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(Stroke. 2005;36:1848.)
© 2005 American Heart Association, Inc.

Original Contributions

Promoter Polymorphisms in the Nitric Oxide Synthase 3 Gene Are Associated With Ischemic Stroke Susceptibility in Young Black Women

Timothy D. Howard, PhD; Wayne H. Giles, MD, MPH; Jianfeng Xu, MD, DrPH; Marcella A. Wozniak, MD, PhD; Ann M. Malarcher, PhD, MSPH; Leslie A. Lange, PhD; Richard F. Macko, MD; Monica J. Basehore; Deborah A. Meyers, PhD; John W. Cole, MD Steven J. Kittner, MD, MPH

From the Center for Human Genomics (T.D.H., J.X., M.J.B., D.A.M.), Wake Forest University School of Medicine, Winston-Salem, NC; Division of Adult and Community Health (W.H.G., A.M.M.), Centers for Disease Control and Prevention, Atlanta, Ga; Department of Neurology (M.A.W., R.F.M., J.W.C., S.J.K.) and the Department of Epidemiology and Preventive Medicine (S.J.K.), University of Maryland at Baltimore, Md; the Geriatrics Research, Education, and Clinical Center (R.F.M., J.W.C., S.J.K.), Baltimore Department of Veterans Affairs Medical Center, Md; and Department of Genetics (L.A.L.), University of North Carolina, Chapel Hill.

Correspondence to Dr Kittner, Bressler Bldg, Rm 12-006, UMAB, 655 W. Baltimore St, Baltimore, MD 21201. E-mail skittner{at}umaryland.edu

Background and Purpose— Endothelial nitric oxide exerts a variety of protective effects on endothelial cells and blood vessels, and therefore the nitric oxide synthase 3 gene (NOS3) is a logical candidate gene for stroke susceptibility.

Methods— We used the population-based Stroke Prevention in Young Women case-control study to assess the association of five NOS3 polymorphisms in 110 cases (46% black) with ischemic stroke and 206 controls (38% black), 15 to 44 years of age. Polymorphisms included 3 single nucleotide polymorphisms (SNPs) in the promoter region (–1468 T>A, –922 G>A, –786 T>C), 1 SNP in exon 7 (G894T), and 1 insertion/deletion polymorphism within intron 4.

Results— Significant associations with both the –922 G>A and –786 T>C SNPs with ischemic stroke were observed in the black, but not the white, population. This association was attributable to an increased prevalence of the –922 A allele (OR=3.0, 95% CI=1.3 to 6.8; P=0.005) and the -786 T allele (OR=2.9, 95% CI=1.3 to 6.4; P=0.005) in cases versus controls. These 2 SNPs were in strong linkage disequilibrium (D'=1.0), making it impossible to determine, within the confines of this genetic study, whether 1 or both of these polymorphisms are functionally related to NOS3 expression. Two sets of haplotypes were also identified, 1 of which may confer an increased susceptibility to stroke in blacks, whereas the other appears to be protective.

Conclusion— Promoter variants in NOS3 may be associated with ischemic stroke susceptibility among young black women.

Key Words: genetics • nitric oxide • women and minorities • young, stroke in

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