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.
In addition to Weder, Burmeister, Sen and Nesse, the paper is co-authored by research fellow Li Sheng, Ph.D., former postdoctoral fellow Scott Stoltenberg, now at Black Hills State University, and internal medicine research investigator Lillian Gleiberman, Ph.D. Burmeister is a professor in the U-M Medical School's departments of Psychiatry and Human Genetics. Nesse also holds positions in the Department of Psychology in the U-M College of Literature, Science and the Arts, and in the U-M Institute for Social Research.
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.
Reference: American Journal of Hypertension, (18) 9, September 2005, pp. 1206-1210