery patients by identifying vulnerable patients and potentially directing these at-risk individuals towards other therapeutic modalities such as off pump cardiac surgery or percutaneous valvuloplasty. Furthermore, this study will provide insights into inter-individual variation in steroids response, one of the most widely used drugs.
With funding from CIHR and Sanofi-Aventis, we plan to create a comprehensive algorithm for prediction of incident CVD using combined genetic-biomarker-clinical risk factor panels in individuals with dysglycemia. This project seeks to reduce morbidity and costs associated with the two leading complications of diabetes by identifying high-risk individuals from the ORIGIN clinical trial, such that comprehensive risk reduction therapies can be provided early and maximally. Type 2 diabetes is a chronic and progressive metabolic disease defined by the presence of chronic hyperglycemia and associated with substantial societal costs. Type 2 diabetes is a major cause of CVD and the leading cause of chronic kidney disease (CKD) in Canada. The overarching goal of this project is to improve the health through better identification of individuals with prediabetes or early diabetes who are at high risk of CVD and CKD, the two leading complications of diabetes. This project builds on the recently completed 7 year randomized phase III clinical trial ORIGIN (Outcome Reduction With Initial Glargine Intervention) that was conducted in 12,537 people with prediabetes or early type 2 diabetes and that was designed to determine whether serious CVD and other outcomes could be reduced by: (1) normalizing fasting glucose levels with basal insulin glargine; and/or (2) a 1 gm omega-3 fatty acid supplement. ORIGIN reported that both interventions clearly had a neutral effect on CVD outcomes. We are proceeding with whole-genome genotyping of the subset of ORIGIN participants with stored DNA (buffy coat) samples (N=5,433) in whom 273 plasma biomarkers have been measured at baseline. This approach is unique in that this will be the first study to integrate clinical data (age, BMI, blood glucose, etc.), highly-multiplexed biomarker information and comprehensive genomics characterization for the prediction of CVD and CKD in people with diabetes. We hypothesize that such a 3-dimensional approach to identifying people with diabetes at the highest risk of CVD and CKD will be much more effective than clinical, biomarker or genomic approaches alone.