Association between the Glu298Asp polymorphism in the endothelial constitutive nitric oxide synthase gene and brain infarction. The GENIC Investigators.

BACKGROUND AND PURPOSE Nitric oxide (NO) synthesized by endothelial constitutive NO synthase (ecNOS) plays a key role in vascular regulation and atherosclerosis. Little is known concerning the role of the ecNOS gene (NOS3) as a risk factor for brain infarction (BI). Our aim was to investigate the relation between the Glu298Asp polymorphism in exon 7 of NOS3 with BI and its subtypes. METHODS Patients (n=460; cases) with BI were consecutively recruited and classified into etiological subtypes. Control subjects (n=460; controls) without a history of stroke were recruited among individuals hospitalized at the same institutions and individually matched on age, sex, and center. Genotypes of the polymorphism were determined by polymerase chain reaction. RESULTS The distribution of genotypes was significantly different between cases and controls (P=0.008); the GG genotype was more frequent in cases (46.1%) than in controls (35.4%; OR, 1.56; 95% CI, 1.19 to 2.04). Among subtypes, the frequency of the GG genotype was significantly higher in cases than in controls in the lacunar subtype (OR, 2.00; 95% CI, 1.05 to 3. 80); in this group, the relation between BI and LDL level was stronger among carriers of the GG genotype than among noncarriers (P for interaction, 0.05). CONCLUSIONS Homozygosity for the G allele of the Glu298Asp polymorphism in NOS3 was associated with BI, and especially with lacunar stroke. Our findings suggest that genetic susceptibility and LDL cholesterol have a synergistic relation. Although these findings should be replicated in a larger sample of subjects and the functionality of the Glu298Asp polymorphism has not been established, these results may help us to understand the cause of the arteriolopathy underlying lacunae and have future implications in their treatment and prevention.