Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Quantity, not quality: Risk of sudden cardiac death tied to protein overproduction


Understanding of mechanism could lead to new drug treatment

A genetic variant linked to sudden cardiac death leads to protein overproduction in heart cells, Johns Hopkins scientists report. Unlike many known disease-linked variants, this one lies not in a gene but in so-called noncoding DNA, a growing focus of disease research.

The discovery, reported in the June 5 issue of The American Journal of Human Genetics, also adds to scientific understanding of the causes of sudden cardiac death and of possible ways to prevent it, the researchers say.

"Traditionally, geneticists have studied gene variants that cause disease by producing an abnormal protein," says Aravinda Chakravarti, Ph.D., a professor of medicine, pediatrics, molecular biology and genetics, and biostatistics in the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins University School of Medicine. "We think there will turn out to be many DNA variants that, like this one, cause disease by making too much or too little of a normal protein."

... more about:
»DNA »Medicine »NOS1AP »cardiac »death »genes »noncoding

Chakravarti's interest in sudden cardiac death emerged a decade ago, when it claimed several of his colleagues within a few months. An expert in complex common diseases, he and his team knew that sudden cardiac death can be caused by many conditions. They focused on one: abnormalities in what is known as cardiac repolarization — the time it takes for the heart to gear up to beat again.

The team compared the genetic sequences of tens of thousands of people with their electrocardiogram (ECG) results, identifying several regions on the genome with genetic variations associated with lengthened QT interval, a measure of cardiac repolarization, in the ECG. "The problem is that most of these variants lie outside of genes, in the noncoding DNA that controls how genes are used," Chakravarti says, "so it's hard to tell what genes they're affecting."

Despite the challenge, Chakravarti and his colleagues were able to home in on one suspect region of the genome housing a gene called NOS1AP. "There were many variants grouped in this area," says Ashish Kapoor, Ph.D., a postdoctoral researcher in Chakravarti's laboratory, "so we catalogued all 200 that we found." The team then went through a process of elimination using genetically engineered, lab-grown cells and zebra fish to identify a variant in the noncoding DNA that affected how much protein was made by the nearby NOS1AP gene.

Next, they cultured rat heart cells and engineered them to overproduce NOS1AP. When the concentration of the protein rose in a particular type of heart cell called a cardiomyocyte, the cells' electrical properties changed in a way that is similar to the pattern seen in long QT syndrome.

Kapoor notes that 67 percent of the general population carries the NOS1AP-overproducing genetic variant. "We have observed that NOS1AP genetic variants are associated with sudden cardiac death whether or not they affect a particular person's QT interval, raising the risk by about 40 percent," he says.

Chakravarti notes that the results also add to scientific understanding of how the heart and QT interval work — knowledge with far-reaching implications. For example, many drugs developed for noncardiac conditions have turned out to temporarily lengthen QT interval, a side effect that only turns up after much time and money are spent on drug development. By better understanding regulation of the QT interval, researchers would be better able to predict what types of drugs could affect it.

"Hundreds of genome-wide association studies have been done to find genetic variants associated with disease, but this is one of just a handful of follow-up studies to look for the mechanism behind such a variant," Chakravarti says. "I think we've shown there's great value in asking why."


Link to the article:

Other authors on the paper were Rajesh B. Sekar, Karen Fox-Talbot, Vasyl Pihur, Sumantra Chatterjee, Dan E. Arking, Marc K. Halushka and Gordon F. Tomaselli of the Johns Hopkins University School of Medicine; Nancy F. Hansen, Jim Mullikin and Eric D. Green of the National Human Genome Research Institute; Michael Morley, Jeffrey Brandimarto and Thomas P. Cappola of Perelman School of Medicine at the University of Pennsylvania; Christine S. Moravec of the Cleveland Clinic Foundation; Sara L. Pulit of the University Medical Center Utrecht; Arne Pfeufer of the Helmholtz Zentrum Munchen; Mark Ross and David Bentley of Illumina United Kingdom; Christopher Newton-Cheh of Massachusetts General Hospital; Eric Boerwinkle of the University of Texas Health Science Center; and the QT Interval-International GWAS Consortium.

This work was supported by the National Heart, Lung and Blood Institute (grant numbers RO1 HL086694 and RO1HL105993) and the Donald W. Reynolds Foundation. Affymetrix, Inc. sells products used in the study described in this article. Aravinda Chakravarti was a paid consultant to and member of the Scientific Advisory Board of Affymetrix until December 31, 2013. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Mark Ross and David Bentley are employees of Illumina, Inc., a public company that develops and markets systems for genetic analysis.

Related stories:

Hopkins Scientists ID 10 Genes Associated With a Risk Factor for Sudden Cardiac Death:

New Genes Implicated in High Blood Pressure:

Scientific Team Sequences 1092 Human Genomes To Determine Standard Range Of Human Genetic Variation:

Shawna Williams | Eurek Alert!

Further reports about: DNA Medicine NOS1AP cardiac death genes noncoding

More articles from Life Sciences:

nachricht Two decades of training students and experts in tracking infectious disease
27.11.2015 | Hochschule für Angewandte Wissenschaften Hamburg

nachricht Increased carbon dioxide enhances plankton growth, opposite of what was expected
27.11.2015 | Bigelow Laboratory for Ocean Sciences

All articles from Life Sciences >>>

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 >>>