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Common gene variants increase risk of
hypertension, may lead to new therapies
A new study has identified the first common
gene variants associated with an increased
incidence of hypertension – a significant
risk factor for heart attack, stroke and
kidney failure.
The report receiving early online release in
the journal Nature Genetics
identifies variants in genes for proteins
involved with cardiovascular response to
stress that also appear to influence blood
pressure levels, an association previously
seen in animals but not demonstrated in
humans.
"It's well known that hypertension can run
in families, and a few rare genetic
syndromes that raise blood pressure have
been identified.
"But
the common genetic basis for the type of
hypertension that affects a billion
individuals around the world has been very
difficult to establish," says Christopher
Newton-Cheh, MD, MPH of the Massachusetts
General Hospital (MGH) Center for Human
Genetic Research and Cardiovascular Research
Center, first author of the Nature
Genetics report.
To search for hypertension-associated
variants, the investigators focused on two
genes called NPPA and NPPB that are involved
in the production of atrial and B-type
natriuretic peptides (ANP and BNP) –
proteins known to relax blood vessels and to
be involved in the excretion of dietary
sodium.
Animals in which both copies of NPPA have
been knocked out are hypertensive, and even
those with a single functional copy will
develop hypertension on a high-sodium diet.
The overall study involved analyzing genetic
data from almost 30,000 individuals.
The researchers first screened 1,700
participants in the Framingham Heart Study
for 13 common variations – called
single-nucleotide polymorphisms (SNPs) – in
the NPPA and NPPB genes, looking for any
correlation with levels of ANP and BNP. SNPs
identified in that first stage were
validated in three other study groups,
including participants from Sweden and
Finland; and variants associated with
changes in natriuretic peptide levels were
then tested in the same individuals for any
association with blood pressure levels.
Results of that third stage – which
suggested two hypertension-associated SNPs –
were validated in another study group.
One identified variant, found in almost 90
percent of the population, was associated
with a 20 percent reduction of ANP levels
and an 18 percent greater incidence of
hypertension.
The other variant had a similar although
less pronounced effect on ANP levels and
blood pressure.
"Natriuretic peptides are known to be
produced by the heart when it is stressed,
and screening for peptide levels is widely
used to diagnose heart failure, a condition
in which they are sharply elevated," says
senior author Thomas Wang, MD, of the MGH
Cardiology Division.
"It's currently premature to advocate
screening natriuretic peptide levels or gene
variants to diagnose hypertension risk, but
someday it may be possible to treat
natriuretic-peptide-deficient individuals
with therapies that restore normal levels
and reduce risk."
Newton-Cheh adds, "It's likely that many
more genes will be found to contribute to
changes in blood pressure, and the real
challenge will be understanding the
mechanism behind their effects.
An advantage of these variants is that we
know they act by influencing a well-studied
pathway that may be modified with therapies
that are currently being developed."
He and Wang are both assistant professors of
Medicine at Harvard Medical School and were
co-corresponding authors on the paper.
###
Support for the Nature Genetics study
included grants from the National Institutes
of Health, the Doris Duke Charitable
Foundation, the Burroughs Wellcome Fund and
the American Heart Association.
Co-authors of the paper are Kenneth Bloch
and Sekar Kathiresan, MGH Cardiology; Martin
Larson, Ramachandran Vasan, Daniel Levy,
Emelia Benjamin, and Xiaoyan Yin, Framingham
Heart Study of the National Heart Lung and
Blood Institute and Boston University; Aarti
Surti, Candace Guiducci, and Joel Hirschhorn,
Broad Institute of Harvard and MIT; Joachim
Struck, Nils Morgenthaler and Andreas
Bergmann, BRAHMS AG, Germany; Stefan
Blankenberg, Johannes Gutenberg University,
Mainz, Germany; Frank Kee, Royal Victoria
Hospital, Belfast, UK; Peter Nilsson,
University Hospital, Malmo, Sweden; Leena
Peltonen, Erki Vartiainen and Veikko Salomaa,
National Public Health Institute, Finland;
and Olle Melander, Lund University, Sweden
Massachusetts General Hospital, established
in 1811, is the original and largest
teaching hospital of Harvard Medical School.
The MGH conducts the largest hospital-based
research program in the United States, with
an annual research budget of more than $500
million and major research centers in AIDS,
cardiovascular research, cancer,
computational and integrative biology,
cutaneous biology, human genetics, medical
imaging, neurodegenerative disorders,
regenerative medicine, systems biology,
transplantation biology and photomedicine.
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