CARDIOVASCULAR DISEASE RESEARCH

Cardiovascular disease (CVD) refers collectively to the broad spectrum of different conditions affecting the heart, coronary arteries, and systemic vasculature; these conditions include hypertension, metabolic heart disease, ischaemic heart disease, heart muscle disease, valve disease, arrhythmia, and atherosclerosis. Despite myriad combinations of initial causes and risk factors, all CVDs converge on the final common pathway of heart failure (HF).

Much of this convergence is underpinned by unifying genomic and gene programme changes, emphasising the cornerstone of our programme in the Genome Institute of Singapore. As a collection, HF and CVD afflict millions of patients globally, and the incidence is increasing because of ageing populations in many different countries. In Singapore, CVD accounted for approximately 30 percent of all deaths in 2015, equating to 16 deaths per day. CVD is a top disease and healthcare burden in our country. Moreover, especially in Singapore (and Asia), CVD appears to affect Singaporeans approximately ten years younger than Western contemporaries. Most crucially, the five-year mortality for HF is about 50 percent, which is even worse than for some well-known cancers. However, despite the scale of the global health problem, there was only one drug approved by the FDA for CVD in 2018.

New approaches and a deep understanding of CVD and HF in the Asian population are thus urgently needed, and these efforts will ideally be driven by our own part of the world. The treatment steps and drug classes being used to treat CVD and HF today are the same as those used for the past two to three decades. This theme sets out to leverage advanced technologies of single-cell RNA-seq, high content high-throughput phenotypic screens, and CRISPR-based in vitro and in vivo screening to identify and prioritise candidate genes (and epigenetic loci) for therapeutic targeting.

CVD Research Themes at GIS

• Asian-centric CVD genomics, genetics, and regulatory epigenomics
  Collaborations involved: Foo, Liu, Khor, and Prabhakar labs
  Thus far, CVD research at GIS has built upon the BMRC-funded ATTRaCT Heart Failure (HF) research programme. ATTRaCT is Asia’s single largest HF cohort with over 2,500 patients and matched controls, two-year longitudinal follow-up, and deep and wide phenotyping, including whole genome sequencing, circulating biomarkers, and echo, MRI, and CT-based cardiac imaging. The overarching aim of this theme is to map the genomic architecture of HF disease among Asians and to identify Asian-centric genetic markers of disease and prognosis associated with the multiple phenotypic datasets in the same cohort. The regulatory epigenomic study of HF, using precious and limited heart muscle biopsies, focuses on identifying functionally important genetic variants across the vast non-coding genome, by employing ChIP-seq and chromatin conformation analysis, to map out enhancer and regulatory elements in the cardiac genome.
• Therapeutic target discovery, screens, and gene/epigenetic therapies for HF
  Collaborations involved: Foo and Chew labs, AstraZeneca, and NovoNordisk
  This theme sets out to leverage advanced technologies of single-cell RNA-seq, high-content high-throughput phenotypic screens, and CRISPR-based in vitro and in vivo screening to identify and prioritise candidate genes (and epigenetic loci) for therapeutic targeting. We make use of at least two platforms of disease models. In the first, human pluripotent stem cell-derived cardiomyocytes are cultured in vitro or fashioned into three-dimensional engineered heart tissue organoids, and their electrophysiological and contractile properties are studied using time-lapse videomicroscopy. The other platform involves a small rodent model of surgery-induced HF or genetic knockout models of HF. Mice are phenotyped for HF using echocardiography, LV catheterisation, and histological analysis. AAV viruses are generated at scale in our labs to perform proof-of-concept tests for gene targets.