Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Hopkins scientists ID 10 genes associated with a risk factor for sudden cardiac death

One minute, he's a strapping 40-year-old with an enviable cholesterol level, working out on his treadmill. The next, he's dead.

That an abnormality in his heart's electrical system had managed to stay on the Q.T. — until it proved lethal — is characteristic of sudden cardiac death, which annually claims more than a quarter million Americans.

A dearth of discernable symptoms and lack of detectable molecules circulating in the blood makes the prediction of sudden cardiac death largely dependent on genetic risk factors.

Having identified 10 common variants of genes that modify the timing of the contraction of the heart, known as the QT interval, scientists in the Johns Hopkins University School of Medicine, in collaboration with an international contingent of researchers, now provide new insight about the underpinnings of the QT interval which, when prolonged or shortened, predisposes to sudden cardiac death.

QT interval, which is determined from a standard electrocardiogram (ECG), reflects the time it takes for the heart (ventricles) to contract and then reset for the next heartbeat.

Publishing March 22 in Nature Genetics, the international team including researchers from the Technical University in Munich, Johns Hopkins and others, used DNA samples previously collected for epidemiological studies to analyze the genomes of 15,842 individuals whose QT intervals had been measured by electrocardiogram. With DNA microarray chips, each able to assess hundreds of thousands of markers in each sample, followed by bioinformatic techniques to increase the number of markers, the researchers screened approximately 2.5 million markers to detect subtle alterations in the sequences of these genomes that modify the QT interval.

By focusing on 2.5 million sites in a genome of 3 billion sites, the scientists surveyed one-one-thousandth of nearly 16,000 genomes. This relatively small but "still extremely powerful" screen correlates genomic architecture with QT intervals, according to Aravinda Chakravarti, Ph.D., a professor in the McKusick-Nathans Institute of Genetic Medicine.

These common variants at 10 locations across the genome represent perhaps dozens of yet-to-be-identified genes that affect this trait, Chakravarti adds. Of the 10, one that had been previously identified — Nos1ap — was confirmed. Several others were suspected culprits, the effects of which hadn't been demonstrated in preliminary screens.

"However, almost half were surprising new genes that no one would have guessed as being involved in cardiac biology," says Dan Arking, Ph.D., an assistant professor in the McKusick-Nathans Institute of Genetic Medicine. "So it really does open up a new world of investigation because these are genes that would have never come up if we had only focused on a list of known candidate genes."

A separate study, led by Christopher Newton-Cheh, M.D., M.P.H., of the Massachusetts General Hospital Center for Human Genetic Research and Cardiovascular Research Center , found similar results from more than 13,000 individuals. "We were very reassured to see such strong replication in two independent studies," says Newton-Cheh.

While any single genetic variation in any one individual does not necessarily imply a significant alteration to QT interval, much less increased risk of sudden cardiac death, there is meaning that resides in the collective.

The power of this genetic analysis is a result of screening many thousands of samples, says Chakravarti: "We're not very good at predicting what happens to any one, single sample. It's sort of like, I could examine in great detail how important my vote was in the last election, but it's trivial compared to the collective vote. An individual's genome is important as part of the study's whole, but individually, it's of little consequence."

Likewise, if scientists analyze the effect on QT interval by any one of the genetic variants, the alteration amounts to just a couple milliseconds, which is not a huge amount, says Arking: "But if you put all 10 genetic variants together, that bumps up the QT interval by about 20 milliseconds, which is significant."

This latest study builds on research published in 2006, when a screen of 100,000 sites in individuals of European ancestry first showed that the Nos1ap gene is associated with the QT interval; and subsequent research showing that sequence changes in Nos1ap are also a risk factor for sudden cardiac death. A third paper, published in January 2009 in PLoS one, widened the original screen to include multiethnic populations; that study confirmed that Nos1ap genetic variants alter QT interval in all populations and, in fact, have a stronger effect in women than men.

"The reason people die from this cardiovascular disorder is because we know nothing about the antecedents," Chakravarti says. "It's like a truck barreling down a slope: there's no way to stop it. The only way out is to understand the science of this in a deep, meaningful way. If we know, we can begin to intervene."

The research was supported in part by National Heart, Lung and Blood Institute, National Human Genome Research Institute, National Institute on Aging, National Institutes of Health, Donald W. Reynolds Cardiovascular Clinical Research Center at Johns Hopkins University, German Federal Ministry of Education and Research, Fondation Leducq, State of Bavaria, Ministry of Health of the Autonomous Province of Bolzano, South Tyrolean Sparkasse Foundation, and the Heinz Nixdorf Foundation.

Authors of the paper, in addition to Chakravarti and Arking, are Georg B. Ehret, Anna Köttgen, W.H. Linda Kao, Josef Coresh and Man Li, Johns Hopkins University; Arne Pfeufer and Christine Happle, Technical University Munich, Germany; Serena Sanna, Gianluca Usala, Mariano Dei, Silvia Naitza and Marco Orrú, Istituto di Neurogenetica e Neurofarmacologia, Cagliari, Italy; Martina Müller and H.-Erich Wichmann, Helmholtz Center Munich; Gerhard Steinbeck and Stefan Kääb, Klinikum Grosshadern, Munich; Gonçalo R. Abecasis and Vesela Gateva, University of Michigan; Christian Fuchsberger, Peter P. Pramstaller and Andrew A. Hicks, EURAC European Academy, Italy; Siegfried Perz, Helmholtz Center Munich; Maja Barbalic and Eric Boerwinkle, University of Texas Health Science Center; Benno Pütz and Bertram Müller-Myhsok, Max Planck Institute of Psychiatry, Munich; Angelo Scuteri, Istituto Ricovero e Cura per Anziani, Rome; Ronald J. Prineas, Wake Forest University School of Medicine; Samer S. Najjar and Edward Lakatta, National Institute on Aging; Thomas W. Mühleisen, University of Bonn; Stefan Möhlenkamp and Karl-Heinz Jöckel, University Hospital of Essen, University Duisburg-Essen; and David Schlessinger, National Institute on Aging.

Maryalice Yakutchik | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München

nachricht Second research flight into zero gravity
21.10.2016 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>