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POLYMORPHISMS OF ENOS LINKED TO INCREASED RISK OF EARLY ONSET STROKE

PHOENIX — Investigators with the Stroke Prevention in Young Women Study reported a link in the genetics of stroke: two polymorphisms of endothelial nitric oxide synthase (eNOS) are associated with early onset ischemic stroke in African-American women.

Timothy D. Howard, PhD, Assistant Professor of Pediatrics at the Center for Human Genomics at Wake Forest University School of Medicine in Winston-Salem, NC, presented the findings at the American Stroke Association Conference. He said the two polymorphisms – -922 AA and -786 TT – were almost twice as prevalent in African-American women with ischemic stroke as in white women with stroke.

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Dr. Timothy D. Howard

“This finding has to be replicated to confirm that the gene is important in the disease process,” Dr. Howard explained in an interview. “What is unique about this study is that we investigated five single nucleotide polymorphisms rather than just looking at a single target.”

If these findings are confirmed, it could mean that some type of treatment targeting this gene could be developed, Dr. Howard said.

NEED FOR REPLICATION

Steven Kittner, MD, Professor of Neurology and Director of the Maryland Stroke Center at the University of Maryland School of Medicine in Baltimore, cautioned that the influence of these two polymorphisms should also be replicated in other populations.

“We need to confirm that what we have observed is specific to stroke and so we would like to take a more comprehensive approach in evaluating the gene,” Dr. Kittner said. “This is preliminary work.”

Dr. Howard and colleagues conducted a population-based case-control study of stroke in young women. Fifty-nine hospitals in the Baltimore-Washington area participated and 100 cases of first ischemic stroke among women aged 15 to 44 were identified. Forty-four percent of the cases occurred in African-American women. The cases were compared to 183 controls – 40 percent African-American – identified by random digit dialing from the same region. Historical risk factor data were collected by standard interview.

Five eNOS polymorphisms were genotyped: four single nucleotide polymorphisms – 1468 T/A, -922 G/A, -786 T/C, and G894T, as well as one insertion/deletion polymorphism within intron 4. The frequency for -922 AA and -786 was 65 percent in African-Americans compared with 37 percent and 36 percent frequency for -922 AA and -786 TT respectively in whites. There was no association with stroke for the other three polymorphisms, Dr. Howard said.

LOGICAL TARGET

Michael A. Moskowitz, MD, Professor of Neurology at Harvard Medical School in Boston, MA, who is Chair of the International Stroke Conference Program Committee, said many investigators are interested in the “role of genes in determining susceptibility to ischemic stroke, and eNOS is a logical target for inquiry since it is considered a protective molecule in that it protects both endothelial cells and the blood vessels.”

But Dr. Moskowitz, who was not involved in the study, noted that it is difficult to establish a relationship between function and “single nucleotide switches. The next step would be to determine if these mutations affect the natural life cycle of the protein [eNOS], which would eventually affect function.”

If the finding is replicated, Dr. Moskowitz said women with these genotypes “might be considered for prophylaxis such as aspirin or more aggressive monitoring of any known risk factors. What this study really does is confirm our impression that genes are important in the disease process of stroke.”