Gene study to unlock causes of stroke

Dr Jim Jannes and Dr Simon Koblar examine a CT scan of a stroke patient's brain.
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Dr Jim Jannes and Dr Simon Koblar examine a CT scan of a stroke patient's brain.
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Dr Jim Jannes and Dr Simon Koblar examine the polymorphic forms of six of the genes involved in blood clotting.
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A CT scan of a stroke victim's brain. A finger points to a dark area indicating a blockage of the left middle cerebral artery.
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A CT scan of blood vessels in a stroke victim's brain. The pencil points to a clear area, indicating blockage of a blood vessel and damage to the region that it formerly supplied.
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Tuesday, 30 January 2001

Good ideas do not always get the funding they deserve, but an enterprising study of the problem of stroke prevention has been rewarded with an important grant. The results of the Adelaide University study could have enormous implications worldwide.

"Almost everyone can think of a friend or relative who has suffered a stroke." The sobering remark from Dr Simon Koblar underlies the urgency with which he is about to undertake a novel research project with fellow neurologist and PhD researcher Dr Jim Jannes.

The study will examine genetic factors that might predispose people to ischaemic stroke; where a blood clot chokes off oxygen supply to part of the brain, leaving the victim in many cases dead and in most cases disabled.

Blood clots account for 85% of the total number of strokes, which kill 12,000 Australians each year. As a cause of mortality, stroke sits just behind heart disease, but in terms of disability, stroke is the international leader, costing billions of dollars every year and causing untold misery.

Stroke is a bit of a mystery, too. Interest in heart disease has led to huge changes in public attitudes to smoking, fat consumption and exercise; all factors that are also implicated in stroke. But some who smoke heavily, have high cholesterol levels and eat huge quantities of fatty food don't succumb to stroke, while others who obey all the rules are struck down.

Just as with heart problems and Alzheimer's disease, a few family studies have suggested a genetic link in strokes.

"If you have a first-degree relative who has had such a stroke, it roughly doubles your own risk," said Dr Koblar, Senior Lecturer in the Department of Medicine. "Studies of twins have shown that an identical twin whose sibling has suffered from a stroke has a three or four-fold increase in the risk of doing so," he said. "That suggests to us that there are genetic factors that underlie stroke. If so, we want to know what they are."

The work will be supported by a $55,000 Viertel Clinical Investigatorship won by Dr Koblar. It is a prestigious research grant made to new Australian researchers in medicine, and to fund medical research in a new direction.

The direction of this research could not be much newer. It relies upon findings of the Human Genome Project, which has isolated and sequenced, among others, various genes that could be implicated in stroke.

"From genetic studies, we can now say that we know of a number of genes with a role in ischaemia in the brain," said Dr Jannes, from the Department of Medicine, Queen Elizabeth Hospital.

"The situation is complicated because of polymorphism; subtle variations in these genes among different members of the population," said Dr Jannes. "From the Genome Project we now have genetic code to study these genes in stroke victims, and determine whether any of the variations are associated with higher risk of stroke."

Some 20 years worth of study of the pathology of stroke have isolated many physiological factors that are implicated in its onset. They include the blood's clotting process, the condition of blood vessels and the presence of various proteins. The researchers have selected eight genes whose effects are largely known. Seven of them are involved in blood clotting, and one plays a role in fat metabolism. All are implicated in cardiovascular disease; another pointer to their possible implication in stroke.

"We are very excited about this study," said Dr Koblar. "Not only is it a national 'first', but there is no multiple gene analysis study so far published in the world, though we are sure this will be the way of future research in this field," he said.

According to Dr Jannes, the genetic analysis will use a novel molecular strategy developed by collaborators at the Australian Red Cross. It will allow 100 patients to be screened for a polymorphism in a matter of a couple of hours. "Being able to genetically screen rapidly and reliably is essential in such a study," Dr Jannes explained.

The researchers hope that their study will reveal the importance of variations in these eight genes, and identify those that might predispose people to a stroke.

The consequences of such a finding could be immense. There are already treatments for patients who have suffered one stroke. They include administering drugs such as aspirin that help prevent clots from forming, but they are only effective in preventing a subsequent stroke in about one third of patients.

Anything that can increase that level of protection would be a medical achievement of real significance, but the researchers caution that such treatment would take some time to develop step following completion of this study.

'There will be no single gene for stroke," said Dr Jannes. "The causes are likely to involve many factors, some enhancing each other. Even if we can isolate genes that are involved, we will then have to determine what exactly they do in the body, and only then can we expect to develop suitable treatments," he said.

The researchers regard the city of Adelaide as the perfect size for their work. They already have data from 50 patients, and plan to collect more from a total of 500, drawn from The Queen Elizabeth, Lyell McEwin, Flinders Medical Centre and Royal Adelaide Hospitals.

"It will give us a resource in Adelaide that has enormous potential for future studies, as well,' said Dr Koblar. "The patients have given their permission for their blood samples to be stored, so any future study, subject to ethical approval and patient permission, will be able to make use of them," he said.

Studies of this kind must compare patients with a comparable control group drawn from the population. This control group will be selected by an independent body, which will contact members of the public and ask them to become involved.

"We hope that anyone who is approached to take part in this study will do so," said Dr Koblar. "When stroke claims us or our relatives and or friends, we feel powerless. Participation in this study may allow people to make a difference for all of our future health," he said.

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