ENDOTHELIAL NITRIC-OXIDE SYNTHASE EXON-7 POLYMORPHISM, ISCHEMIC CEREBROVASCULAR-DISEASE, AND CAROTID ATHEROMA

Background and Purpose-The role of endothelial nitric oxide synthase ( eNOS) in normal physiology suggests that it could be a potential candi date gene for stroke. Reduced eNOS activity could mediate an increased stroke risk through hypertension or independent of hypertension throu gh abnormal vasomotor responses, promoting atherogenesis, or increased platelet adhesion and aggregation. Recently, a common polymorphism in axon 7 of the eNOS gene (894G-->T) has been reported to be a strong r isk factor for coronary artery disease. We determined whether it was a lso a risk factor for transient ischemic attack (TIA) and ischemic str oke and for carotid atheroma. Methods-We studied 361 consecutive white patients presenting with ischemic stroke or TIA to a neurological cer ebrovascular disease service and 236 normal white controls. In all pat ients CT and/or MR head imaging and high-resolution carotid duplex ult rasound were performed. The presence of the polymorphism (N/n) was det ermined by polymerase chain reaction and restriction with the enzyme B anII. Results-There was no difference in the frequency of the NN genot ype 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 w ith genotype when only patients with stroke (excluding those with TIA) or when only individuals aged less than or equal to 65 years were con sidered In contrast, there was a highly significant independent associ ation 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 polymorphi sm 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%) I:P= 0.68, chi(2)) There was no difference in the mean degree of carotid st enosis 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 N N genotype or th(: N allele and hypertension. Conclusions-We failed to find a relationship between this exon 7 polymorphism and ischemic cer ebrovascular 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 un likely that this particular polymorphism or any closely linked polymor phism is a major risk factor in the majority of white patients with st roke.