June 30, 1998
Seeking Clues to High Blood Pressure
Some people can pour table salt on their meals for years without
suffering negative consequences. For others, habitual use of salt is
poisonous, causing blood pressure to skyrocket and increasing the risk
of heart disease, stroke or kidney failure.
Physicians want to know who is at the mercy of salt and why?
“These studies will be key to understanding why hypertension runs in families and why people vary in their blood pressure response to changes in dietary salt.”
Theodore Kurtz
Richard Lifton, a
Hughes investigator at Yale University, thinks the answer is to be
found in each person's genes. In studying newborn infants with a
genetic disorder that causes low blood pressure, Lifton's research team
traced the cause of the disorder to an abnormal protein that helps to
process sodium in the kidney.
Absence of the protein leads to a rare but mild low blood pressure
disorder in newborns that results in loss of salt from the blood.
Studying how this protein, the mineralocorticoid receptor (MLR),
regulates sodium channels in the kidney may offer more general clues
about how blood pressure is controlled by the kidney.
The research may also explain how hypertension develops in the 50
million Americans with the disease. "Our studies raise the question of
whether more common variants of the same gene could be responsible for
more modest effects on blood pressure in the general public," says
Lifton, whose report appears on the July, 1998, issue of Nature
Genetics. "It's another piece of the puzzle."
Lifton and his colleagues have now identified nine genes that play a
role in the biological "pathway" used by kidneys to maintain a balance
of salt and water in the blood and body. Too much salt in the blood
results in a higher volume of blood fluid, which increases pressure on
the circulatory system and causes hypertension. Too little salt in the
blood reduces the volume of blood serum, resulting in low blood
pressure.
The trail leading to MLR began when Lifton's team studied five
families in which children were born with a dominant form of
pseudohypoaldosteronism type 1 (PHA1), a potentially deadly disease of
newborns. Since Lifton's group had shown that PHA1 families with a
recessive form of the disease had mutations in a sodium channel, Lifton
assumed that they would find that PHA1 was caused by different
mutations in that same channel.
To their surprise, however, the culprit was found to be MLR, the
regulator of these sodium channels. MLR mutations were found both in
families in which the mutant gene was transmitted from affected parents
to their children. MLR was also mutated spontaneously in a child born
to two parents who did not have PHA1.
Lifton notes that patients with MLR mutations who survive the
neonatal period improve clinically with age. They are usually free of
symptoms by age 10, but they continue to show biochemical signs of the
disease. These findings indicate the important role of MLR in
regulating of blood pressure, Lifton says. "It raises the possibility
that there may be more common and more subtle abnormalities not only in
this gene but in other genes along this pathway that accounts for many
variations in blood pressure regulation," he says.
Theodore Kurtz, an expert in hypertension at the University of
California, San Francisco, calls Lifton's study "outstanding" because
of its widespread implications. "The results dovetail perfectly with a
series of other compelling studies by Lifton and colleagues indicating
that genetic variation in the kidney's ability to regulate blood
pressure. These studies will be key to understanding why hypertension
runs in families and why people vary in their blood pressure response
to changes in dietary salt," Kurtz said.
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