The Laboratory of Translational Genomics is focused on the genetics of coronary artery disease (CAD). Through unbiased Genome-Wide Association Studies (GWAS), the team has identified common genetic variants at over 40 loci that augment the risk of CAD (Science, 2007, 316: 1488-1491; Nature Genetics, 2011, 43: 333-338; Lancet, 2011, 377: 383-392; Cell Reports, 2014, 7: 834-847). Importantly, these studies reveal novel disease mechanisms that fundamentally alter our view of CAD, beyond cholesterol and blood pressure.
The Laboratory of Translational Genomics is currently working on three loci, 9p21, SPG7 and IRF2BP2, to elucidate their biological impact on CAD risk and to transform GWAS discoveries to therapeutic applications.
Genetic Loci for Cardiovascular Disease
The 9p21 locus (with 52 linked variants) is the first genetic risk factor for CAD identified by 3 independent GWAS, including ours (Science, 2007, 316: 1488-1491). We found that it disrupts regulatory sequences and affects expression of genes controlling cell proliferation (ATVB, 2009, 29(10): 1671-1677; JACC, 2013, 61(2): 143-147). The laboratory is addressing mechanisms affected by 9p21 variants, including disrupted regulation by TEAD transcription factors and how this disruption impacts vascular cell proliferation and atherosclerosis progression.
Dr. Stewart is a founding member of the international CARDIoGRAM consortium comprising GWAS of > 20 centres in 8 countries for the discovery of genetic risk of CAD. CARDIoGRAM has published the landmark papers on the genetics of CAD.
A genetic variant of SPG7, a mitochondrial protease, elevates mitochondrial reactive oxygen species production, inflammation, smooth muscle cell proliferation and increases CAD risk (Cell Reports, 2014, 7: 834-847). The team is using a mouse model bearing the human SPG7 variant to identify the kinases and phosphatases that control this cellular mechanism and identify therapeutic targets.
The laboratory’s recent work shows that a novel regulator of innate immunity, IRF2BP2, suppresses macrophage inflammation, promotes macrophage cholesterol handling and limits foam cell formation. The team discovered a deletion variant that disrupts a microRNA target in the human IRF2BP2 3’UTR, lowers protein levels and increases CAD risk. Dr. Stewart and his collaborators have made transgenic mice that delete IRF2BP2 in macrophages and found increased propensity to develop atherosclerosis. They are using this unique mouse model to reveal key cellular pathways and potential therapeutic targets (including dysregulated miRNAs and snoRNAs) regulated by IRF2BP2.
- Almontashiri NAM, Antoine D, Zhou X, Vilmundarson RO, Zhang SX, Hao KN, Chen HH, Stewart AFR*. 9p21.3 coronary artery disease risk variants disrupt tead transcription factor-dependent tgfβ regulation of p16 expression in human aortic smooth muscle cells. Circulation, 2015; 132(21):1969-78.
- Chen HH, Keyhanian K, Zhou X, Vilmundarson RO, Almontashiri NAM, Cruz SA, Pandey NR, Yap NL, Ho T, Stewart CA, Huang H, Hari A, Geoffrion M, McPherson R, Rayner KJ, Stewart AFR*. IRF2BP2 reduces macrophage inflammation and susceptibility to atherosclerosis. Circulation Research, 2015; 117(8):671-83.
- Amontashiri NA, Vilmundarson RO, Ghasemzadeh N, Dandona S, Roberts R, Quyyumi AA, Chen HH, Stewart AF. Plasma PCSK9 levels are elevated with acute myocardial infarction in two independent retrospective angiographic studies. PLoS One. 2014 Sep 2;9(9):e106294.
- Almontashiri NA, Chen HH, Mailloux RJ, Tatsuta T, Teng AC, Mahmoud AB, Ho T, Stewart NA, Rippstein P, Harper ME, Roberts R, Willenborg C, Erdmann J; CARDIoGRAM Consortium, Pastore A, McBride HM, Langer T, Stewart AF. SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes. Cell Rep. 2014 May 8;7(3):834-47.
- Fan M, Dandona S, McPherson R, Allayee H, Hazen SL, Wells GA, Roberts R, Stewart AF. Two chromosome 9p21 haplotype blocks distinguish between coronary artery disease and myocardial infarction risk. Circ Cardiovasc Genet. 2013 Aug;6(4):372-80.
- Almontashiri NA, Fan M, Cheng BL, Chen HH, Roberts R, Stewart AF. Interferon-γ activates expression of p15 and p16 regardless of 9p21.3 coronary artery disease risk genotype. J Am Coll Cardiol. 2013 Jan 15;61(2):143-7.
Current Team Members
Ragnar Vilmundarson, PhD Candidate
To enquire about available positions, please submit your CV with a cover letter detailing what you can bring to the team.
The laboratory has ongoing collaborations with faculty at the University of Ottawa Heart Institute (R McPherson & K Rayner), the Ottawa Hospital Research Institute (H-H Chen), McGill University (S Dandona & H McBride), and Köln University (T Langer).