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

24.03.2009
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:
http://www.jhmi.edu
http://www.nature.com/ng/index.html
http://www.hopkinsmedicine.org/geneticmedicine/

More articles from Life Sciences:

nachricht Climate Impact Research in Hannover: Small Plants against Large Waves
17.08.2018 | Leibniz Universität Hannover

nachricht First transcription atlas of all wheat genes expands prospects for research and cultivation
17.08.2018 | Leibniz-Institut für Pflanzengenetik und Kulturpflanzenforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Color effects from transparent 3D-printed nanostructures

New design tool automatically creates nanostructure 3D-print templates for user-given colors
Scientists present work at prestigious SIGGRAPH conference

Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and...

Im Focus: Unraveling the nature of 'whistlers' from space in the lab

A new study sheds light on how ultralow frequency radio waves and plasmas interact

Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...

Im Focus: New interactive machine learning tool makes car designs more aerodynamic

Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.

When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...

Im Focus: Robots as 'pump attendants': TU Graz develops robot-controlled rapid charging system for e-vehicles

Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.

Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....

Im Focus: The “TRiC” to folding actin

Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.

Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

LaserForum 2018 deals with 3D production of components

17.08.2018 | Event News

Within reach of the Universe

08.08.2018 | Event News

A journey through the history of microscopy – new exhibition opens at the MDC

27.07.2018 | Event News

 
Latest News

Smallest transistor worldwide switches current with a single atom in solid electrolyte

17.08.2018 | Physics and Astronomy

Robots as Tools and Partners in Rehabilitation

17.08.2018 | Information Technology

Climate Impact Research in Hannover: Small Plants against Large Waves

17.08.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>