August 23, 2002
Gene Variant Increases Risk of Cardiac Arrhythmia for African-Americans
A variant form of a gene found in the heart muscle of some
African-Americans may increase the chances of developing a potential
deadly heart condition called cardiac arrhythmia, say researchers from
the Howard Hughes Medical Institute at Children’s Hospital in
Boston.
The researchers estimate that 4.6 million African-Americans carry
this gene variant. The finding could benefit African-Americans by
making it possible to detect who is at increased risk for developing
arrhythmia and allowing those affected to take preventive measures. The
study is one of the first in which researchers have been able to
discern how genetics influences arrhythmia risk across a range of
populations of people who originated from different geographic
regions.
“It is worth knowing if you have the variant because there are simple things you can do to prevent arrhythmias.”
Mark T. Keating
In an article published in the August 23, 2002, issue of the journal
Science, the research team led by HHMI investigator Mark T.
Keating reported that 13.2 percent of African-Americans in the study
carried an altered form of the gene SCN5A. This gene codes for a
protein called a sodium channel, a molecular pore that initiates
heartbeats by allowing sodium to flow across the membrane of the
cardiac muscle cell.
The variant form of the gene creates sodium channels in heart muscle
cells that remain open longer than normal sodium channels, prolonging
contraction of the heart and contributing to arrhythmia. Keating
authored the paper with colleagues at Harvard Medical School, the
University of Utah, Columbia University and St. George's Hospital
Medical School in London.
Keating emphasized that although arrhythmias are serious disorders,
the effect of the gene variant is subtle. "People who have this gene
variant are not likely to have an arrhythmia,” he said.
“All of us harbor gene variants that we may not know about.
Fortunately, our hearts are remarkably well buffered against such
problems, and arrhythmias are rare. What’s often required for a
dangerous arrhythmia is that several things go wrong at the same
time."
Keating does not believe that routine testing is warranted. The test
is fairly simple and inexpensive, so many people may elect to have it,
if and when it becomes commercially available, he said. Those most
likely to seek testing are people whose medical condition or
medications might make them vulnerable to arrhythmias. Currently the
test is available only as part of a research study.
"It is worth knowing if you have the variant because there are
simple things you can do to prevent arrhythmias," he said. According to
Keating, these steps include avoiding any of a broad range of drugs,
including antibiotics such as erythromycin and antihistamines such as
Seldane, which affect heart rhythm. People with a risk of arrhythmia
should monitor their potassium levels to ensure that they remain in the
normal range and take beta-blockers to stabilize the heartbeat.
In beginning their search for polymorphisms (gene variants) that
might contribute to arrhythmia, Keating and his colleagues started with
the gene SCN5A because mutations in that gene were known to play
a role in rare inherited arrhythmia disorder, called long QT syndrome,
that can cause sudden death.
"Almost nothing was known about the effects of polymorphisms on
cardiac arrhythmias, but we were among those predicting that variants
would be discovered that were reasonably common and would have a subtle
effect on arrhythmia risk," said Keating. He pointed out that the
effort to understand the genetic and environmental origins of
arrhythmias is spurred by the seriousness of the disorder, which kills
about 450,000 people in the United States each year.
In their initial studies, the scientists found the same
polymorphism, which they named Y1102, in several patients with
arrhythmias that did not appear to run in their families. Their studies
showed that changing one nucleotide in the SCN5A gene resulted
in a sodium channel that carried an alteration in a single amino
acid.
A broader survey of several population groups revealed that the
Y1102 polymorphism occurred in 19.2 percent of people of West Africans
and Caribbean descent, and in 13.2 percent of African-Americans
studied. However, the gene variant was not found in Caucasians or
Asians, and in only one of 123 Hispanics.
Keating and his colleagues also found that the Y1102 polymorphism
occurred disproportionately in African-American patients with
arrhythmia and in all phenotypically affected members of one
African-American family.
"It would appear that this variant originated in Africa long ago,
and been in that population for some time," said Keating. "And the
people who migrated out of Africa to found other populations still
carry it."
The scientists also conducted cell culture studies that revealed how
the Y1102 variant affected the sodium channel by subtly altering its
"gating," causing it to remain open slightly longer, which prolongs
action potential duration and increases the excitability of cardiac
muscle cells. This effect could cause transient conduction
abnormalities between heart cells, contributing to arrhythmia risk.
Finally, the scientists compared a computer simulation of the effects
of Y1102 with actual clinical findings of drug effects on arrhythmia,
discovering that the polymorphism did produce the predicted
sensitivity.
While the researchers hope their findings will benefit people who
have the Y1102 variant, they also emphasize the broader implications of
their discovery. "We believe this finding is especially significant
because it constitutes a proof of principle that points the way to
identifying more of these variants in different population groups,"
said Keating.
"This is among the first pieces of a big puzzle of genetic affects
on arrhythmia," he said. "We need to have many more pieces before we
can begin large-scale genetic testing of people for such variants. And
although testing for the variant we have discovered may prove useful,
it is only one of many risk factors. So, I would hope that such testing
will be done in a research setting, where these findings can be
confirmed and extended, and put into a larger clinical context," said
Keating.
The research was partially funded by the National Heart, Lung, and
Blood Institute.
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