Le Laboratoire de génomique de l’athérosclérose vise à acquérir une compréhension complète et intégrée de l’étiologie génétique et moléculaire de phénotypes complexes, en mettant l’accent sur la coronaropathie et l’obésité. Pour cela, son équipe applique simultanément un éventail de méthodes : phénotypage clinique et métabolique rigoureux, génétique, expression génétique spécifique des tissus, génomique intégrative et bioanalyse fonctionnelle.
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Projets
Current Projects
Genetic Origins of Coronary Heart Disease
Coronary artery disease (CAD), the leading cause of death in the western world, is a heritable condition not fully explained by known risk factors. We first identified a common allele on chromosome 9p21 robustly associated with CAD (Science 2007). In subsequent studies in collaboration with other groups, over 45 common genetic variants that cumulatively increase CAD risk have been identified. We now have comprehensive phenotypic and genetic data on over 10,000 individuals with or without premature CAD. We continue to mine these data using bioinformatic approaches and laboratory based studies to obtain a better understanding of the biological basis of this important disease.
Genetics of Human Obesity
In collaboration with Dr. Robert Dent, of the Weight Management Clinic at The Ottawa Hospital, we have recruited a population of over 3,000 severely obese individuals and 1,000 age and gender matched ultra-lean subjects. We have identified several novel rare variants contributing to an obesity phenotype. More recently, using DNA microarrays followed by 1000 Genomes imputation, we have obtained data on more than 20 thousand common genetic variants. This project involves a close collaboration with Drs. Mary-Ellen Harper (PhD), at the University of Ottawa, and Katey Rayner (PhD) to unravel the complex genetic, genomic and metabolic basis of obesity and its response to intervention.
Methodologies
Metabolic and Anatomical Phenotyping
Precise and accurate phenotyping is key to deciphering the relationship of genetic variants to complex disease. For CAD studies, we collaborate closely with Drs. Marino Labinaz (MD) and Derek So (MD) , in the cardiac catheterization laboratory and with Dr. Benjamin Chow (MD) in the CT angiography lab. For studies related to obesity, we work closely with Dr. Robert Dent in the Weight Management Clinic at the Ottawa Hospital.
Genetic Studies
Techniques include genome wide association studies using the Affymetrix 6.0 array, carried out in the John & Jennifer Ruddy Cardiovascular Genetics Laboratory in collaboration with Dr. Alex Stewart (PhD) and in the GeneChip facility in the Atherogenomics Laboratory. SNP genotyping is performed using a range of techniques including high throughput TaqMan assays using Roche LightCycler technology and resequencing approaches. Regions of high potential functionality that are likely to encompass disease-causative variants can now be subjected to deep sequencing using the Roche GX FLX 454 sequencer.
Bioinformatics
One of the challenges of genetic epidemiology is to identify causative genetic variants that contribute significantly to disease etiology. We use a range of bioinformatics approaches, including eQTL information and public databases, generated by the ENCODE and Roadmap Epigenomics projects to identify functional regulatory elements to be followed up with more specific methodologies, including chromatin immunoprecipitation sequencing and DNase I hypersensitive site sequencing. Thus, we can determine whether a risk locus is likely to harbour functional cis-acting regulatory modules whose activity is altered by a particular risk variant prior to standard molecular biology approaches in the laboratory. Other bioinformatic approaches include pathway and topological analyses of GWAS data.
Molecular and Cellular Analyses
Bioinformatically predicted function of DNA regions are then validated at the cellular and biochemical level using a range of conventional approaches from promoter and enhancer assays to CHiP and Chirp and functional studies in cell types relevant to atherosclerosis, including human aortic endothelial cells and human aortic smooth muscle cells. Current studies are focused on the COL4A1/COL4A2, SMAD3, ZC3HC1 and TRIB1 loci for CAD.
Personnel
Current Team Members
Sebastien Soubeyrand, PhD: Senior Research Associate & Laboratory Manager
Paulina Lau, MSc: Senior technician
Amy Martinuk, MSc: Technician
Heather Doelle, BSc, MLT: Genetics recruiter
Adam Turner, PhD: Postdoctoral Fellow
Anh-Thu Dang, BSc: MSc candidate
Offres d'emploi
Opportunities
To enquire about available positions, please submit your CV with a cover letter detailing what you can bring to the team.
Contact
Publications
Voir la liste des publications actuelles sur PubMed.