Gene Linked to Stroke Is Found

By William J. Cromie

Gazette Staff

The first gene associated with an increased risk for stroke has been identified by an international team of researchers that includes scientists from Harvard University. A mutation of the gene appears to double the risk of stroke.

"We had found a region in the genetic material of rats that made them prone to strokes," explains Klaus Lindpaintner, associate professor of medicine at Harvard Medical School. "A gene known to affect heart and blood vessel function in humans had previously been found in the same region. We took a bold guess that this gene put both rats and humans at higher risk for the disease. We tested the idea in humans and got lucky."

"This is an important finding toward development of a more comprehensive way of assessing a person's overall risk of experiencing a stroke," says Speranza Rubattu, a member of the research team from La Sapienza University, in Italy. "Identification of genes . . . that contribute to stroke could help us diagnose the risk earlier and suggest lifestyle modifications or develop new medicines to reduce the overall risk of stroke."

The findings were announced yesterday at a meeting of the American Heart Association in Philadelphia. At the same meeting, researchers from the Medical University of South Carolina reported that injecting this gene into rats reduces stroke deaths by 69 percent.

"If these benefits of gene therapy could be duplicated in people, it could significantly reduce death and disability from stroke," notes Lee Chao, leader of the South Carolina team. Every year in the United States, 600,000 people suffer a new or recurrent stroke, and such "brain attacks" kill approximately 158,000 men and women.

Doctors and Rats Tested

The stroke gene carries instructions for making atrial natriuretic peptide, or ANP, a hormone that lowers blood pressure by relaxing blood vessels and increasing excretion of sodium. Lindpaintner, Rubattu, and their colleagues determined that ANP protects a strain of rats prone to high blood pressure from succumbing to stroke. Rats with alterations, or mutations, in that gene do not enjoy such protection.

To check out ANP in humans, Lindpaintner's group turned to the Physicians' Health Study, a continuing investigation of 22,000 health professionals begun in 1982. The researchers selected 696 participants, 348 who had experienced strokes and an equal number who did not. The two groups were matched by age and smoking habits. Both the Physicians' Health Study and the search for stroke-associated mutations were done at Harvard-affiliated Brigham and Women's Hospital, in Boston.

Blood samples from the physicians clearly showed a particular variant of the ANP gene to be much more common in those who experienced strokes. A closer look at the gene revealed an alteration, or mutation, in its makeup.

"We're not sure what this mutation does," Lindpaintner admits. "It may make less of the hormone that lowers blood pressure. What we do know for sure is that people with the mutation are twice as likely to suffer brain attacks than those without it."

But you can still get a stroke without the altered form of the gene. Some genes work like an on-off switch: if you have the gene you get the disease; if not, you don't. Hemophilia and Huntington's disease are examples. However, strokes result not from one, but from a combination of genes and other risk factors such as smoking and age.

A mutated ANP gene would be only one of several risk factors, albeit a major one for about 10 percent of the population, Lindpaintner estimates. Nevertheless, he says, "it might be worthwhile to screen all people for this gene variant, because you could confirm or rule out one factor contributing to stroke." Those with the mutation could be warned about behaviors, such as smoking or a diet rich in saturated fat, that would make them more likely to die or be disabled by brain attacks.

Before such tests become widespread, Lindpaintner notes, his experiment must be repeated by other groups working with different people to make sure his results are not a fluke. Rubattu is now looking for the same association among stroke victims in Italy, and Lindpaintner is participating in a large study of strokes in China.

"In China strokes are more common than heart attacks, the reverse of the situation in the U.S.," he points out.

Dramatic Results

Knowledge gained from such studies could motivate drug companies to create new drugs that counter effects of the mutation.

Then there's the possibility of gene therapy, already being pursued at the Medical University of South Carolina. Lee Chao and his colleagues enclosed normal ANP genes in harmless virus coats and injected them into salt-sensitive rats. Such animals serve as models for humans whose blood pressure reaches dangerously high levels when they consume too much salt, a particular problem among blacks in this country.

The results were dramatic. Three weeks after they received the genes, less than 17 percent of the rats died of brain attacks, compared with almost 54 percent of untreated animals on a high salt diet. This saving treatment, however, does not last long because the rats' immune system clears the dummy viruses from their bodies.

"We are continuing to engineer the virus and are near the point that . . . the virus can evade the immune system," Chao said at a press conference Wednesday. "We believe our work indicates that gene delivery is the potential solution to treat people whose salt-sensitivity puts them at high risk of stroke."

"It's a very nice and interesting experiment from the point of view of proving a principle," Lindpaintner comments. "It has all kinds of major implications. However, I have reservations because gene therapy has not yet been used to successfully treat any diseases, not even those caused by a single gene."

Stroke is determined by multiple genes, as well as outside environmental factors. The same holds true for other common diseases including cancer, heart disease, and rheumatoid arthritis. Lindpaintner thinks the future of prediction, treatment, and prevention of such diseases lies in being able to compile genetic profiles of each individual and to know how each gene works.

Although fraught with the possibilities of abuse, such information, he says, "would immensely improve the human condition. I think it's where the future lies, and I see the kind of work now being done on the ANP gene as a small step in that direction."