Researchers Identify Gene Associated with Stroke

A gene's variation is associated with a tripling of stroke risk among whites - a finding that could lead to early identification of people who are at increased risk for stroke, researchers reported in the April issue of Stroke: Journal of the American Heart Association.

The study is the first to attack the genetics of stroke by tapping into the more advanced knowledge of the genetics of hypertension, or high blood pressure, the main risk factor for stroke. Researchers found that variation in a gene known as the G-protein Beta 3 subunit, previously associated with hypertension, increases stroke risk among whites by 1.5 to 3 times, but does not affect risk for blacks.

"The established relationship between hypertension and stroke, and the fact that both are related to heredity, indicate they may share some of the same genes," said senior author Dr. Eric Boerwinkle, a professor and director of the Human Genetics Center at the University of Texas Health Science Center at Houston School of Public Health.

"Our knowledge of the genes contributing to stroke risk lags behind that of other common diseases such as heart disease and cancer," Dr. Boerwinkle said. "There is a desperate need for research in this area."

Researchers found that the gene influences stroke risk apart from its effect on hypertension. "This means that GNB3 is acting on stroke risk by other, yet unknown, pathways," he said.

Work on this "candidate gene" - meaning it may cause disease - offers hope for stroke prevention, writes Dr. Robert A. Hegele of the Robarts Research Institute in London, Ontario, Canada in an editorial in Stroke. "GNB3 is a good candidate, but more work is required before it can be elected to serve as a clinical marker of stroke risk," Dr. Hegele writes. "This sustains hope that common genetic factors will have a predictable impact on stroke, although these factors are largely unspecified at present."

Stroke afflicts 600,000 Americans each year and kills about 160,000, making it the third leading cause of death behind heart disease and cancer. It is the number one cause of adult disability. Stroke is caused by a complex blend of behavioral, genetic and other risk factors such as hypertension, cardiovascular disease and diabetes. Incidence and severity of stroke can vary by a person's age, race, ethnicity and gender.

The magnitude and complexity of the problem make genetic findings such as this an important advance, said Dr. James C. Grotta, professor of neurology and holder of the Roy M. and Phyllis Gough Huffington Distinguished Chair in Neurology at The University of Texas Medical School at Houston.

"A major implication of this research is that we may be able to identify high-risk patients better with genetic information than we can with traditional epidemiological methods," Dr. Grotta said. Prevention is crucial because post-stroke treatment, which has improved tremendously in recent years, is still limited.

Dr. Grotta leads stroke care teams at Memorial Hermann Healthcare System hospitals in Houston that are national leaders in the diagnosis and treatment of stroke patients. He also conducts extensive clinical research examining new approaches to treatment, most notably participating in a national trial that established the clot-busting drug tPA, or tissue plasminogen activator, as an effective treatment against the most common form of stroke. He is not involved in the current study.

Immersed in the front-line fight against stroke, Dr. Grotta knows it will take time for genetic weapons to arrive but believes they will be worth the wait. "I think it's exciting. This is just the tip of the iceberg," he said. "Stroke literature will be full of genetic research for years to come."

Dr. Boerwinkle noted that the findings in this study will need to be verified and extended, and appropriate trials conducted before they can be used in clinical applications.

Drs. Boerwinkle and Grotta say genetic research, in addition to identifying people at risk for stroke and guiding them to preventive treatment, also is expected to permit a customized approach to care by matching a person's genetic makeup to a specific treatment. Identifying stroke susceptibility genes and the proteins they produce also should point the way to new therapies.

Dr. Boerwinkle will focus on all three areas as he continues stroke research under grants from the National Heart, Lung and Blood Institute and the National Institute of Neurological Disorders and Stroke. Dr. Boerwinkle and colleagues at the Human Genetics Center and UT-Houston's Institute of Molecular Medicine for the Prevention of Human Disease are branching into stroke after years of cutting-edge research on the genetics of common diseases in general, and hypertension in particular. They have pinpointed two susceptibility genes for hypertension and collaborated on four other genes.

In this study, researchers with the NHLBI's Atherosclerosis Risk in Communities Study redirected research aimed at the genetics of hypertension toward common genes that hypertension and stroke may share. Two genes, GNB3 and alpha-adducin, were targeted as stroke candidate genes because of their role in hypertension.

Black and white men and women, aged 45 to 64, from the ARIC study were divided into two groups: those who had a clinically recognized stroke during the ARIC study, and those without clinical stroke history but on whom MRI scans showed minute areas of damage in the brain such as a "silent" stroke would cause. Participants' blood pressure, body-fat distribution, potential for diabetes, cigarette-smoking status, and other confounding factors were determined. Subjects also filled out questionnaires about antihypertensive medication. Finally, their gene sequences were determined from blood samples.

"We followed a large group of people over time and noted which individuals had a stroke," Dr. Boerwinkle said. "We then asked what factors predict who will and will not have a stroke."

White study subjects with a clinically recognized stroke were observed to have the GNB3 825T form of the gene significantly more often when compared to a group that did not have strokes. The GNB3 825T specific form of the gene was significantly associated with clinical stroke in whites after adjustment for age, gender and other stroke risk factors. Among the MRI group, the proportion of individuals with the GNB3 825T form of the gene was not greater than the comparison group. A change in the ADD gene was not associated with stroke.

Paper co-authors include lead author Alanna C. Morrison, a graduate student in the UT-Houston Graduate School of Biomedical Sciences; Dr. Peter A. Doris of UT-Houston's Institute of Molecular Medicine; Dr. Aaron R. Folsom of the University of Minnesota School of Public Health; and Dr. F. Javier Nieto of the Johns Hopkins School of Hygiene and Public Health.

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©2006 Texas Medical Center

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