From the Department of Clinical Neurosciences, King's College
School of Medicine and Dentistry and the Institute of Psychiatry (H.S.M.,
Y.R., N.A.), and the Department of Neuroscience, Institute of Psychiatry
(J.F.P.), London, UK.
Correspondence to Dr Hugh Markus, Department of Clinical Neurosciences, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, UK, SE5 8AF. E-mail h.markus{at}iop.bpmf.ac.uk
Background and Purpose—The role
of endothelial nitric oxide synthase (eNOS) in normal
physiology suggests that it could be a potential candidate gene for
stroke. Reduced eNOS activity could mediate an increased stroke risk
through hypertension or independent of hypertension through abnormal
vasomotor responses, promoting atherogenesis, or increased platelet
adhesion and aggregation. Recently, a common polymorphism in exon 7
of the eNOS gene (894G
Methods—We studied 361 consecutive white patients presenting
with ischemic stroke or TIA to a neurological cerebrovascular
disease service and 236 normal white controls. In all patients CT
and/or MR head imaging and high-resolution carotid duplex ultrasound
were performed. The presence of the polymorphism (N/n) was
determined by polymerase chain reaction and restriction with the enzyme
BanII.
Results—There was no difference in the frequency of the
NN genotype between patients and controls
(13.0% versus 15.3%; P=0.44) or in N allele
frequency (39% versus 37%; P=0.57). There was no
association with genotype when only patients with stroke
(excluding those with TIA) or when only individuals aged
Conclusions—We failed to find a relationship between this exon 7
polymorphism and ischemic cerebrovascular disease. In
particular, it was not associated with stroke and TIA secondary to
large-vessel atherosclerosis or with the degree of
carotid stenosis in patients with cerebrovascular disease. It
is unlikely that this particular polymorphism or any closely linked
polymorphism is a major risk factor in the majority of white
patients with stroke.
© 1998 American Heart Association, Inc.
Original Contributions
Endothelial Nitric Oxide Synthase Exon 7 Polymorphism, Ischemic Cerebrovascular Disease, and Carotid Atheroma
T) has been reported to be a strong risk
factor for coronary artery disease. We determined whether it
was also a risk factor for transient ischemic attack (TIA) and
ischemic stroke and for carotid atheroma. 
65 years
were considered. In contrast, there was a highly significant
independent association between cerebrovascular disease and
hypertension (odds ratio, 2.87; 95% CI, 2.0 to 4.15;
P<0.00001), smoking (odds ratio, 2.58; 95% CI, 1.80 to
3.70; P<0.00001), and diabetes (odds ratio, 2.68; 95%
CI, 1.38 to 5.24; P=0.004). There was no relationship
between the polymorphism and any particular stroke subtype:
large-vessel disease, for NN, 15 of 105 (14.3%);
lacunar disease, 10 of 75 (13.3%); cardioembolic and unknown, 18 of
151 (11.9%); and tandem pathology, 4 of 30 (13.3%)
(P=0.68, 
2). There was no difference in
the mean degree of carotid stenosis between the 3
genotypes: NN, 31.1% (SD, 27.1);
Nn, 30.1% (29.0); and nn, 31.2%
(26.3) (P=0.9). There was no association between
the NN genotype or the N allele and
hypertension.
Key Words: atherosclerosis • cerebrovascular disorders • genetics • nitric oxide • risk factors
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