By William J. Cromie

Gazette Staff

A gene thought to predispose people to stroke, and two genes believed to protect against it, have been isolated by an international team that includes Medical School researchers.

The genes have been found in rats bred to have the equivalent of strokes suffered by humans. People who have had strokes are now being recruited to compare their genes with those recruits not considered at risk for these "brain attacks."

"Our ultimate goal is to develop a genetic test for identifying people at risk for stroke and to introduce new types of treatment," says Speranza Rubattu, a research fellow at Brigham and Women's Hospital (BWH).

Brain attacks kill 150,000 Americans each year. On average, someone in the U.S. suffers a stroke every minute; every 3.5 minutes someone dies of one.

"People with high blood pressure are at greatest risk for strokes," notes Klaus Lindpaintner, associate professor of medicine and leader of the research. "However, only 3 to 5 percent of these hypertensives actually have strokes. Right now, there's no way to identify those people in advance, but someday we may be able to do so by looking at their genes."

Rats As Teachers

Rats can teach humans a lot because their genes aren't all that different from our own. Lindpaintner and his colleagues took advantage of two laboratory-bred strains, both of which have high blood pressure, but only one of which is stroke-prone.

"These rodents are as good a model as you can get for heart disease and stroke," Lindpaintner comments.

After studying genes involved in high blood pressure for many years, he realized there must be additional genes that predispose some, but not all, people with hypertension to heart attack, stroke, and other complications. He set out to find those genes. Lindpaintner reasoned that he could crossbreed two hypertensive strains of rats, one with and another without, a predisposition to stroke. All of the offspring would have high blood pressure, but only some of them would get strokes. By studying differences in their genes, he could isolate those factors involved only with stroke.

By a stroke of luck, it worked. After almost three years of research, he recently isolated three areas where stroke genes are present.

Genes are spaced along chromosomes like so many beads on a twisted, folded necklace. Altogether, there is a staggering 3 billion beads on 46 chromosomes. Lindpaintner's group searched among the interbred rodents for inherited stretches of chromosomes that were most common in those who suffered strokes.

"This strategy allows you to home in on a relatively short section of a chromosome that carries the gene or genes you are looking for," Lindpaintner explains.

His team found stretches, some 300 to 1,000 "beads" long, on three chromosomes where genes likely to affect stroke are positioned. The actual genes have not been isolated, but the local neighborhood where they operate is now known for the first time.

Two of the genes are associated with a protective effect. Their absence or mutation could contribute to brain attacks. A third one raises the likelihood of stroke.

"These results prove what we suspected, that stroke risk is determined, not by a single gene, but by multiple genes," Lindpaintner concludes. "That pretty much rules out the possibility of preventing stroke by replacing a single gene."

His group is focusing on a gene that produces a protein capable of dilating or expanding arteries. Dilation would lower blood pressure, but, if not working right, such a gene could contribute to a stroke.

"We've compared the chromosomal area where this gene is located in stroke-prone and stroke-resistant rats," Lindpaintner says. "Small differences have been found, but we do not know yet if they are functionally important."

Pinpointing the genes in rats, and identifying changes that impose a risk for stroke, should provide clues to the location and workings of similar genes in humans. These genes carry instructions for making proteins which can hasten blockage or rupture of blood vessels in both rats and humans. Clots that plug arteries cause about 75 percent of brain attacks in humans. Ruptured blood vessels account for the rest, but such strokes lead to more deaths.

Lindpaintner has begun recruiting matched pairs of humans, those who had and those who didn't have strokes, in an effort to find the human genes and determine how they produce their effects.

Lifestyle and Stroke

Stroke, of course, is not a disease of genes alone. Like other complex diseases -- cancer, heart disease, diabetes, AIDS -- it involves lifestyle. The quickest way to reduce risk of stroke is to control high blood pressure. That can often be done by eating a healthy diet, exercising, and maintaining proper weight. If such lifestyle changes aren't sufficient, several drugs effectively lower blood pressure.

"Lowering blood pressure has been responsible for a 50 percent decrease in stroke over the past 20 years," Lindpaintner points out. "Quitting smoking and reducing stress also will significantly cut stroke risk."

Such lifestyle changes are of greatest importance for people with risky genes. Those without a natural handicap do not have to work as hard to control weight and blood pressure. At present, there's no way to tell which group you are in.

Someday, Lindpaintner says, "we will be able to do a simple blood test to determine which people with high blood pressure are at a particular risk for stroke. These individuals could be targeted for more aggressive treatment in the form of drugs and changes in lifestyle. Other hypertensives could be treated more conservatively and, perhaps, spared the undesirable side-effects of potent blood-pressure-lowering drugs."

The stroke sleuthing involves an international collaboration. The different rat strains are bred in Berlin. The rodents then go to Naples, where trained researchers watch them for strokes.

How do you tell when a rat has a stroke? "You have to watch them quite closely," Lindpaintner answers. Usually, they start to limp. Or if an animal suffers a series of small brain attacks, it becomes withdrawn, stops moving around, and loses interest in food. The final answer is determined by autopsy.

Blood taken from the rats is then shipped to the Medical School for genetic analysis. The arrangement seems complicated, but it takes advantage of each lab's specialized expertise. In the end, results are obtained faster and more cheaply than would otherwise be possible.