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 discernible symptoms and
lack of detectable molecules circulating in
the blood make 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 that, when prolonged or
shortened, predisposes to sudden cardiac
death.
QT interval, which is determined from a standard
electrocardiogram, 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
elsewhere, 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, a professor in
the
McKusick-Nathans Institute of Genetic Medicine at Johns
Hopkins.
These common variants at 10 locations across the
genome represent perhaps dozens of yet-to-
be-identified genes that affect this trait, Chakravarti
said. 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," said Dan Arking, 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 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," Newton-Cheh said.
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, Chakravarti said,
is a result of screening many thousands of
samples. "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, Arking said, if scientists analyze the
effect on QT interval by any one of the genetic
variants, the alteration amounts to just a couple of
milliseconds, which is not a huge amount. "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 said. "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 the 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 Heinz Nixdorf Foundation.
In addition to Chakravarti and Arking, authors of the
paper from Johns Hopkins are Georg B.
Ehret, Anna Kottgen, W.H. Linda Kao, Josef Coresh and Man
Li.
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