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Updated 5:00 PM October 25, 2005
 

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Genetic link to high blood pressure found by U-M team

A genetic discovery made by U-M researchers may help explain why some people develop high blood pressure and others don't, and why blood pressure for some 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, the U-M team reports 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.

Finding the link between DRD4 and blood pressure came as a surprise to researchers who tested the 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.

In recent years, however, dopamine also has been found to play a role in regulating the release of salt by the kidneys. The U-M finding adds more evidence of this 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 Dr. Alan Weder, professor of internal medicine at the 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 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 previously have been linked to blood pressure regulation.

Blood pressure tends to rise as a person gets older—especially the systolic pressure or that which is forced through blood vessels by contraction of the heart. In older people, high systolic pressure is considered the greatest risk factor for cardiovascular disease.

Another important implication of the finding is 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 kidneys 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 it is 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 a person's ability to regulate sodium levels, and therefore blood pressure, Weder explains.

In addition to Weder and his Tecumseh study team, researchers included Margit Burmeister, a geneticist in the Molecular & Behavioral Neurosciences Institute and professor in the Medical School departments of psychiatry and human genetics; Dr. Srijan Sen, a Medical Scientist Training Program graduate now at Yale University; Dr. Randolph Nesse, professor in the departments of psychiatry and psychology, and research professor, Institute for Social Research; Li Sheng, research fellow; Scott Stoltenberg, former postdoctoral fellow now at Black Hills State University; and Lillian Gleiberman, internal medicine research investigator.

The study was supported by the Nancy Pritzker Depression Research Network, the Michigan Society of Fellows, the Rachel Upjohn Clinical Scholars Program, and the National Heart, Lung and Blood Institute, which funds the GenNet study as part of the Family Blood Pressure Program.

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