This project will deliver pharmacogenomic tests for more efficient management of patients with cardiovascular disease. By bringing our understanding of genes that influence cardiovascular drug efficacy and toxicity into the clinical setting, we can provide guidance to health professionals in the selection and dosing of a specific drug, resulting in improved health care.

The project will benefit the Canadian healthcare system substantially by:

• Improving the treatment of patients while reducing harmful-side effects
• Increasing patient confidence (and adherence) to medications (more likely to avoid or accurately identify side effects and derive benefits)
• Reducing costs for the healthcare system (by reducing ineffective use of drugs in non-responsive patients and unnecessary spending by healthcare payers)
• Increasing reimbursement, and thus market access, for new drugs due to more effective use of drugs based on pharmacogenomic tests

Of note, 80,000 Canadians died in 2010 from cardiovascular disease, which accounts for 35% of all deaths in the country. Currently, 1.3 million Canadians suffer from cardiovascular disease causing a serious economic burden of $22.2 billion/year, representing the highest healthcare costs in Canada.

Résumé

Pakistan has the highest rate of consanguineous marriage in the world due to historical, religious, cultural and social reasons. A long history of such intracommunity and/or consanguineous marriage has divided the Pakistani population into many rural isolated clans, segregated by geography, language, religion and tribal group, and creating genetic isolates with individual mutation profiles. Consanguineous pedigrees have been successfully used in mapping rare recessive Mendelian disorders in the past. However, the potential influence of such long standing endogamous and consanguineous unions on overall levels of homozygosity genomewide and genetic disease profiles, especially for more common diseases, for such particular genetic isolates remains largely underinvestigated. Schizophrenia (SCZ), schizoaffective (SAF) and bipolar (BP) disorders are common brain diseases in all populations with largely unknown etiology and molecular pathogenesis pathways. Genetic factors have been considered important contributing causes and have been the focus of intensive research efforts in the past decades. To date, the genetic architecture of these three main psychiatric disorders remain largely unknown and very few convincing genetic factors have been identified. We propose to launch a thorough genomewide genetic investigation of 10 collected and clinically well characterized large consanguineous pedigrees from Pakistan to identify causative genetic variants contributing to these major mental disorders. The study of such isolated consanguineous populations with major psychiatric disorders offers a unique opportunity to identify transmitted mutations contributing to SCZ etiology. Thorough genetic and genomic investigations in these pedigrees will also help us better understand the effect of long-term endogamous/consanguineous marriage on the genetic profile and structure of such populations, particularly for complex genetic traits like SCZ.

Canadian Research Information System

Résumé

In Canada, the number of individuals coping with heart disease is steadily increasing and now affects more than 1.3 million individuals. Cardiovascular disease (CVD) represents the most important health care spending in Canada and costs the Canadian economy $20.9 billion/year. Current standard of care requires patients with heart disease to be treated with lipid-lowering medications known as statins. Still, despite being treated with highly potent statins, the risk of cardiovascular events remained very elevated for these patients. We are at the forefront of CVD pharmacogenomic testing and are currently involved in several clinical trials and genetic consortia that aim at developing personalized medical tools to optimize management of CVD in Canada and around the world. Our objective is to take advantage of our increasing knowledge of the human genome along with the most recent technologies used for surveying it to identify genes that influence both the efficacy of these drugs and the risk of CVD in this population. On top of opening novel research opportunities on the newly discovered genes that influence CVD, this project will directly improve personal health by delivering molecular diagnostic tools able to identify patients that are likely to benefit the most from high-dose statin therapy. As a consequence, this approach will help determine whether or not a specific subgroup of patients do not drive any benefits from atorvastatin therapy and therefore expose themselves to avoidable potential side-effects in such a way that they are likely to derive more risk than benefits from atorvastatin therapy. The identification of these non-responsive patients could help avoid a considerable amount of useless prescriptions and provide substantial savings for healthcare systems across Canada and around the world.

Résumé

Warfarin is the most widely prescribed blood thinner medication for the treatment and prevention of blood clots. Its use, however, is greatly complicated by the drug's narrow therapeutic dose range and by the extensive variation in safe doses among different individuals to avoid exposing patients to clots formation or to bleeding events. Recent studies showed that two genes, together with environmental factors, can explain some of the variability between patients. New blood thinner medications are being developed that could eventually provide an alternative to warfarin treatment. In order to identify patients who are most likely to be exposed to serious bleeding or clot formation we propose to evaluate the genetic and clinical determinants of adverse responses to warfarin treatment. These include: (i) severe and potentially fatal bleeding, the most serious adverse response; (ii) major complications related to clot formation; and (iii) fluctuations in the International Normalised Ratio (INR), a parameter used to monitor warfarin treatment in order to establish the safe therapeutic dosage for each patient.

This study will recruit 2,500 patients initiating warfarin therapy over a 2-year period. Patients will be selected from the warfarin clinics of 4 greater-Montreal area. They will be followed-up for 1 year as part of this research project. The prediction of adverse events in warfarin therapy is expected to allow a better management of treatment with blood thinner medications. This effort offers great potential for the improvement of personal and public health.