ACE Gene Linked To High Blood Pressure In Men But Not Women

May 11, 1998

DALLAS, May 12 -- Researchers have zeroed in on a gene linked to high blood pressure -- a disease that affects one in four adults -- according to two reports in today's Circulation: Journal of the American Heart Association. Two separate studies found that a variation in a gene called ACE (angiotensin converting enzyme) may be an important contributor to high blood pressure in men. Untreated high blood pressure can lead to heart disease, stroke and kidney failure. The cause of the most common form of high blood pressure, essential hypertension, is unknown.

The researchers from the Framingham Heart Study and the Genetics of Atherosclerosis Network (GENOA), which is part of the Family Blood Pressure Program, used the technique of genetic linkage to track a marker -- a gene that has already been identified within the family and is located on the same chromosome as the "ACE" gene. Researchers then tracked the variants of the gene to see which ones "hold hands" with the marker. Gene variants that travel from one generation to the next and associate with high blood pressure are likely candidates for the high blood pressure gene.

According to Christopher O'Donnell, M.D., lead author of the Framingham Heart Study report, linkage analysis is a powerful tool for scientists to identify a gene region, called a locus, that is involved in specific disease. However, the studies cannot distinguish whether the ACE variant or another gene that is also closely linked to ACE is responsible for raising blood pressure.

"If you think about a person's entire genetic make-up in terms of a large city, we have narrowed the location down to one city block," he says. "However, we are still not sure if we have the right address."

The gene region must now be analyzed for "finer mapping" to reveal the exact "address." Once it is located, scientists can study the ACE variant (or a gene next to it) and determine its function. This will help them understand causes of high blood pressure and ways to develop better-targeted treatments. "In the future, we might be able to tailor therapy differently for someone with a genetic predisposition," or even find ways to prevent the disease, says O'Donnell.

He and other scientists from the Framingham Heart Study of the National Heart, Lung, and Blood Institute examined 1,044 pairs of siblings and found the ACE variant gene in 30 percent of men. They had a 59 percent increased risk of high blood pressure.

The other group of scientists was from the University of Texas Health Science Center in Houston. They studied 1,488 siblings belonging to the youngest of a three-generation family taking part in the Family Blood Pressure Program in Rochester, Minn. Blood samples were taken to analyze the DNA, the spiral-shaped molecule that contains a person's entire genetic make-up. The ACE gene accounted for 38 percent of the difference in blood pressure levels among men. Both Framingham and UT family studies found that the gene exerts its effects on men but not on women. "We were not expecting to find that, and the fact that both studies found the same thing provides stronger evidence that the ACE gene may be sex-specific," says O'Donnell. "High blood pressure is a leading cause of cardiovascular disease in both men and women and the possible differences in genetic influence on high blood pressure deserve further study."

The data support the hypothesis that ACE, or a nearby gene, is a sex-specific candidate gene for hypertension, says O'Donnell. "High blood pressure may not just be a black box -- we may start to understand what causes it. We know that obesity and an unhealthy lifestyle can contribute, but now there is a growing body of evidence that genes are playing a role."

Eric Boerwinkle, Ph.D, director of the Human Genetics Center at UT and senior author of the GENOA Network report, notes that the ACE gene was a likely suspect for high blood pressure because the enzyme that the gene encodes plays a role in keeping the blood volume normal by controlling salt and water balance. This system, called the renin angiotensin system, maintains salt and water balance to keep blood pressure normal and is also involved in heart muscle and blood vessel growth.

While previous research has found that people who carry a certain genetic variation of the gene were more likely to have elevations of the enzyme, studies had failed to link such elevations to heart disease, says Boerwinkle. "Despite evidence for a substantial genetic component underlying differences among an individual's blood pressure, progress toward identifying the gene has been slow," he says. "A logical approach is to examine the gene encoding products with known biological effects on blood pressure regulation, such as the renin angiotensin system."

Drugs are already available, called ACE-inhibitors, that can lower blood pressure by altering the renin angiotensin system. "An exciting new potential benefit of the research is to use a genetic test to predict who will benefit most from ACE-inhibitor use," says Boerwinkle.

The National, Heart, Lung, and Blood Institute (NHLBI) funded both studies. According to Claude Lenfant, director of the NHLBI, the studies are important because they both looked at different populations and came up with the same conclusion. "The results provide important direction for learning how genes affects a person's risk for high blood pressure."

O'Donnell's co-authors are Klaus Lindpainter, M.D.; Martin Larson, Sc.D.; Valluri Rao, Ph.D.; Jose Ordovas, Ph.D.; Ernst Schaefer, M.D.; Richard Myers; Ph.D.; and Daniel Levy, M.D.

Boerwinkle's co-authors are Myriam Fornage; Christpher Amos; Sharon Kardia; Charles Sing; and Stephen Turner.
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American Heart Association

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