Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Studies provide important new information on genetic risk of sudden cardiac death


MGH-led reports identify greater role for calcium signaling in regulation of cardiac function

Two international research studies, both led by investigators affiliated with Massachusetts General Hospital (MGH) and the Broad Institute of MIT and Harvard, have uncovered new information about genes that may increase the risk of serious cardiac arrhythmias. The studies recently received back-to-back advance online publication in Nature Genetics and Nature Methods.

The Nature Genetics report identifies several new gene regions associated with variations in the QT interval – a stage in the heart's electrical cycle that, if prolonged, increases the risk of drug-induced arrhythmias and sudden cardiac death. A surprising finding of that paper was the extent to which genes involved in calcium signaling influence the QT interval, the time from electrical activation of heart cells, which stimulates contraction, to the end of electrical relaxation.

"We have known that calcium signaling is critically important in regulating the contraction of muscle cells that generates the heartbeat," says Christopher Newton-Cheh, MD, MPH, of the MGH Center for Human Genetic Research and Cardiovascular Research Center, corresponding and co-senior author of the Nature Genetics report. "But finding that calcium is also involved in resetting the heart after each beat was a total surprise and represents a new avenue to pursue in the causes of arrhythmias."

The Nature Methods paper describes a novel approach to analyze and map the protein networks that drive cardiac repolarization – the biological process disturbed in arrhythmias. By integrating this network with results from the Nature Genetics paper, the researchers were able to pinpoint specific genes involved in the biology of cardiac repolarization, which would have been challenging to accomplish from the genetics alone. This approach also allowed identification of three genetic variants involved in arrhythmias that had been missed in earlier studies.

"Like people, genes like to work in groups, and we used the newest technologies in genomics and proteomics to derive the working group of genes involved in processes that coordinate the beating of the heart and, when malfunctioning, can cause arrhythmias or sudden cardiac death," says Kasper Lage, PhD, of the MGH Department of Surgery and the Analytic and Translational Genetics Unit, co-senior author of the Nature Methods paper. "Potassium signaling is known to be involved in cardiac repolarization, but our network analysis also pointed to a calcium pump and two proteins regulating this pump as culprits. Finding that calcium signaling also plays a role in repolarization was an unexpected and intriguing discovery."

The Nature Genetics paper describes a meta-analysis of genome-wide association studies (GWAS) involving more than 100,000 individuals that identified 35 common gene variant locations – 22 for the first time – associated with alterations in the QT interval. Identifying a previously unknown role for calcium signaling in the QT interval constitutes, according to Newton-Cheh, "a quantum leap in our ability to study one of the major causes of death in people with heart failure – which is well known to involve calcium abnormalities – and an important cause of fatal arrhythmias that occur as a side effect of several medications."

The team behind the Nature Methods paper used quantitative interaction proteomics, which determines not just whether two proteins interact but the extent of their interaction, to map in mouse hearts networks of proteins encoded by known repolarization genes and confirmed those findings in frog eggs and in zebrafish. Integrating those results with the GWAS analysis revealed that 12 genes in locations identified by the Nature Genetics study encoded proteins in the network described in the Nature Methods paper, providing a strong link between genes well-established to cause rare sudden death syndromes and genes associated with common QT-interval variation in the general population.

"These studies are more than the sum of their parts, because their integration of proteomic networks with genomic findings catalyzes the interpretation of the genetic findings to reveal new biology relevant to dangerous arrhythmias," says Lage. "We also provide a general methodology to interpret genetic data using tissue-specific proteomics networks. Importantly, our analysis also shows that we are able to use computational algorithms such as one developed by Elizabeth Rossin, a co-lead author of our paper, to functionally interpret large genetic association studies.

"The genetics communities' worldwide now use Elizabeth's tools," he adds, "and our study rigorously follows up and confirms their predictions. This is an important result because the ongoing revolution in methods of sequencing genomes and mapping genetic variation has produced massive amounts of genetic data, and we need scalable computational ways to interpret these datasets to guide biological insight and therapeutic intervention. Our study proves the predictions made by our computational tools, thus supporting their ability to provide insight into the molecular networks perturbed by genetics in many common complex disorders."

The consortium behind the Nature Genetics study involved more than 230 investigators at more than 180 institutions in 17 countries. In addition to Newton-Cheh, an assistant professor of Medicine at Harvard Medical School (HMS) and associate member of the Broad Institute, co-senior authors of the Nature Genetics study are Paul de Bakker, PhD, University Medical Center, Utrecht, the Netherlands; Arne Pfeufer, MD, Institute of Human Genetics, Munich, Germany, and Michael Ackerman, MD, PhD, Mayo Clinic. MGH co-authors include co-lead author Sara Pulit, Elizabeth Rossin, MD, PhD, and Mark Daly, PhD.

Along with Lage, an assistant professor at HMS and associate member of the Broad, co-senior authors of the Nature Methods paper are de Bakker and Jesper Olsen, PhD of the University of Copenhagen, Denmark. Additional co-authors include co-lead authors Alicia Lundby, University of Copenhagen, and Elizabeth Rossin, MD, PhD, MGH and Broad Institute; Newton-Cheh and Daly; and David Milan, MD, and Patrick Ellinor, MD, PhD, MGH Cardiology. Both studies were supported by a large number of funders in the U.S. and Europe.


Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $785 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.

Sue McGreevey | Eurek Alert!

Further reports about: Genetics Massachusetts Nature arrhythmias cardiac death genes networks proteins

More articles from Studies and Analyses:

nachricht Climate study finds evidence of global shift in the 1980s
26.11.2015 | Leibniz-Institut für Gewässerökologie und Binnenfischerei (IGB)

nachricht Network analysis shows systemic risk in mineral markets
16.11.2015 | International Institute for Applied Systems Analysis (IIASA)

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Climate study finds evidence of global shift in the 1980s

Planet Earth experienced a global climate shift in the late 1980s on an unprecedented scale, fuelled by anthropogenic warming and a volcanic eruption, according to new research published this week.

Scientists say that a major step change, or ‘regime shift’, in the Earth’s biophysical systems, from the upper atmosphere to the depths of the ocean and from...

Im Focus: Innovative Photovoltaics – from the Lab to the Façade

Fraunhofer ISE Demonstrates New Cell and Module Technologies on its Outer Building Façade

The Fraunhofer Institute for Solar Energy Systems ISE has installed 70 photovoltaic modules on the outer façade of one of its lab buildings. The modules were...

Im Focus: Lactate for Brain Energy

Nerve cells cover their high energy demand with glucose and lactate. Scientists of the University of Zurich now provide new support for this. They show for the first time in the intact mouse brain evidence for an exchange of lactate between different brain cells. With this study they were able to confirm a 20-year old hypothesis.

In comparison to other organs, the human brain has the highest energy requirements. The supply of energy for nerve cells and the particular role of lactic acid...

Im Focus: Laser process simulation available as app for first time

In laser material processing, the simulation of processes has made great strides over the past few years. Today, the software can predict relatively well what will happen on the workpiece. Unfortunately, it is also highly complex and requires a lot of computing time. Thanks to clever simplification, experts from Fraunhofer ILT are now able to offer the first-ever simulation software that calculates processes in real time and also runs on tablet computers and smartphones. The fast software enables users to do without expensive experiments and to find optimum process parameters even more effectively.

Before now, the reliable simulation of laser processes was a job for experts. Armed with sophisticated software packages and after many hours on computer...

Im Focus: Quantum Simulation: A Better Understanding of Magnetism

Heidelberg physicists use ultracold atoms to imitate the behaviour of electrons in a solid

Researchers at Heidelberg University have devised a new way to study the phenomenon of magnetism. Using ultracold atoms at near absolute zero, they prepared a...

All Focus news of the innovation-report >>>



Event News

Fraunhofer’s Urban Futures Conference: 2 days in the city of the future

25.11.2015 | Event News

Gluten oder nicht Gluten? Überempfindlichkeit auf Weizen kann unterschiedliche Ursachen haben

17.11.2015 | Event News

Art Collection Deutsche Börse zeigt Ausstellung „Traces of Disorder“

21.10.2015 | Event News

Latest News

Siemens to supply 126 megawatts to onshore wind power plants in Scotland

27.11.2015 | Press release

Two decades of training students and experts in tracking infectious disease

27.11.2015 | Life Sciences

Coming to a monitor near you: A defect-free, molecule-thick film

27.11.2015 | Materials Sciences

More VideoLinks >>>