The intron 4c allele of the NOS3 gene is associated with ischemic stroke in African Americans.
BACKGROUND
Ischemic stroke is the most common cause of disability in North America and in addition to the generally accepted risk factors, there is increasing evidence for the potential pathophysiological role of genes. One of these genes, the endothelial nitric oxide synthase gene (NOS3) has been reported as a genetic risk factor for ischemic stroke. To independently confirm and extend the results of these previous reports, we investigated this gene as a risk factor for stroke in an ethnically diverse study population.


METHODS
Using the TOAST classification, we characterized and studied 377 patients with ischemic stroke. We genotyped two common variants in the NOS3 gene, the intron 4 insertion/deletion and an exonic single nucleotide polymorphism (SNP), G894T, in these patients and compared them with 502 controls. Chi-square or Fisher's exact tests were used to examine allele effects on stroke and stroke subtypes. Logistic regression analysis was used to adjust for confounding covariate effects.


RESULTS
All genotypes are in Hardy-Weinberg equilibrium except for intron 4c, which is overrepresented in ischemic stroke patients. In pooled analysis of all patients, intron 4c, but not intron 4a, intron 4b or G894T alleles are associated with stroke (p < 0.01). In subgroup analysis by race, the intron 4c allele is most strongly associated with large artery ischemic stroke in African Americans (p < 0.01).


CONCLUSIONS
We are unable to confirm previous reports of an association of the intron 4a or the G894T alleles with ischemic stroke. However, although limited by a relatively small sample size, our study suggests a potentially important role of the intron 4c allele as a genetic marker of ischemic stroke in African Americans.
Grewal
R P
RP
New Jersey Neuroscience Institute at JFK Medical Center, 65 James Street, Edison, NJ 08818, USA. rgrewal@solarishs.org
Dutra
A V C
AV
Liao
Yi C
YC
Juo
Ss H
SH
Papamitsakis
N I H
NI
D001741:Black or African American; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002545:Brain Ischemia / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D020521:Stroke / Q000208:ethnology / Q000235:genetics*
D005819:Genetic Markers; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III