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Many
African-Americans have a gene that prolongs
life after Heart Failure
Newswise
— About 40 percent of African-Americans have
a genetic variant that can protect them
after heart failure and prolong their lives,
according to research conducted at
Washington University School of Medicine in
St. Louis and collaborating institutions.
The genetic variant has an effect that
resembles that of beta blockers, drugs
widely prescribed for heart failure. The new
study offers a reason why beta blockers
don't appear to benefit some
African-Americans.
"For several years a controversy has existed
in the cardiovascular field because of
conflicting reports about whether beta
blockers helped African-American patients,"
says senior author Gerald W. Dorn II, M.D.,
professor of medicine, associate chairman
for translational research and director of
the Center for Pharmacogenomics at
Washington University.
"By mimicking the effect of beta blockers,
the genetic variant makes it appear as if
beta blockers aren't effective in these
patients," he explains. "But although beta
blockers have no additional benefit in heart
failure patients with the variant, they are
equally effective in Caucasian and
African-American patients without the
variant."
Co-author Stephen B. Liggett, M.D.,
professor of medicine and physiology at the
University of Maryland School of Medicine
and director of its cardiopulmonary genomics
program says the discovery adds to the
accumulating evidence that genetic
differences contribute to the way people
respond to medications and should encourage
the use of genetic testing in clinical
trials to identify people who can benefit
from therapy tailored to their genetic
makeup.
About 5 million people in the United States
have heart failure, and it results in about
300,000 deaths each year. Beta blockers slow
heart rate and lower blood pressure to
decrease the heart's workload and prevent
lethal cardiac arrhythmias.
While Caucasians with heart failure
participating in clinical studies of beta
blockers have shown clear benefit from the
drugs, the evidence for benefit in
African-Americans has been ambiguous. The
current study, reported online April 20,
2008, in Nature Medicine, identified one
particular race-specific gene variant that
seems to account mechanistically and
biologically for these indeterminate
results.
The gene codes for an enzyme called GRK5,
which depresses the response to adrenaline
and similar hormonal substances that
increase how hard the heart works.
Adrenaline is a hormone released from the
adrenal glands that prompts the
"fight-or-flight" response — it increases
cardiac output to give a sudden burst of
energy.
In heart failure, decreased blood flow from
the struggling heart ramps up the body's
secretion of adrenaline to compensate for a
lower blood flow. Overproduction of the
hormone makes the weakened heart pump
harder, but eventually worsens heart
failure.
Beta blockers alleviate this problem by
blocking adrenaline at its receptor in the
heart and blood vessels. GRK enzymes mimic
this effect by serving as "speed governors"
that work like the governor in an engine to
prevent adrenaline from over-revving the
heart, says Dorn.
The researchers — including three equally
contributing co-authors: Liggett, Sharon
Cresci, M.D., assistant professor of
medicine in the Cardiovascular Division at
Washington University and a cardiologist at
Barnes-Jewish Hospital, and Reagan J. Kelly,
Ph.D., at the University of Michigan — found
that 41 percent of African-Americans have a
variant GRK5 gene that more effectively
suppresses the action of adrenaline than the
more common version of the gene. People with
the variant gene could be said to have a
natural beta blocker, Dorn says. The variant
is extremely rare in Caucasians, accounting
for its predominant effects in
African-Americans.
The researchers showed that African-American
heart failure patients with this genetic
variant have about the same survival rate
even if they don't take beta blockers as
Caucasian and African-American heart failure
patients who do take beta blockers.
"That doesn't mean African-Americans with
heart failure need to be tested for the
genetic variant to decide whether to take
beta blockers," Dorn says. "Under the
supervision of a cardiologist, beta blockers
have very low risk but huge benefits, and I
am comfortable prescribing them to any heart
failure patients who do not have a specific
contraindication to the drug."
"This is a step toward individualized
therapy," Cresci says. "Medical research is
working to identify many genetic variants
that someday can ensure that patients
receive the medications that are most
appropriate for them. Right now, we know one
variant that influences beta blocker
efficacy, and we are continuing our research
into this and other relevant genetic
variants."
The human heart has two forms of GRK: GRK2
and GRK5. The researchers meticulously
searched the DNA sequence of these genes in
96 people of European-American,
African-American or Chinese descent to look
for differences. They found most people, no
matter their race, had exactly the same DNA
sequence in GRK2 or GRK5. But there was one
common variation in the DNA sequence, a
variation called GRK5-Leu41, the variant
that more than 40 percent of
African-Americans have.
To determine the effect of the GRK5-Leu41
variant, the team studied the course of
progression of heart failure in 375
African-American patients. They looked for
survival time or time to heart transplant,
comparing people with the variant to those
without. Some of these patients were taking
beta blockers and some were not.
In patients who did not take beta blockers,
the researchers found that those with the
variant lived almost twice as long as those
with the more common version of the GRK5
gene. Beta blockers prolonged life to the
same degree as the protective GRK5 variant,
but did not further increase the already
improved survival of those with the variant.
"These results offer an explanation for the
confusion that has occurred in this area
since clinical trials of beta blockers
began," Dorn says. "Our study demonstrates a
mechanism that should lay to rest the
question about whether beta blockers are
effective in African-Americans — they
absolutely are in those who don't have this
genetic variant."
Other institutions collaborating in the
study are the University of Cincinnati,
Thomas Jefferson University and the
University of Missouri, Kansas City.
Liggett SB, Cresci S, Kelly RJ, Syed FM,
Matkovich SJ, Hahn HS, Diwan A, Martini JS,
Sparks L, Parekh RR Spertus JA, Koch WJ,
Kardia SLR, Dorn II GW. A GRK5 polymorphism
that inhibits beta-adrenergic receptor
signaling is protective in heart failure.
Nature Medicine April 20, 2008 (advance
online publishing).
Funding from National Heart, Lung, and Blood
Institute supported this research.
Washington University School of Medicine's
2,100 employed and volunteer faculty
physicians also are the medical staff of
Barnes-Jewish and St. Louis Children's
hospitals. The School of Medicine is one of
the leading medical research, teaching and
patient care institutions in the nation,
currently ranked third in the nation by U.S.
News & World Report. Through its
affiliations with Barnes-Jewish and St.
Louis Children's hospitals, the School of
Medicine is linked to BJC HealthCare.
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