The Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre supports several large scale publicly and privately funded research projects in pharmacogenomics. The Centre also supports ongoing pharmacogenomic substudies for large pharma, as well as working with public agencies such as the Public Health Agency of Canada.
PHARMACOGENOMICS OF STATINS
PRINCIPAL INVESTIGATORS: JEAN-CLAUDE TARDIF M.D and MARIE-PIERRE DUBÉ, Ph.D.
Statins have revolutionized primary and secondary prevention of coronary atherosclerotic disease due to their lipid-lowering properties. Despite reducing cardiovascular events by 30%, statins are underutilized. A recent study estimated that 20% of patients with heart disease do not use statins. Most patients tolerate statins well; however, 10% of patients develop muscle-related adverse effects. Accurate diagnosis of statin-induced myopathy is important given the large and expanding numbers of patients eligible for statin therapy and the fact that muscle pain is one of the most frequent causes of discontinuation of therapy.
In current practice, circulating CK levels are measured to assess the severity of statin-induced myotoxicity, however its clinical interpretation is limited due to the broad range of reference CK values and because the majority of patients with statin-induced pain show CK levels within the currently used population-level “normal range”.
As part of our previous studies, we have discovered a genetic biomarker that, when used in the context of a prediction algorithm along with clinical information, can refine the normal range of plasma CK measured in patients on statin. This allows for the more accurate identification of patients with statin-induced myotoxicity who present with CK levels above their personalized normal CK range. We are now conducting a large scale clinical validation study using 6000 study participants from a previously conducted randomized trial to refine the genetic biomarkers and prediction algorithm using targeted sequencing technologies. Over 10,000 study participants from the Montreal Heart Institute Biobank, a longitudinal cohort study will be used for the final clinical validation study using the newly developed diagnostic genotyping panel.
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THE QUEBEC WARFARIN COHORT: A PROSPECTIVE STUDY OF INCIDENT WARFARIN USERS
PRINCIPAL INVESTIGATORS: MARIE-PIERRE DUBÉ, Ph.D. and SYLVIE PERREAULT, B. Pharm., Ph.D.
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. Studies have shown that genes together with environmental factors, can explain some of the variability between patients.
In the present study, we will develop predictive algorithms that can help identify patients who are most likely to be experience serious bleeding or thromboembolic events while taking warfarin. This study is recruiting over 1200 patients initiating warfarin therapy from 18 clinics throughout the province of Quebec. Participants are questioned every 3 months (5 times) in the first year to collect information on life style habits, off-the counter medication and medical history. There is an additional 10 years of follow up for events and medication use via governmental registries and health records. Patient’s DNA will be analysed in depth for the identification of genetic biomarkers.
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.
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The Montreal Heart Institute (MHI) hosts a hospital cohort of more than 17,000 participants designed to accelerate clinical research in cardiovascular disease (CVD). Participant samples are stored in a GLP facility at the Pharmacogenomics Center. The MHI Biobank is a specialized and unique facility for collection and storage of biological samples which currently employs 19 people handling this longitudinal hospital cohort study of finely-phenotyped participants (including information on medications, co-morbidities, and fine-imaging data). These 17,000 participants have already filled a detailed 35-page case report form with a study nurse at baseline and are all followed prospectively with hospital records and scheduled interviews. The mean follow-up of current participants will exceed 3 years in 2012 and the Biobank possesses extensive cardiovascular health outcomes data. Recruitment efforts are still underway to reach the target of 30,000 participants.
The MHI Biobank is one of the largest internationally for a hospital cohort and constitutes a unique resource (DNA and large numbers of aliquots of plasma are banked for every patient) for the investigation of the genetic basis of CVD, risk factors, and associated diseases. 250,000 expressed rare and common genetic variants have been analyzed using the ExomeChip from Illumina for each cohort sample, providing a valuable resource for in silico biomarker research and validation in cardiovascular disease. All the data and samples are encoded and no nominal information exists that can allow a person’s identification. All samples are stored in the GLP facilities of the Pharmacogenomics Centre, while the research data is archived at the MHICC. The Biobank operates under robust SOPs and has a management policy respecting national and international standards for data and biological material management as well as legal and ethical safeguards. Patient consent enables the repeated use of bio-specimen samples for studies while at the same time making it possible to contact patients for focused sub-studies. The MHI Biobank is mostly funded by the MHI Foundation and its donors.