New genetic link to high blood pressure found

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Public release date: 17-Oct-2005

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University of Michigan Health System

New genetic link to high blood pressure found

Variation in dopamine receptor gene is associated with hypertension,

could help explain why people have different risk, especially as they

age

ANN ARBOR, Mich. -- A new genetic discovery made by a University of

Michigan team may help explain why some people develop high blood

pressure and others don't -- and why some people's blood pressure

increases as they age.

It also gives new insight into how the kidneys govern the balance of

salt in the body, a crucial task for regulating blood pressure. And,

it reveals how a gene already linked to behavior and mental health

can play a role in the body, as well as the brain.

In a paper published in the American Journal of Hypertension, U-M

researchers report that blood pressure was higher, and more likely to

rise with age, among people who had an extra-long form of a gene

called DRD4.

They made the discovery by studying the genes of 864 people from 286

families taking part in a long-term blood pressure genetics study

called GenNet. The families all live in or near the town of Tecumseh,

Mich., which since 1958 has been home to a U-M clinical research

initiative called the Tecumseh Community Health Study.

The finding of a link between DRD4 and blood pressure came as a

surprise to researchers who tested this gene initially to look at

genetics and behavior.

Cells use the DRD4 gene to make a receptor for a chemical called

dopamine, which transmits messages between cells. Dopamine is best

known for its role in the brain, where it is involved in feelings of

pleasure, and in governing movement. Some studies have suggested that

variations in genes for dopamine receptors are linked to certain

behavioral traits or personality types.

But in recent years dopamine has also been found to play a role in

regulating the release of salt by the kidneys. The new U-M finding

adds more evidence for that role.

" While many genes are involved in blood pressure and the inherited

risk of developing hypertension, we're learning that variations in

genes for dopamine receptors play a significant role, " says senior

author Alan Weder, M.D., professor of internal medicine at the U-M

Medical School. " As we learn more, we may be able to determine which

patients need the most aggressive blood pressure treatment, and to

develop drugs that can lower blood pressure by intervening directly

in the proximal tubules of the kidneys, where dopamine acts --

something today's drugs don't do. "

The new study is the first to show that the DRD4 receptor plays a

role in the regulation of blood pressure by the kidneys, and to show

that a common variation in the gene is associated with higher blood

pressure. Two other dopamine receptors have previously been shown to

be linked to blood pressure regulation.

One in four American adults has high blood pressure, also called

hypertension -- and many don't know it. If high blood pressure isn't

lowered with the help of diet, exercise and medication, it can

dramatically raise the risk of heart attack, stroke or kidney problems.

Blood pressure is expressed in two numbers, one on top of the other,

that measure the pressure of blood traveling in blood vessels, both

during and between heartbeats. The top number is the " systolic " blood

pressure, and the bottom number is the " diastolic " blood pressure.

Pressures are measured in millimeters of mercury, or mm Hg. People

are considered to have high blood pressure if their blood pressure is

greater than 140 mm Hg systolic, or 90 mm Hg diastolic.

Blood pressure, especially the systolic pressure, tends to rise as a

person gets older. And in older people, high systolic pressure is

considered the greatest risk factor for cardiovascular disease.

That's one reason the new finding is especially significant, says

Weder, who directs the Tecumseh and GenNet studies and is a member of

the U-M Cardiovascular Center. " This gene variation may be useful in

developing a predictor of which patients are likely to have a rapid

rise in blood pressure as they age, and may need more aggressive

monitoring and treatment, " he says. However, he and his co-authors

say, no one gene variation is enough to predict an individual

person's blood pressure tendencies, and further research on the genes

involved in hypertension will be needed.

The other important implication of the finding is to create a fuller

understanding of dopamine's action in the kidneys, and changes in

that action brought about by variations in the receptor gene.

Dopamine in the kidney helps the body respond to large loads of

sodium, or salt, coming into the body. After a salty meal, for

example, higher levels of dopamine can be detected in the urine after

being produced and used by the kidneys to regulate the removal of

salt from the body.

Problems or perturbations anywhere in the system that produces

dopamine or receives its signals on the cell surface could alter

someone's ability to regulate sodium levels, and therefore blood

pressure, Weder explains.

The new finding is published by a team that includes Weder and his

Tecumseh study team -- but also researchers whose specialties are

psychiatry and the genetics of human behavior. Co-author Margit

Burmeister, Ph.D., a geneticist in the Molecular & Behavioral

Neurosciences Institute, explains how the unusual pairing came about.

" We wanted to do a population-based study of genes associated with

personality and behavioral traits, and were able to work with Alan to

survey the Tecumseh study participants for such traits, " she

explains. The genotyping was done by her laboratory team, led by

Srijan Sen, M.D., Ph.D., a Medical Scientist Training Program

graduate now at Yale University.

Burmeister and her U-M colleague, psychiatry professor Randolph

Nesse, M.D., set out to look at whether variations in genes such as

DRD4 were associated with any particular behavioral traits, such as

attention problems or a novelty-seeking personality type -- links

suggested by other researchers.

They didn't find any significant association with those traits. But

when Weder asked if they could cross-reference blood pressure and

gene variations, they turned up the link to variations in DRD4.

Specifically, the analysis shows that people with a repeated stretch

of duplicate DNA within one copy of their DRD4 gene -- the " long "

form of the gene -- tended to have blood pressures that were several

points higher than those with the shorter form of the gene.

Weder notes that the surprising blood pressure-DRD4 findings could

only have come about through collaboration between blood pressure

specialists and behavioral geneticists. " We did not expect to have

this result, because DRD4 is not considered a standard hypertension

gene, " he says. " But when you don't know what the genes are, you just

have to take your best shot and throw a wide net. "

Now that the net has been cast, he adds, he and his colleagues will

continue to look at the genes for other dopamine receptors and see if

there are any ties with blood pressure traits and trends. Meanwhile,

Burmeister plans to continue to look at the Tecumseh study DNA

samples and behavioral survey data for other possible relationships.

http://www.eurekalert.org/bysubject/medicine.php