Mount Sinai Research Collaboration Identifies Genes Responsible for Risk of Developing Heart Attack, Stroke, and Related Cardiometabolic Diseases
In a study being published in the August 19 issue of Science, researchers from the Icahn School of Medicine at Mount Sinai, in collaboration with scientists from Tartu University Hospital in Estonia, the Karolinska Institutet and Science for Life Laboratory (SciLifeLab) in Sweden, and AstraZeneca, have identified a profound new level of complexity and interaction among genes within specific tissues responsible for mediating the inherited risk for cardiometabolic diseases, including processes that lead to heart attack and stroke.
“By analyzing gene-expression data from multiple tissues in hundreds of patients with coronary artery disease, we were able to identify disease-causing genes that either were specific to single tissues or acted across multiple tissues in networks to cause cardiometabolic diseases,” said Johan Björkegren, MD, PhD, senior author of the study, Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, visiting professor at the University of Tartu and senior investigator at the Karolinska Institutet.
The ground-breaking research was done as part of the STARNET study, the first systematic analysis of RNA sequence data from blood, vascular, and metabolic tissues from patients with coronary artery disease (CAD). RNA sequences are copies of the DNA in each cell that serve as templates for protein synthesis and determine whether a tissue remains healthy or becomes diseased.
“Genome-wide association studies (GWAS) have identified thousands of DNA variants increasing risk for common diseases like CAD,” said Dr. Björkegren. “However, while GWAS was an important first line of investigations of the genetics of CAD, in order to translate these risk markers into opportunities for new diagnostics and therapies, we must now move into a new phase of discovery and identify the genes perturbed by these DNA variants responsible for driving disease development. Furthermore, we also need to understand in which tissues, pathways, and molecular networks these disease genes are active. Unraveling disease-driving genes with their tissue-belonging, as we have started to achieve using STARNET, will also be a prerequisite for developing precision medicine with individualized diagnostics and therapies.”
STARNET was launched in 2007 by Dr. Björkegren and Arno Ruusalepp, MD, PhD, Chief Cardiac Surgeon at Tartu University Hospital and senior co-author on the study. Unlike similar studies, STARNET obtained samples of several key tissues from 600 clinically well-characterized patients with CAD during coronary artery bypass surgery. By using sophisticated data analysis techniques, the researchers found that the gene expression data from STARNET were highly informative in identifying causal disease genes and their activity in networks not only in CAD but also for other cardiometabolic diseases as well as Alzheimer’s disease.
“One unexpected and thus potentially important finding of the study was that besides the liver, abdominal fat emerged as a key site for regulation of blood lipid levels,” said Oscar Franzén, MSc, PhD, Postdoctoral Fellow at the Icahn School of Medicine at Mount Sinai, first author of the study, and computational biologist in Dr. Björkegren’s laboratory. “For example, a gene called PCSK9, which is implicated in controlling plasma levels of low-density lipoprotein (LDL)—the so-called bad cholesterol—was found to do so by acting in abdominal fat, not in the liver where blood levels of LDL are mainly regulated.” PCSK9 has lately gained substantial attention as the latest target for lipid-lowering drugs now reaching the market.
“The STARNET project is fundamentally relevant for studies of the causes of CAD and other complex diseases,” said Eric Schadt, senior co-author on the paper and the Jean C. and James W. Crystal Professor of Genomics at the Icahn School of Medicine at Mount Sinai, and Founding Director of the Icahn Institute for Genomics and Multiscale Biology. “We were not only able to assign a high number of individual genes to DNA markers previously identified by GWAS but also, and quite unexpectedly, we found that many of these downstream genes appeared in disease-causal gene regulatory networks that were shared across tissues and diseases.”
In collaboration with AstraZeneca and the SciLifeLab team, Dr. Björkegren’s team has also used STARNET to try to improve drug target development. “We are excited about our joint project with Dr. Björkegren’s team at the Karolinska Institutet and AstraZeneca, which now with the Science report has delivered the first wave of ground-breaking data that we have supported for the past 3 years,” said Li-Ming Gan, MD, PhD, a co-author of the study, Senior Medical Director and collaboration lead at AstraZeneca. “During the course of our project we have found that Dr. Björkegren’s datasets including STARNET provide essential translation information to help us identify new drug targets, as well as informing on existing targets in cardiovascular and metabolic diseases, a main therapy area for AstraZeneca.”
“The PCSK9 finding together with the unexpected cross-tissue and even cross-disease activity of many disease-causing genes shows how little we currently understand about the cause of CAD,” said Dr. Ruusalepp. “As a cardiac surgeon actively treating CAD patients, I am confronted by the massive global burden of CAD and the toll it takes on our society every day. STARNET has opened the door to a new era of understanding in CAD, and brings exciting new hope for future therapies.”
Oscar Franzén, et al. Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases. Science. DOI: 10.1126/science.aad6970
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is an international leader in medical and scientific training, biomedical research, and patient care. It is the medical school for the Mount Sinai Health System, an integrated health care system which includes seven hospitals and an expanding ambulatory network serving approximately 4 million patients per year.
The School has more than 1,800 students in MD, PhD, and Master’s programs and post-doctoral fellowships; more than 5,600 faculty members; over 2,000 residents and fellows; and 23 clinical and research institutes and 34 academic departments. It is ranked among the highest in the nation in National Institutes of Health funding per principal investigator. The School was the first medical school in the country to create a progressive admissions approach for students who seek early assurance of admission through the FlexMed program.
The Graduate School of Biomedical Science trains PhD and MD/PhD students, and offers master’s-level programs in areas such as genetic counseling, clinical research, biomedical sciences, and public health, and an online master’s degree in health care delivery leadership. The seamless connections between our medical school, graduate school, and hospital campuses provide an extraordinary environment for translating scientific discoveries into clinical treatments.
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About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time — discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked by U.S. News & World Report's Best Hospitals, receiving high "Honor Roll" status, and are highly ranked: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. U.S. News & World Report’s “Best Children’s Hospitals” ranks Mount Sinai Kravis Children's Hospital among the country’s best in several pediatric specialties. The Icahn School of Medicine at Mount Sinai is one of three medical schools that have earned distinction by multiple indicators: It is consistently ranked in the top 20 by U.S. News & World Report's "Best Medical Schools," aligned with a U.S. News & World Report "Honor Roll" Hospital, and top 20 in the nation for National Institutes of Health funding and top 5 in the nation for numerous basic and clinical research areas. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.