Researchers Close In On Stroke Candidate Gene

This gene known as GNƒÒ3 has been associated with hypertension, increased body mass, low birth weight, and weight retention after pregnancy. Now researchers found it also is linked to a 1.5 increased risk of stroke in whites, but not in blacks. In addition, this association appears to be independent of blood pressure levels.

The results are surprising for two reasons, says Eric Boerwinkle, Ph.D., professor and director of the Human Genetics Center at the University of Texas Health Science Center in Houston. First, he says, the gene was only a predictor of clinically recognized stroke; it was not a predictor of ¡§silent¡¨ strokes that are not obvious to the patient. The second reason is that it was predictive of stroke even after considering the effects of blood pressure level and hypertension status.

¡§This means that GNƒÒ3 is acting on stroke risk by other, yet unknown, pathways,¡¨ he says. The GNƒÒ3 825T specific form of the gene was significantly associated with clinical stroke in whites after adjustment for age, gender and other stroke risk factors.

Work on this ¡§candidate gene¡¨ ¡V meaning it may be responsible for causing disease ¡V offers hope for stroke prevention, writes Robert A. Hegele, M.D., of the Robarts Research Institute in London, Ontario, Canada in an accompanying editorial.

¡§GNƒÒ3 is a good candidate, but more work is required before it can be elected to serve as a clinical marker of stroke risk,¡¨ Hegele writes. ¡§This sustains hope that common genetic factors will have a predictable impact on stroke, although these factors are largely unspecified at present.¡¨ Boerwinkle plans to continue research on the genetics of stroke aiming to identify people who are at increased risk of disease so they may seek preventive treatment, to develop new therapies and to be able to better match a person¡¦s genetic susceptibility to a particular treatment.

¡§It is well known that some people respond to one treatment and not to another, yet much of medicine remains trial-and-error. It is hoped that genetic information can be used to apply effective therapy to the appropriate patient,¡¨ says Boerwinkle. ¡§Of course, the findings in this paper must be verified and extended, and appropriate trials carried out, before these goals may be achieved.¡¨

In this study researchers with the Atherosclerosis Risk in Communities (ARIC) Study redirected research originally established to study the genetics of hypertension, toward exploring the common genes that hypertension and stroke may share.

¡§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,¡¨ explains Boerwinkle.

Two genes called alpha-adducin (ADD) and a G-protein beta 3 (GNƒÒ3) subunit, have been targeted as stroke ¡§candidate genes¡¨ because of their role in hypertension susceptibility.

For the study, 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,¡¨ says Boerwinkle. ¡§We then asked what factors predict who will and will not have a stroke.¡¨

Individuals with a clinically recognized stroke were observed to have the GNƒÒ3 825T form of the gene significantly more often when compared to a group that did not have strokes. Among the MRI group, the proportion of individuals with the GNƒÒ3 825T form of the gene was not greater than the comparison group. Researchers found that a change in the ADD gene was not associated with stroke.

ARIC researchers included Alanna C. Morrison, B.S.; Peter A. Doris, Ph.D.; Aaron R. Folsom, MD; and F. Javier Nieto, MD, Ph.D.

This work was funded in part by the National Heart, Lung and Blood Institute.