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New Genetic Link To High Blood Pressure Found

October 18, 2005
University of Michigan Health System
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.

ANN ARBOR, Mich. -- A new genetic discovery made by a University ofMichigan team may help explain why some people develop high bloodpressure and others don't -- and why some people's blood pressureincreases as they age.

It also gives new insight into how the kidneys govern the balance ofsalt in the body, a crucial task for regulating blood pressure. And, itreveals how a gene already linked to behavior and mental health canplay 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 likelyto rise with age, among people who had an extra-long form of a genecalled DRD4.

They made the discovery by studying the genes of 864 people from 286families taking part in a long-term blood pressure genetics studycalled GenNet. The families all live in or near the town of Tecumseh,Mich., which since 1958 has been home to a U-M clinical researchinitiative called the Tecumseh Community Health Study.

The finding of a link between DRD4 and blood pressure came as asurprise to researchers who tested this gene initially to look atgenetics and behavior.

Cells use the DRD4 gene to make a receptor for a chemicalcalled dopamine, which transmits messages between cells. Dopamine isbest known for its role in the brain, where it is involved in feelingsof pleasure, and in governing movement. Some studies have suggestedthat variations in genes for dopamine receptors are linked to certainbehavioral traits or personality types.

But in recent years dopamine has also been found to play a rolein regulating the release of salt by the kidneys. The new U-M findingadds more evidence for that role.

"While many genes are involved in blood pressure and the inherited riskof developing hypertension, we're learning that variations in genes fordopamine receptors play a significant role," says senior author AlanWeder, 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 themost aggressive blood pressure treatment, and to develop drugs that canlower blood pressure by intervening directly in the proximal tubules ofthe 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 rolein the regulation of blood pressure by the kidneys, and to show that acommon variation in the gene is associated with higher blood pressure.Two other dopamine receptors have previously been shown to be linked toblood pressure regulation.

One in four American adults has high blood pressure, also calledhypertension -- and many don't know it. If high blood pressure isn'tlowered with the help of diet, exercise and medication, it candramatically raise the risk of heart attack, stroke or kidney problems.

Blood pressure is expressed in two numbers, one on top of theother, 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" bloodpressure. Pressures are measured in millimeters of mercury, or mm Hg.People are considered to have high blood pressure if their bloodpressure is greater than 140 mm Hg systolic, or 90 mm Hg diastolic.

Blood pressure, especially the systolic pressure, tends to rise as aperson gets older. And in older people, high systolic pressure isconsidered the greatest risk factor for cardiovascular disease.

That's one reason the new finding is especially significant, saysWeder, who directs the Tecumseh and GenNet studies and is a member ofthe U-M Cardiovascular Center. "This gene variation may be useful indeveloping a predictor of which patients are likely to have a rapidrise in blood pressure as they age, and may need more aggressivemonitoring and treatment," he says. However, he and his co-authors say,no one gene variation is enough to predict an individual person's bloodpressure tendencies, and further research on the genes involved inhypertension will be needed.

The other important implication of the finding is to create a fullerunderstanding of dopamine's action in the kidneys, and changes in thataction brought about by variations in the receptor gene. Dopamine inthe kidney helps the body respond to large loads of sodium, or salt,coming into the body. After a salty meal, for example, higher levels ofdopamine can be detected in the urine after being produced and used bythe kidneys to regulate the removal of salt from the body.

Problems or perturbations anywhere in the system that produces dopamineor receives its signals on the cell surface could alter someone'sability to regulate sodium levels, and therefore blood pressure, Wederexplains.

The new finding is published by a team that includes Weder and hisTecumseh study team -- but also researchers whose specialties arepsychiatry and the genetics of human behavior. Co-author MargitBurmeister, Ph.D., a geneticist in the Molecular & BehavioralNeurosciences Institute, explains how the unusual pairing came about.

"We wanted to do a population-based study of genes associated withpersonality and behavioral traits, and were able to work with Alan tosurvey 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 YaleUniversity.

Burmeister and her U-M colleague, psychiatry professor Randolph Nesse,M.D., set out to look at whether variations in genes such as DRD4 wereassociated with any particular behavioral traits, such as attentionproblems or a novelty-seeking personality type -- links suggested byother researchers.

They didn't find any significant association with those traits. Butwhen Weder asked if they could cross-reference blood pressure and genevariations, they turned up the link to variations in DRD4.Specifically, the analysis shows that people with a repeated stretch ofduplicate DNA within one copy of their DRD4 gene -- the "long" form ofthe gene -- tended to have blood pressures that were several pointshigher than those with the shorter form of the gene.

Weder notes that the surprising blood pressure-DRD4 findings could onlyhave come about through collaboration between blood pressurespecialists and behavioral geneticists. "We did not expect to have thisresult, because DRD4 is not considered a standard hypertension gene,"he says. "But when you don't know what the genes are, you just have totake your best shot and throw a wide net."

Now that the net has been cast, he adds, he and his colleagues willcontinue to look at the genes for other dopamine receptors and see ifthere are any ties with blood pressure traits and trends. Meanwhile,Burmeister plans to continue to look at the Tecumseh study DNA samplesand behavioral survey data for other possible relationships.


In addition to Weder, Burmeister, Sen and Nesse, the paper isco-authored by research fellow Li Sheng, Ph.D., former postdoctoralfellow Scott Stoltenberg, now at Black Hills State University, andinternal medicine research investigator Lillian Gleiberman, Ph.D.Burmeister is a professor in the U-M Medical School's departments ofPsychiatry and Human Genetics. Nesse also holds positions in theDepartment of Psychology in the U-M College of Literature, Science andthe Arts, and in the U-M Institute for Social Research.

The study was supported by the Nancy Pritzker Depression ResearchNetwork, the Michigan Society of Fellows, the Rachel Upjohn ClinicalScholars Program, and the National Heart, Lung and Blood Institute,which funds the GenNet study as part of the Family Blood PressureProgram.

Reference: American Journal of Hypertension, (18) 9, September 2005, pp. 1206-1210

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