Frazer LabDepartment of Pediatrics, Genome Information Sciences

Cardiovascular Disease


The goal of the CARDiPS project at UCSD is to understand the genetic underpinnings of drug-induced cardiotoxicity using a large cohort of human iPSC-derived cardiomyocytes

Cardiovascular diseases are the main cause of mortality in developed countries, with the incidence on the rise all over the world, and are the result of both environmental and genetic factors. Drug treatments for many of these conditions are often ineffective, produce adverse affects in certain populations, and in general show a high degree of inter-individual variability. Personalized medicine, a concept that has gained popularity since the advent of sequencing the human genome, aims to provide patient-specific treatments to minimize side effects and maximize drug effectiveness. However, technical limitations, such as the difficulty of acquiring primary human tissues (e.g. heart) from large numbers of individuals with varied genetic backgrounds, have hampered its advancement. The advent of a series of new technological breakthroughs over the last years (iPSCs, Next-Gen sequencing, high-throughput phenotyping) is enabling us to study the associations between genetic variability and disease susceptibility to a level of detail unimagined a few years ago, with critical implications for the implementation of personalized medicine. As a result of dramatic improvements in the methods for generating iPSC-derived cardiomyocytes and continuous efforts to refine existing procedures, our group now has access to virtually unlimited amounts of high-quality, patient-specific human cardiomyocytes (currently derived from ~225 individuals). These individuals have all been subjected to extensive genetic characterization and thus we will be able to conduct in-depth genotype-phenotype studies. Importantly, our cohort contains several large-extended families with multi-generational histories of cardiovascular disease.

We are performing high-throughput phenotypic characterization of the iPSC-derived cardiomyocytes. To this end, we will use a novel, state-of-the-art high-throughput microeletrode array system (MEAS). This equipment is able to capture in real time a wide spectrum of cardiomyocyte phenotypic traits (beat frequency, period, field depolarization potentials, etc) by minimally invasive means, thus providing detailed information about the cardiomyocyte phenome of each specific line. Furthermore, a subset of the most interesting lines will be submitted to Kinetic Imaging Citometry (KIC) to obtain further detail about the specifics of calcium, sodium and potassium channel involvement. We will use our phenotypic analysis in cardiomyocytes to test a variety of FDA-approved drugs, as well as appropriate positive and negative control drugs and correlate with detailed genomic and transcriptomic data. We expect to find certain patterns of adverse drug reactions tied to specific genetic backgrounds, thus providing a basis for pharmacogenomics studies and personalized medicine applications.

Investigators associated with this research project include:
Juan Carlos Izpisúa Belmonte, PhD
Neil Chi, MD, PhD
Sylvia Evans, PhD
Lawrence “Larry” Goldstein, PhD
Daniel O’Connor, MD
Michael “Geoff” Rosenfeld, MD
Gene Yeo, PhD

Initiated in 2011, this is a five-year study funded by the National Heart, Lung, and Blood Institute.

click here to see human iPSC-derived cardiomyocytes beating autonomously in culture.

MEAS analysis of cardiomyocyte activity in a healthy cardiomyocyte versus a long QT syndrome cardiomyocyte.

Gene Variants and Risk of Venous Thrombosis

In collaboration with Dr. John-Bjarne Hansen at the University of Tromsø (Norway), we are examining genetic risk factors for venous thromboembolism (VTE), a common disease encompassing deep-vein thrombosis and pulmonary embolism. It is potentially fatal, has a high recurrence rate, and serious short- and long-term complications. VTE is a multifactorial disease influenced by environmental exposures (e.g., cancer, immobilization, surgery, and pregnancy); genetic factors (e.g., FV-Leiden mutation); and interactions between genetics and the environment. A family history of VTE is a strong risk factor, but genes currently associated with VTE do not explain the increase in risk. Novel, rare genetic variation may be responsible.

To identify novel variants and genes associated with VTE, we have conducted targeted sequencing and array genotyping in coding genes in a large Norwegian cohort (600 VTE cases and 600 controls) and are evaluating the impact the variation identified on risk of VTE. We have identified genes that show an excess of rare variation in VTE cases and in collaboration with several international groups, are validating our findings. This work has the potential to identify new pathways involved in VTE pathogenesis and suggest novel routes for treatment, prevention, and prediction.

Investigators associated with this research project include:
John-Bjarne Hansen, MD, PhD

Initiated in 2010, this study is led by the University of Tromsø with funds obtained from the University of Tromsø Faculty of Health Sciences, the Northern Norway Regional Health Authority, and the K.G. Jebsen Foundation

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